In Vivo
. 2020 Jun;34(3 Suppl):1603-1611. doi: 10.21873/invivo.11950.
Medical and Surgical Education Challenges and Innovations in the COVID-19 Era: A Systematic Review
Aikaterini Dedeilia 1, Marinos G Sotiropoulos 2, John Gerrard Hanrahan 3, Deepa Janga 4, Panagiotis Dedeilias # 5, Michail Sideris # 6
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PMID: 32503818 DOI: 10.21873/invivo.11950
Abstract
The aim of this systematic review was to identify the challenges imposed on medical and surgical education by the COVID-19 pandemic, and the proposed innovations enabling the continuation of medical student and resident training. A systematic review on the MEDLINE and EMBASE databases was performed on April 18th, 2020, and yielded 1288 articles. Sixty-one of the included manuscripts were synthesized in a qualitative description focused on two major axes, "challenges" and "innovative solutions", and two minor axes, "mental health" and "medical students in the frontlines". Shortage of personal protective equipment, suspension of clinical clerkships and observerships and reduction in elective surgical cases unavoidably affect medical and surgical education. Interesting solutions involving the use of virtual learning, videoconferencing, social media and telemedicine could effectively tackle the sudden cease in medical education. Furthermore, trainee's mental health should be safeguarded, and medical students can be involved in the COVID-19 clinical treatment if needed.

Keywords: COVID-19; Medical education; SARS-CoV-2; coronavirus; medical students; residents; review; tele-education; telemedicine; virtual learning.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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2
In Vivo
. Jul-Aug 2020;34(4):1845-1856. doi: 10.21873/invivo.11979.
Synergistic Anti-cancer Activity of MH-30 in a Murine Melanoma Model Treated With Cisplatin and Its Alleviated Effects Against Cisplatin-induced Toxicity in Mice
Hae-Ran Park 1, Sung-Kee Jo 1, Hyang-Hee Cho 1, Uhee Jung 2
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PMID: 32606154 DOI: 10.21873/invivo.11979
Abstract
Background/aim: Although cisplatin is an effective anticancer drug, its toxic effects on normal tissues limit its use. We developed a herbal formula, MH-30, with increased fat-soluble polyphenols by improving the manufacturing method of HemoHIM. In this study, we examined whether the combination of MH-30 with cisplatin exerts synergistic antitumor effect while it reduces cisplatin-induced toxicities.

Materials and methods: MH-30 was produced by adding the ethanol-insoluble fraction to its extract after decocting herbs in 30% ethanol and water. We used a melanoma-bearing mice model to investigate synergistic anticancer effects. The NK cell activity and cytokine levels were measured by Cr51-release assay and ELISA. The AST, ALT, BUN, and creatinine levels were estimated in the serum.

Results: MH-30 effectively inhibited melanoma growth in vitro. Furthermore, MH-30 had a synergistic effect in combination with cisplatin on melanoma growth inhibition in vitro and in vivo. In melanoma-bearing mice, cisplatin alone decreased the activity of NK cells and the levels of IL-2 and IFN-γ, which were effectively restored by the combination of MH-30 with cisplatin. Combined treatment with MH-30 and cisplatin significantly inhibited the cisplatin-induced increase in the levels of AST, ALT, BUN, and creatinine.

Conclusion: Combination of MH-30 with cisplatin may be a beneficial anticancer treatment with reduced adverse effects.

Keywords: Chemotherapy; anticancer; cisplatin; cisplatin-induced toxicity; herbal; melanoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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Review In Vivo
. Jul-Aug 2020;34(4):1701-1714. doi: 10.21873/invivo.11964.
How to Choose Between Percutaneous Transhepatic and Endoscopic Biliary Drainage in Malignant Obstructive Jaundice: An Updated Systematic Review and Meta-analysis
Alessandro Rizzo 1, Angela Dalia Ricci 2, Giorgio Frega 2, Andrea Palloni 2, Stefania DE Lorenzo 2, Francesca Abbati 2, Veronica Mollica 2, Simona Tavolari 2, Mariacristina DI Marco 2, Giovanni Brandi 2
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PMID: 32606139 DOI: 10.21873/invivo.11964
Abstract
Background/aim: Malignant obstructive jaundice (MOJ) is a common condition caused by several primary and secondary cancers. We performed a systematic review and meta-analysis to investigate technical success rate and safety of percutaneous transhepatic biliary drainage (PTBD) versus endoscopic biliary drainage (EBD) in MOJ.

Materials and methods: Relevant trials were identified by searching electronic databases and conference meetings. We included thirteen retrospective studies and four randomized controlled trials, with PTBD performed in 2353 patients and EBD in 8178 patients. Outcomes of interest included: technical success rate, overall complications, 30-day mortality rate and risk of bleeding, pancreatitis, cholangitis and tube dislocation.

Results: The differences in technical success rate, total complications, 30-day mortality rate and tube dislocation were not statistically significant between the two groups. Patients receiving PTBD showed a lower risk of pancreatitis (OR=0.14, 95%CI=0.06-0.31) and cholangitis (OR=0.52, 95%CI=0.30-0.90) when compared to EBD while PTBD was associated with higher risk of bleeding (OR=1.78; 95%CI=1.32-2.39).

Conclusion: Our meta-analysis indicates the presence of some advantages and limits for both PTBD and EBD. We highlight the paucity of quality-of-life data, a vital element which should be carefully pondered in future studies and in choosing the optimal technique in patients with MOJ.

Keywords: Malignant obstructive jaundice; cholangiocarcinoma; endoscopic biliary drainage; pancreatic cancer; percutaneous transhepatic biliary drainage.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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4
In Vivo
. Jul-Aug 2020;34(4):2087-2093. doi: 10.21873/invivo.12012.
The Lymph Node Ratio Is an Independent Prognostic Factor in Esophageal Cancer Patients Who Receive Curative Surgery
Norio Yukawa # 1, Toru Aoyama # 2, Hiroshi Tamagawa 1, Ayako Tamagawa 1, Yosuke Atsumi 1, Shinnosuke Kawahara 1, Yukio Maezawa 1 3, Kazuki Kano 1, Masaaki Murakawa 1, Keisuke Kazama 1, Masakatsu Numata 1, Takashi Oshima 1 4, Munetaka Masuda 1, Yasushi Rino 1
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PMID: 32606187 DOI: 10.21873/invivo.12012
Abstract
Background/aim: We investigated the clinical impact of the lymph node ratio (LNR) on overall survival (OS) and recurrence-free survival (RFS) in esophageal cancer patients who underwent curative surgery.

Patients and methods: One hundred twenty patients who underwent curative surgery for esophageal cancer between 2005 and 2017 were included in this study. The LNR was defined as the ratio of the number of metastatic lymph nodes (LNs) to the total number of harvested LNs.

Results: A lymph node ratio of 10% was regarded as the optimal critical point for classification based on the overall survival rate. The 3-year and 5-year OS rates were 65.5% and 57.0%, respectively, in the LNR<10% group, and 11.8% and 0% in the LNR≥10% group; the difference was statistically significant (p<0.001). The 3-year and 5-year RFS rates were 52.6% and 44.6%, respectively, in the LNR<10% group, and 0% and 0% in the LNR>10% group; the difference was also statistically significant (p<0.001). When comparing the sites of first relapse, the incidence of distant lymph node metastasis in the LNR>10% group was significantly higher than that in the LNR<10% group.

Conclusion: The LNR was a risk factor for both OS and RFS in patients who underwent curative surgery for esophageal cancer.

Keywords: Esophageal cancer; lymph node ratio; recurrence; survival.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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Review In Vivo
. Jul-Aug 2020;34(4):1715-1727. doi: 10.21873/invivo.11965.
Molecular Classification and Future Therapeutic Challenges of Triple-negative Breast Cancer
Nikolaos Garmpis # 1 2, Christos Damaskos # 3, Anna Garmpi # 4, Konstantinos Nikolettos # 2, Dimitrios Dimitroulis 1, Evangelos Diamantis 5, Paraskevi Farmaki 6, Alexandros Patsouras 7, Errika Voutyritsa 2, Athanasios Syllaios 8, Constantinos G Zografos 8, Efstathios A Antoniou 1 2, Nikos Nikolettos 9, Alkiviadis Kostakis 10, Konstantinos Kontzoglou 1 2, Dimitrios Schizas 8, Afroditi Nonni 11
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PMID: 32606140 DOI: 10.21873/invivo.11965
Abstract
Triple-negative breast cancer (TNBC) is an extremely diverse group of breast tumors, with aggressive clinical behavior, higher rates of distant recurrence and worse overall survival compared to other types of breast cancers. The genetic, transcriptional histological and clinical heterogeneity of this disease has been an obstacle in the progression of targeted therapeutic approaches, as a ubiquitous TNBC marker has not yet been discerned. In terms of that, current studies focus on the classification of TNBC tumors in subgroups with similar characteristics in order to develop a treatment specialized for each group of patients. To date, a series of gene expression profiles analysis in order to identify the different molecular subtypes have been used. Complementary DNA microarrays, PAM50 assays, DNA and RNA sequencing as well as immunohistochemical analysis are some of the methods utilized to classify TNBC tumors. In 2012, the Cancer Genome Atlas (TCGA) Research Network conducted a major analysis of breast cancers using six different platforms, the genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays, in order to assort the tumors in homogenous subgroups. Since then, an increasing number of breast cancer data sets are being examined in an attempt to distinguish the classification with biological interpretation and clinical implementation. In this review, the progress in molecular subtyping of TNBC is discussed, providing a brief insight in novel TNBC biomarkers and therapeutic strategies.

Keywords: Triple-negative breast cancer; classification; molecular; review; targeted; therapies.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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6
In Vivo
. Jul-Aug 2020;34(4):2095-2100. doi: 10.21873/invivo.12013.
Serum CEA and CYFRA Levels in ALK-rearranged NSCLC Patients: Correlation With Distant Metastasis
Takeshi Numata 1, Takeo Endo 1, Hidetoshi Yanai 1, Kyoko Ota 1, Yusuke Yamamoto 2, Kei Shimizu 2, Hideyasu Yamada 3, Kenji Hayashihara 4, Shinichiro Okauchi 5, Hiroaki Satoh 6, Yutaka Yamada 7, Tomohiro Tamura 7, Kazuto Saito 8, Norihiro Kikuchi 9, Koichi Kurishima 10, Hiroichi Ishikawa 10, Hiroko Watanabe 11, Toshihiro Shiozawa 12, Nobuyuki Hizawa 12, Yasunori Funayama 13, Shigen Hayashi 14, Hiroyuki Nakamura 15, Takaaki Yamashita 16
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PMID: 32606188 DOI: 10.21873/invivo.12013
Abstract
Aim: To clarify the correlation between serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) and metastasis and survival in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients.

Patients and methods: CEA and CYFRA levels in 131 ALK-rearranged NSCLC patients were determined using fluorescence in situ hybridization (FISH), real time-reverse transcription polymerase chain reaction, and immunohistochemistry, using biopsy specimens, cytology specimens, and plasma specimens. Cut-off value of each marker was determined as 10 ng/ml.

Results: In logistic regression analysis, higher levels of both markers had a positive relationship with bone metastases, and higher levels of CYFRA was relevant to liver metastases, and multiple-organ metastases. However, these markers were not proven to be poor prognostic factors in Cox's proportional model analysis.

Conclusion: Elevated serum CEA and CYFRA levels seem to provide useful clinical information about presence of bone and liver metastasis and multiple-organ metastases, although they were not a powerful indicator of prognosis. These two markers may suggest the extension of metastasis and would be helpful in considering treatment options.

Keywords: ALK rearranged NSCLC; CEA; CYFRA; Serum tumor markers; carcinoembryonic antigen; cytokeratin 19 fragment; distant metastasis; non-small cell lung cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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In Vivo
. Jul-Aug 2020;34(4):2001-2007. doi: 10.21873/invivo.11998.
Clinicopathological Features in Elderly ALK-rearranged Non-small Cell Lung Cancer Patients
Kunihiko Miyazaki 1, Shinya Sato 2, Takahide Kodama 2, Takeshi Numata 3, Takeo Endo 3, Yusuke Yamamoto 4, Kei Shimizu 4, Hideyasu Yamada 5, Kenji Hayashihara 6, Shinichiro Okauchi 7, Hiroaki Satoh 7, Yutaka Yamada 8, Tomohiro Tamura 8, Kazuto Saito 9, Norihiro Kikuchi 10, Koichi Kurishima 11, Hiroichi Ishikawa 11, Hiroko Watanabe 12, Toshihiro Shiozawa 13, Nobuyuki Hizawa 13, Yasunori Funayama 14, Shigen Hayashi 15, Hiroyuki Nakamura 16, Takaaki Yamashita 17
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PMID: 32606173 DOI: 10.21873/invivo.11998
Abstract
Aim: To clarify the clinicopathological features in elderly anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) patients.

Patients and methods: A retrospective study was performed in 129 ALK rearranged NSCLC patients diagnosed between April 2008 and March 2019 in fifteen Institutions of the Ibaraki prefecture, Japan.

Results: Median age of patients was 63 years. In 59 patients aged 65 and older, the proportions of patients with advanced stage and those treated with ALK-tyrosine kinase inhibitor (TKI) were lower than those younger than 65 years. There was no difference in overall survival (OS) between the two age groups. Among the elderly patients, no difference was observed in OS between the patients aged 65-69 and those aged 70 and older. In 89 patients treated with TKI, no significant differences were observed in the progression-free survival of TKIs and OS between patients aged 65 and older and those younger than 65, respectively.

Conclusion: Evaluation of ALK gene status and TKI treatment are desirable even for elderly patients.

Keywords: ALK; Clinical practice; anaplastic lymphoma kinase fusion gene mutation; elderly; non-small cell lung cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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8
In Vivo
. Jul-Aug 2020;34(4):2119-2126. doi: 10.21873/invivo.12017.
Microsatellite Instability Correlated Inflammatory Markers and Their Prognostic Value in the Rectal Cancer Following Neoadjuvant Chemoradiotherapy: A Hypothesis-generating Study
Joo Ho Lee 1 2, Byung-Hee Kang 2, Changhoon Song 1, Sung-Bum Kang 3, Hye Seung Lee 4, Keun-Wook Lee 5, Eui Kyu Chie 6, Jae-Sung Kim 7
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PMID: 32606192 DOI: 10.21873/invivo.12017
Abstract
Background/aim: This study aimed to analyze the correlation between microsatellite instability (MSI) and inflammatory markers during neoadjuvant CRT in rectal cancer and its influence on prognosis.

Patients and methods: A total of 549 patients with locally advanced rectal cancer underwent neoadjuvant CRT. Complete blood counts before CRT, and 4-8 weeks after CRT were used to measure neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).

Results: MSI was significantly associated with elevated NLR and PLR after CRT as well as with a change in NLR and PLR during CRT. Neither inflammatory markers nor MSI significantly related to survival. However, in patients with MSI, an increase in NLR and PLR before CRT was significantly correlated with poor overall survival and disease-free survival.

Conclusion: There is correlation between inflammatory markers and MSI during CRT and it influences prognosis. Therefore, inflammatory markers might have a role in assessing the microenvironment related to MSI and the immunologic response in rectal cancer.

Keywords: Rectal cancer; chemoradiotherapy; inflammatory markers; microsatellite instability.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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In Vivo
. Jul-Aug 2020;34(4):1871-1874. doi: 10.21873/invivo.11982.
Association Between HMGB1 and Thrombogenesis in a Hyperlipaemia-induced Microminipig Model of Atherosclerosis
Satoru Kake # 1 2, Hiroaki Kawaguchi # 3, Tomoka Nagasato 4 5, Tomonobu Yamada 6, Takashi Ito 4, Ikuro Maruyama 4, Naoki Miura 7, Akihide Tanimoto 8
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PMID: 32606157 DOI: 10.21873/invivo.11982
Abstract
Background/aim: An appropriate animal model is essential to investigate the relationship between inflammation, atherosclerosis, and thrombogenesis, and the development of preventive measures and therapies for atherosclerosis.

Materials and methods: Atherosclerosis was induced in Microminipigs (MMPs) using a high-fat diet. We assessed high mobility group box 1 (HMGB1) expression levels and measured thrombus formation using a Total Thrombus Formation Analysis System (T-TAS). MMPs were divided into a normal diet (control) group and four high-fat diet groups, with differing amounts of cholesterol. After 8 weeks, blood was collected for analysis.

Results: HMGB1 levels increased with increasing dietary cholesterol, and a negative correlation was found between HMGB1 levels and thrombus formation time.

Conclusion: T-TAS is useful in the assessment of thrombogenesis in MMPs and HMGB1 is associated with thrombus formation.

Keywords: HMGB1; Microminipig; thrombus formation.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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10
Comparative Study In Vivo
. 2020 Jun;34(3 Suppl):1629-1632. doi: 10.21873/invivo.11953.
SARS-CoV-2 orf1b Gene Sequence in the NTNG1 Gene on Human Chromosome 1
Steven Lehrer 1, Peter H Rheinstein 2
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PMID: 32503821 DOI: 10.21873/invivo.11953
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus. It is contagious in humans and is the cause of the coronavirus disease 2019 (COVID-19) pandemic. In the current analysis, we searched for SARS-CoV-2 sequences within the human genome. To compare the SARS-CoV-2 genome to the human genome, we used the blast-like alignment tool (BLAT) of the University of California, Santa Cruz Genome Browser. BLAT can align a user sequence of 25 bases or more to the genome. BLAT search results revealed a 117-base pair SARS-CoV-2 sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within an intronic region of the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 orf1b (open reading frames) gene. The SARS-CoV-2 human sequence lies within non-structural proteins 14 and 15 (NSP14 and NSP15), and is quite close to the viral spike sequence, separated only by NSP16, a 904-base pair sequence. The mechanism for SARS-CoV-2 infection is the binding of the virus spike protein to the membrane-bound form of angiotensin-converting enzyme 2 and internalization of the complex by the host cell. It is probably no accident that a sequence from the SARS-CoV-2 orf1b gene is found in the human NTNG1 gene, implicated in schizophrenia, and that haloperidol, used to treat schizophrenia, may also be a treatment for COVID-19. We suggest, therefore, that it is important to investigate other haloperidol analogs. Among them are benperidol, bromperidol, bromperidol decanoate, droperidol, seperidol hydrochloride, and trifluperidol. These analogs might be valuable in the treatment of COVID-19 and other coronavirus infections.

Keywords: COVID-19; NTNG1 gene; haloperidol; orf1b gene; the UCSC Genome Browser.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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Comparative Study In Vivo
. 2020 Jun;34(3 Suppl):1633-1636. doi: 10.21873/invivo.11954.
Human Gene Sequences in SARS-CoV-2 and Other Viruses
Steven Lehrer # 1, Peter H Rheinstein # 2
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PMID: 32503822 DOI: 10.21873/invivo.11954
Abstract
In a previous study, we identified a 117 base severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within an intronic region of the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 Orf1b gene in non-structural protein 14 (NSP14), which is an exonuclease and NSP15, an endoribonuclease. In the current study we compared the human genome with other viral genomes to determine some of the characteristics of human sequences found in the latter. Most of the viruses had human sequences, but they were short. Hepatitis A and St Louis encephalitis had human sequences that were longer than the 117 base SARS-Cov-2 sequence, but they were in non-coding regions of the human genome. The SARS-Cov-2 sequence was the only long sequence found in a human gene (NTNG1). The related coronaviruses SARS-Cov had a 41 BP human sequence on chromosome 3 that was not part of a human gene, and MERS had no human sequence. The 117 base SARS-CoV-2 human sequence is relatively close to the viral spike sequence, separated only by NSP16, a 904 base sequence. The mechanism for SARS-CoV-2 infection is the binding of the virus spike protein to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. We have no explanation for the NSP14 and NSP15 SARS-Cov-2 sequences we observed here or how they might relate to infectiousness. Further studies are warranted.

Keywords: COVID-19; NTNG1 gene; ORF1b gene; the UCSC Genome Browser.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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12
In Vivo
. Jul-Aug 2020;34(4):1789-1796. doi: 10.21873/invivo.11973.
The In Vivo Radiosensitizing Effect of Magnolol on Tumor Growth of Hepatocellular Carcinoma
Yu-Shan Chen # 1, Rou Sun # 2, Wei-Lung Chen # 3 4, Yu-Chen Yau # 5, Fei-Ting Hsu 6, Jing-Gung Chung 6, Chia-Jung Tsai 7, Chia-Ling Hsieh # 8 9, Ying-Ming Chiu # 10 11, Jiann-Hwa Chen # 12 13
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PMID: 32606148 DOI: 10.21873/invivo.11973
Abstract
Background/aim: Radiation (RT) induced ERK/NF-κB in hepatocellular carcinoma (HCC) has been reported in our previous works; it weakens the toxicity of RT or triggers a radioresistance effect. Thus, combining RT with a suitable NF-κB inhibitor may sensitize HCC to RT. Magnolol, a bioactive compound, was known to have anti-inflammatory and anti-tumor functions. Here, we aimed to investigate whether magnolol may enhance anti-HCC efficacy of RT in vivo.

Materials and methods: We established a Hep3B bearing mouse to evaluate the efficacy of the combination treatment of magnolol and RT.

Results: Most significantly, tumor volume and tumor weight inhibition was found in the combination group. Tumor immunohistochemistry staining also illustrated the suppression of RT-induced ERK/NF-κB-related proteins expression by magnolol. In addition, intrinsic apoptosis-related proteins, such as caspase-3 and -9, were markedly increased in the combination group.

Conclusion: Magnolol may effectively enhance anti-HCC ability of RT by downregulating the expression of ERK/NF-κB-related proteins and increasing the expression of apoptosis-related proteins.

Keywords: Magnolol; apoptosis; hepatocellular carcinoma; radiation.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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13
In Vivo
. Jul-Aug 2020;34(4):1863-1870. doi: 10.21873/invivo.11981.
Effects of Testosterone on the Expression of Connexin 26 and Connexin 43 in the Uterus of Rats During Early Pregnancy
Datu Agasi Mohd Kamal 1 2, Siti Fatimah Ibrahim 1, Mohd Helmy Mokhtar 3
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PMID: 32606156 DOI: 10.21873/invivo.11981
Abstract
Background/aim: It was hypothesized that testosterone could affect the distribution and expression of connexin 26 and connexin 43 in the uterus. Thus, the effects of testosterone on these parameters in the uterus during the uterine receptivity period were investigated.

Materials and methods: Intact pregnant rats were administered 1 mg/kg/day testosterone alone or in combination with flutamide, finasteride or anastrozole, subcutaneously on day-1 of pregnancy till day 3. The rats were sacrificed at day 4 of pregnancy, which was considered as the uterine receptivity period for determining the expression and distribution of connexin 26 and connexion 43 by immunohistochemistry and quantitative polymerase chain reaction, respectively.

Results: Treatment with 1 mg/kg/day testosterone increased connexin 26 and decreased connexin 43 mRNA expression and protein distribution in the uterus of early pregnancy rats.

Conclusion: Changes in the uterine connexin 26 and connexin 43 expression by testosterone could disrupt embryo implantation, resulting in early pregnancy loss.

Keywords: Testosterone; connexin; early pregnancy; uterine receptivity.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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14
In Vivo
. Jul-Aug 2020;34(4):2107-2111. doi: 10.21873/invivo.12015.
Correlation Between Demographic and Tumor Characteristics in Non-melanoma Skin Cancers Submitted to Mohs Micrographic Surgery
Ellem T S Weimann 1, Caroline M BrandÃo 2, Luiz R Terzian 3, Francisco M Paschoal 4, Carlos D S Machado Filho 4, Paulo R Criado 5
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PMID: 32606190 DOI: 10.21873/invivo.12015
Abstract
Background/aim: Non-melanoma skin cancer (NMSC) is the most prevalent type of cancer in adults. Surgery remains the golden-standard treatment for this disease. Mohs micrographic surgery (MMS), a surgical technique, is based on the three-dimensional histopathological examination of the margin and surgical bed, layer by layer, in the excised tissue allowing for the determination of the location of the residual tumor, for its complete excision, with high cure rates and preservation of the unaffected tissue. The aim of this study was to present the epidemiological characteristics of the population that was submitted to MMS, as well as, correlate these characteristics with the characteristics of the tumor itself and the surgical procedure.

Patients and methods: A retrospective cross-sectional study was conducted over a 10-year period with an analysis of patient medical records submitted for MMS at the Department of Dermatology of the ABC School of Medicine. Data were presented and evaluated by non-parametric and parametric analyses, using absolute and relative frequency values for the continuous variable, to which a Chi-square test was applied for the verification of power with a significance level of 5%. For the independent variables, the Student's t-test was used to compare means, with a confidence interval (CI) ranging from 95 to 99%, and Friedman's test was used to verify if there were significant differences in the variables of interest.

Results: Female patients accounted for 67% of all enrolled patients (n=335). The mean age was 67 years (SD±12.04; median=68; range=25-93 years). The predominant skin phototype (Fitzpatrick's classification) was phototype II (n=228, 46%). All procedures were performed under local anesthesia. Flap reconstruction was the most predominant surgery type (n=17, 68%). The mean number of MMS's stages was 1.6 (range=1-8). There was a mean of 3.8 fragments of skin tissue (range=1-29) per stage. The mean tumor size was 30 mm (92%). This was associated with female sex (p=0.03), H-zone area (p<0.001), flap reconstruction (p=0.004), tumor removal 7 to 12 months after diagnosis (p<0.001) and non-recurrence tumors (p=0.02).

Conclusion: NMSCs were frequently observed in older women with skin phototypes II/III. Reconstruction of the primary defect was feasible under local anesthesia, even in tumors with a marked diameter, decreasing the morbidity of this surgery, providing very satisfactory functional and aesthetic results, reduction costs and ease of access to the surgical procedure.

Keywords: Mohs micrographic surgery; Non-melanoma skin cancer; epidemiology.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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15
Comparative Study In Vivo
. 2020 Jun;34(3 Suppl):1645-1650. doi: 10.21873/invivo.11956.
Endoplasmic Reticulum Stress Markers in SARS-COV-2 Infection and Pneumonia: Case-Control Study
Aylin Köseler 1, Ramazan Sabirli 2, Tarik Gören 3, Ibrahim Türkçüer 3, Özgür Kurt 4
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PMID: 32503824 DOI: 10.21873/invivo.11956
Abstract
Background/aim: A novel human coronavirus, named SARS-COV-2, has recently caused thousands of deaths all around the world. Endoplasmic reticulum (ER) stress plays an important role in the development of diseases.

Patients and methods: We aimed to to investigate the relationship between ER stress markers in patients infected with SARS-COV-2 and patients with pneumonia. A total of 9 patients (4 patients diagnosed with pneumonia and 5 patients diagnosed with SARS-COV-2 infection) who admitted to the emergency Department with symptoms of pneumonia and SARS-COV-2 were included in the study. A total of 18 healthy individuals without any known chronic or acute disease and drug use were included as the healthy control group. Serum human glucose regulated protein 78 (GRP78), serum human C/EBP homologous protein (CHOP) and serum human phospho extracellular signal regulated kinase (PERK) levels were measured using enzyme-linked immunosorbent assay (ELISA).

Results: GRP78 levels were found to be significantly higher in SARS-COV-2 positive cases compared to individuals in other groups. Serum GRP-78 level median value was statistically significantly higher in SARS-COV-2-positive group compared to the other groups (p=0.0003). Serum PERK level was statistically significantly higher in SARS-COV-2-positive pneumonia cases (p=0.046).

Conclusion: An association was shown between GRP78 and SARS-COV-2 infection. Although a small number of patients was investigated, these results will be important and guide future treatments of SARS-COV-2.

Keywords: Endoplasmic reticulum stress; GRP78; SARS-COV-2; pneumonia.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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16
In Vivo
. Jul-Aug 2020;34(4):1765-1771. doi: 10.21873/invivo.11970.
An Analysis of ESR2 and CYP19A1 Gene Expression Levels in Women With Endometriosis
Tomasz Szaflik # 1, Beata Smolarz # 2, Beata Mroczkowska 1, Bartosz Kulig 1, Malwina Soja 1, Hanna Romanowicz 3, Magdalena BryŚ 4, Ewa Forma 4, Krzysztof SzyŁŁo 1
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PMID: 32606145 DOI: 10.21873/invivo.11970
Abstract
Aim: The analysis of oestrogen receptor (ESR2) and cytochrome P450 family 19 subfamily A member (CYP19A1) gene expression in the context of the risk for endometriosis development.

Materials and methods: Tissue specimens, collected from patients with endometriosis (n=100) and from control patients (n=100) embedded into paraffin blocks, provided the material for genetic studies, oriented towards the expression of ESR2 and CYP19A1 genes. The gene expression was assessed by the reverse transcription-polymerase chain reaction technique.

Results: Higher expression levels of ESR2 gene were demonstrated in the patients with endometriosis in comparison with the healthy controls. The expression intensity of CYP19A1 gene was associated with endometriosis, manifested as abdominal wall nodules. A relationship was observed between CYP19A1 gene expression and the Revised American Society for Reproductive Medicine classification in the group with ovarian endometrioid cysts, as well as in the group with peritoneal endometriosis.

Conclusion: This study suggests the significant role of ESR2 and CYP19A1 gene expression in the pathogenesis of endometriosis.

Keywords: CYP19A1; ESR2; endometriosis; expression.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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17
In Vivo
. Jul-Aug 2020;34(4):2029-2032. doi: 10.21873/invivo.12002.
A Comparison of 18 F-FDG-PET/MRI and 18 F-FDG-PET/CT in the Cancer Staging of Locoregional Lymph Nodes
David Slouka 1, Jiri Krcal 1, Tomas Kostlivy 1, Petr Hrabacka 1, Alena Skalova 2, Hynek Mirka 3, Ondrej Topolcan 4, Radek Kucera 5
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PMID: 32606177 DOI: 10.21873/invivo.12002
Abstract
Aim: The aim of the study was to evaluate the yields of 2-deoxy-2-[18F]-fluoro-D-glucose positron-emission tomography/magnetic resonance imaging (18F-FDG-PET/MRI) and 18F-FDG-PET/computed tomography (CT) for the detection of metastatic involvement of locoregional neck nodes in patients with head and neck malignancy.

Patients and methods: A total of 90 patients (66 men and 24 women) met the inclusion criteria. Preoperative staging was performed: 53 examinations using PET/CT and 37 using PET/MRI.

Results: For PET/MRI, the study demonstrated a sensitivity of 89%, specificity of 64%, positive predictive value of 85%, and negative predictive value of 70%; PET/CT had a sensitivity of 95%, specificity 47%, positive predictive value of 82%, and negative predictive value of 78%.

Conclusion: Both methods have a high yield in N-clinical staging with statistically insignificant differences. We assume PET/MRI to be the first-choice method in organ-targeted examinations, for pediatric patients and repeat examinations. In cases of MRI contraindication, PET/CT can be used with no impact on the quality of care.

Keywords: Head and neck tumours; PET/CT; PET/MRI; cancer staging; hybrid imaging; lymph node.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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18
In Vivo
. Jul-Aug 2020;34(4):1941-1949. doi: 10.21873/invivo.11991.
Impact of Antiplatelet and Anticoagulant Therapies on Platelet-related Prognostic Markers in Patients With Esophageal Cancer
Yusuke Ishibashi 1, Hironori Tsujimoto 2, Keita Kouzu 1, Yujiro Itazaki 1, Satoshi Tsuchiya 1, Seiichiro Fujishima 1, Yoshihisa Yaguchi 1, Hidekazu Sugasawa 1, Shinsuke Nomura 1, Nozomi Ito 1, Manabu Harada 1, Hiromi Nagata 1, Eiji Shinto 1, Yoji Kishi 1, Hideki Ueno 1
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PMID: 32606166 DOI: 10.21873/invivo.11991
Abstract
Background/aim: In recent years, platelet-related markers were recognized as useful prognostic factors in various malignancies. We investigated the relationship between platelet-related prognostic markers and anti-platelet or anti-coagulant therapies for survival outcomes in esophageal squamous cell carcinoma.

Patients and methods: Preoperative platelet-related prognostic markers were evaluated from peripheral blood testing and statistical analyses were performed to evaluate the prognostic value of these markers and reveal the effects of antiplatelets and/or anticoagulants regarding their prognostic relevance.

Results: In all 176 patients, preoperative platelet-to-lymphocyte ratio (PLR) was not found to be a predictor of overall survival (OS). However, in patients without antiplatelet or anticoagulant therapies, PLR was significantly associated with a poor OS (p=0.03). Although platelet large cell ratio (P-LCR) was not associated with the prognosis in patients with antiplatelet and/or anticoagulant therapies, higher P-LCR was associated with a poor prognosis in patients without antiplatelet or anticoagulant therapies (p<0.0001).

Conclusion: Researching detailed antiplatelet and anticoagulant therapies could reinforce the prognostic value of platelet-related prognostic markers in ESCC.

Keywords: Esophageal cancer; platelet-to-lymphocyte ratio; prognostic factors.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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19
In Vivo
. Jul-Aug 2020;34(4):2061-2066. doi: 10.21873/invivo.12008.
Management of Peritoneal Carcinomatosis With Cytoreductive Surgery Combined With Intraperitoneal Chemohyperthermia at a Novel Italian Center
Pinuccia Faviana 1, Laura Boldrini 2, Barbara Musco 3, Mauro Ferrari 3, Alfonso Greco 3, Lorenzo Fornaro 4, Gianluca Masi 4, Francesco Forfori 2, Sergio Ricci 4, Augusto Brogi 2, Fulvio Basolo 2, Alfredo Falcone 4, Angelo Gadducci 5, Piero Vincenzo Lippolis 3
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PMID: 32606183 DOI: 10.21873/invivo.12008
Abstract
Background: Peritoneal carcinomatosis (PC) is a common manifestation of many gastrointestinal (GI) malignancies and is an advanced stage that is often associated with disseminated disease. Considerable progress has been made to achieve safe elimination of macroscopic disease using cytoreductive surgery (CRS) and more recently in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of microscopic disease or disease with minimal volume. The aim of this study was to assess the effects of such procedures on the quality of life (QoL), the long-term benefit and the functional status of the treated patients.

Patients and methods: Data from patients who underwent CRS-HIPEC for peritoneal metastasis (PM) at our center from November 2016 to November 2018 were analyzed retrospectively. The drugs administered were mitomycin and cisplatin. Quality of life (QoL) was assessed using the Euroquol-5D-5L and National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index v2 questionnaires before CRS-HIPEC, and 1, 3 and 6 months after were administered.

Results: In our series, the survival efficacy of CRS plus HIPEC was confirmed in the treatment of primary and secondary peritoneal pathologies, particularly in ovarian cancer, although larger studies are needed to investigate its role in the pathology of gastric, colonic and rectal cancer. The QoL data were promising, with essentially stable values between the preoperative and the 1-month follow-up, but with incremental benefits from the second to the third month.

Keywords: HIPEC; colon cancer; gastric cancer; ovary cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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20
Review In Vivo
. 2020 Jun;34(3 Suppl):1619-1628. doi: 10.21873/invivo.11952.
Ocular Manifestations of COVID-19 (SARS-CoV-2): A Critical Review of Current Literature
Konstantinos A A Douglas # 1 2, Vivian Paraskevi Douglas # 1, Marilita M Moschos 3
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PMID: 32503820 DOI: 10.21873/invivo.11952
Abstract
The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China in the city of Wuhan in December of 2019 and since then more than 5,000,000 people have been infected, with approximately 338,000 deaths worldwide. The virus causes the coronavirus disease 2019 (COVID-19), which is characterized by fever, myalgia and cough, with severe acute respiratory syndrome being the most fearsome complication. Nevertheless, the vast majority of cases present mild symptoms or none. Central nervous system and cardiovascular manifestations have been reported. The range of ocular manifestations, either as a result of the infection or as a result of the treatment, has not yet been discussed. In this study, a systematic review of current literature relevant to COVID-19 was performed with focus on modes of transmission, ocular manifestations related to infection and medications, as well as the control of infection in ophthalmic practice.

Keywords: COVID-19; ocular manifestations; ophthalmology; prevention; review; side-effects; treatment.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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21
In Vivo
. Jul-Aug 2020;34(4):1965-1974. doi: 10.21873/invivo.11993.
Histopathological Features and Ann Arbor Stage in Periocular Lymphoma
Marco Zschoche 1, Annette Zimpfer 2, Björn O Scheef 3, Anselm M Jünemann 3, Rudolf F Guthoff 3, Christian Junghanss 4, Guido Hildebrandt 5, Steffen Emmert 6, Andreas Erbersdobler 2, Günther Kundt 7, Vinodh Kakkassery 1 8
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PMID: 32606168 DOI: 10.21873/invivo.11993
Abstract
Background: To evaluate biodata, symptoms/signs, lymphoma type, localization, stage level, treatment choice and outcome of ocular adnexal lymphoma (OAL).

Patients and methods: A single-center retrospective analysis of 56 patients with OAL was performed from 1998 to 2018.

Results: OAL involved the orbit in 44.6%, the conjunctiva in 32.1%, the lacrimal apparatus in 14.3% and the eyelid in 8.93%. Extranodal marginal zone B-cell lymphoma (EMZL) was found in 60.7%, follicular lymphoma (FL) in 21.4%, diffuse large B-cell lymphoma in 7.14%, mantle cell lymphoma in 5.36% and chronic lymphatic leukaemia in 5.36% patients. No relapse was seen in 76%. EMZL and FL had a significantly better overall survival compared to other lymphoma types (p=0.002). Patients with Ann Arbor stage IE had a significantly better prognosis than those with stages higher than IE (p=0.048).

Conclusion: Our data suggest that clinicopathological features such as Ann Arbor stage influence survival.

Keywords: Ann Arbor stage; Periorbital lymphoma; histopathology; ocular adnexal lymphoma; orbital lymphoma; survival.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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22
In Vivo
. 2020 Jun;34(3 Suppl):1675-1680. doi: 10.21873/invivo.11960.
Radiation Therapy During the COVID-19 Pandemic: Experience From Beijing, China
Weiping Wang # 1, Xiaoliang Liu # 1, Fuquan Zhang 2, Jie Qiu 2, K E Hu 2
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PMID: 32503828 DOI: 10.21873/invivo.11960
Abstract
Background: Coronavirus disease 2019 (COVID-19) is now a global pandemic. It is unclear to radiotherapy practitioners how to carry out radiotherapy during the epidemic.

Patients and methods: After the outbreak of COVID-19, our Institute established measures for the prevention and control of COVID-19, and continues to treat patients according to these measures. The Radiotherapy Department has been divided into a clean zone and a semi-contaminated zone, and corresponding personal protective equipment is used in these zones. The temperature of patients and their escorts, and history of fever are assessed daily. Special procedures are performed during radiotherapy setup and intracavitary brachytherapy.

Results: Over a period of 2 months, 655 patients were treated in the Department. Sixteen patients with fever were identified and no patient undergoing radiotherapy or medical staff have been infected with COVID-19.

Conclusion: Our protective measures were found to be effective and can be used as a reference in places where COVID-19 situations are not markedly serious.

Keywords: COVID-19; personal protective equipment; radiotherapy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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23
In Vivo
. Jul-Aug 2020;34(4):1805-1809. doi: 10.21873/invivo.11975.
Increased Expression of p-GSK3β Predicts Poor Survival in T -III/IV Stage OSCC Patients
Bharath Kumar Velmurugan # 1, Chun-Wen Chiu # 2, Yueh-Min Lin 3 4 5, Mahalakshmi Bharath 6, Chung-Min Yeh 3 7, Yu-En Chen 3, Chia-Min Chung 8 9, Shu-Hui Lin 10 5
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PMID: 32606150 DOI: 10.21873/invivo.11975
Abstract
Background/aim: Glycogen synthase kinase 3 beta (GSK3-β) acts either as a tumor suppressor or an oncogene in various human cancers. The present study aimed to investigate the expression and activity of p-GSK3-β (Ser9) in oral cancer patients.

Materials and methods: We investigated the levels of p-GSK3β in 152 oral cancer tissues by immunohistochemistry, and explored their prognostic impact.

Results: To investigate the role of p-GSK3β (Ser9) in OSCC progression, we first analyzed the expression levels of protein p-GSK3β in normal and oral cancer tissues using immunohistochemical staining. p-GSK3β immunostaining was detected in 32 of 152 (21.1%) oral cancer specimens. High p-GSK3β expression was significantly associated with T (III/IV) stage. Kaplan-Meier survival analysis revealed that high levels of p-GSK3β were correlated with poor survival (p=0.001) in T stage (III/IV) OSCC patients. Multivariate analyses indicated that TN stage, AJCC tumor stage, tumor differentiation status and clinical therapy, but not p-GSK3β levels, were independent prognostic factors. Significant mortality risk was found in T stage (III/IV) oral cancer patients with high levels of p-GSK3β (p=0.0006).

Conclusion: GSK3β inactivation is a key event in oral cancer patients and targeting GSK3β might be valuable in treating oral cancer patients.

Keywords: AJCC; IHC; OSCC; T stage; pGSK3β; prognostic factors; survival.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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24
In Vivo
. Jul-Aug 2020;34(4):1779-1788. doi: 10.21873/invivo.11972.
Characterization of Optimal Strain, Frequency and Duration of Mechanical Loading on Skeletal Myotubes' Biological Responses
Athanasios Moustogiannis # 1, Anastassios Philippou # 1, Evangelos Zevolis # 1, Orjona Taso 1, Antonios Chatzigeorgiou 1, Michael Koutsilieris 2
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PMID: 32606147 DOI: 10.21873/invivo.11972
Abstract
Background/aim: Mechanical loading of differentiated myoblasts in vitro may mimic loading patterns of skeletal muscle in vivo. However, it is still uncharacterized the loading conditions that can produce the most effective muscle cells' biological responses, in vitro. This study investigated the effects of different loading protocols on the expression of myogenic regulatory factors, anabolic, atrophy and pro-apoptotic factors in skeletal myotubes.

Materials and methods: C2C12 myoblasts were differentiated and underwent various stretching protocols by altering their elongation, frequency and duration, utilizing an in vitro cell tension system. The loading-induced expression changes of MyoD, Myogenin, MRF4, IGF-1 isoforms, Murf1, Atrogin, Myostatin, Foxo and Fuca were measured by Real Time-PCR.

Results: Stretching by 2% elongation at 0.25 Hz for 12 h was overall the most effective in inducing beneficial responses.

Conclusion: A low strain, low frequency intermediate duration stretching can most effectively up-regulate myogenic/anabolic factors and down-regulate pro-apoptotic and atrophy genes in myotubes.

Keywords: Mechanical loading; mechanotransduction; myogenesis; myotubes.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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25
In Vivo
. Jul-Aug 2020;34(4):1773-1778. doi: 10.21873/invivo.11971.
Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer
Klaudia Holeckova 1 2, Katarina Baluchova 3, Mark Hives 4, Ludovit Musak 2, Jan Kliment Sr 1, Maria Skerenova 5 6
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PMID: 32606146 DOI: 10.21873/invivo.11971
Abstract
Background/aim: The aim of this study was to analyse the genetic profiles of metastatic castration-resistant prostate cancer (mCRPC) by using next generation sequencing to identify variants with pathogenic potential in nine DNA repair genes - BRCA1, BRCA2, RAD50, RAD51, RAD51C/D, ATM and ATR.

Materials and methods: Isolated genomic DNA from peripheral blood of 50 patients with mCRPC was used for the sequencing of 111 genes associated with hereditary cancer on an Illumina platform. Identified variants were tested in Integrative Genomic Viewer, their clinical significance confirmed in databases and their potential impact on protein function predicted by in silico tools.

Results: From nine analysed DNA repair genes, we identified 14 relevant variants; three pathogenic variants - BRCA2 (rs80359306), RAD50 (rs786201531) and ATM (rs1555099760), and eleven other variants with pathogenic potential.

Conclusion: The pathogenic variants identified in this study are located in evolutionarily conserved regions of proteins and are highly likely to affect DNA repair efficiency.

Keywords: DNA repair genes; Prostate cancer; germline mutations; next generation sequencing.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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26
In Vivo
. Jul-Aug 2020;34(4):1835-1843. doi: 10.21873/invivo.11978.
Protective Effects of Pinus halepensis Bark Extract and Nicotine on Cigarette Smoke-induced Oxidative Stress in Keratinocytes
Panagoula Pavlou 1, Ioanna Antoniadou 1, Asimina Peraki 1, Andreas Vitsos 1, Paraskevas Dallas 1, Dimitrios Mostratos 1, Georgios Deliconstantinos 2, Georgios Papaioannou 1, Sergei A Grando 3, Michail Rallis 4
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PMID: 32606153 DOI: 10.21873/invivo.11978
Abstract
Background/aim: Cigarette smoke (CS) is a major environmental health threat. The oxidative stress induced by CS on keratinocytes and the possible protective effect of nicotine, its receptor inhibitors, and Pinus halepensis bark extract in relation to known antioxidants were investigated.

Materials and methods: Primary mouse keratinocytes were exposed to cigarette smoke in the presence and absence of Pinus halepensis bark extract (1 μg/ml), rutin (50 μM) and ascorbic acid (250 μM), nicotine (1 μM) with or without mecamylamine (5 μM) and α-bungarotoxin (0.1 μM). Keratinocyte viability and oxidative stress were evaluated by MTT and fluorescence assays.

Results: Pinus halepensis bark extract decreased the oxidative stress and increased the viability of keratinocytes, and moreover, these effects were more pronounced compared to the mixture of rutin and L-ascorbic acid. Nicotine significantly enhanced the viability potentiation of the beneficial effect induced by Pinus halepensis bark extract. Mecamylamine and α-bungarotoxin showed no specific effect.

Conclusion: Pinus halepensis bark extract in combination with nicotine may successfully reverse skin damage induced by cigarette smoke.

Keywords: Oxidative stress; Pinus halepensis bark extract; cigarette smoke; keratinocytes; nicotine.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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27
In Vivo
. Jul-Aug 2020;34(4):2187-2191. doi: 10.21873/invivo.12028.
The Influence of "Omental Cake" Presence on the Completeness of Cytoreduction in Advanced-stage Ovarian Cancer
Nicolae Bacalbasa 1 2 3, Camelia Diaconu 1 4, Laura Iliescu 1 5, Cornel Savu 1 6, Ovidiu Gabriel Bratu 1 7, Ciprian Bolca 6, Dragos Cretoiu 1 8, Alexandru Filipescu 1 9, Simona Dima 3, Cristian Balalau 1 10, Irina Balescu 11
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PMID: 32606203 DOI: 10.21873/invivo.12028
Abstract
Background/aim: The presence of "omental cake" has been considered since long as a negative prognostic factor in patients diagnosed with advanced-stage ovarian cancer. The aim of this paper was to study the impact of "omental cake" presence on the perioperative outcomes in advanced-stage ovarian cancer.

Patients and methods: Between 2015 and 2020, 85 patients were submitted to surgery for advanced-stage ovarian cancer.

Results: Among cases diagnosed with "omental cake" the rate of complete cytoreduction was significantly diminished when compared to cases in which this entity was not revealed. In the meantime, the presence of omental cake among cases in which complete debulking was achievable was significantly associated with a higher number of digestive resections when compared to the other cases submitted to surgery and in which tumoral transformation of the omentum was encountered.

Conclusion: The presence of "omental cake" is associated with a higher rate of incomplete resections. However, in cases in which complete debulking was achieved, the presence of omental cake was associated with a significantly higher number of digestive tract resections.

Keywords: Omental cake; debulking; ovarian cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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28
In Vivo
. 2020 Jun;34(3 Suppl):1651-1659. doi: 10.21873/invivo.11957.
Breast Cancer and COVID-19: The Effect of Fear on Patients' Decision-making Process
Gianluca Vanni 1, Marco Materazzo 2, Marco Pellicciaro 1, Sara Ingallinella 1, Maurizio Rho 1, Francesca Santori 1, Maria Cotesta 1, Jonathan Caspi 1, Anna Makarova 3, Chiara Adriana Pistolese 4, Oreste Claudio Buonomo 1
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PMID: 32503825 DOI: 10.21873/invivo.11957
Abstract
Background/aim: Coronavirus-19 (COVID-19) pandemic outbreak is currently having a huge impact on medical resource allocation. Breast Cancer (BC) patients are concerned both with BC treatment and COVID-19. This study aimed to estimate the impact of anxiety among patients, caused by the spreading of COVID-19.

Patients and methods: Between the 16th of January and the 20th of March 2020, we retrospectively enrolled 160 patients. Eighty-two patients with a suspected breast lesion (SBL) were divided into two groups: PRE-COVID-19-SBL and POST-COVID-19-SBL. Seventy-eight BC patients were divided into PRE-COVID-19-BC and POST-COVID-19-BC. Patient characteristics including age, marital status, SBL/BC diameter, personal and family history of BC, clinical stage and molecular subtype were recorded. Procedure Refusal (PR) and Surgical Refusal (SR) were also recorded with their reason.

Results: BC and SBL analysis showed no difference in pre-treatment characteristics (p>0.05). Both POST-COVID-19-SBL and POST-COVID-19-BC groups showed higher rates of PR and SR (p=0.0208, p=0.0065 respectively). Infection risk represented primary reason for refusal among POST-COVID-19 patients.

Conclusion: COVID-19-related anxiety could affect patients' decision-making process.

Keywords: COVID-19; SARS-SOV-2; anxiety; breast cancer; decision-making process; surgery; surgery refusal.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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29
Review In Vivo
. 2020 Jun;34(3 Suppl):1567-1588. doi: 10.21873/invivo.11946.
COVID-19: The Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2
Andri Andreou 1, Sofia Trantza 2, Demetrios Filippou 3 4, Nikolaos Sipsas 4, Sotirios Tsiodras 4
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PMID: 32503814 DOI: 10.21873/invivo.11946
Abstract
Background: On March 11, 2020, the World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19) a pandemic. Since then, thousands of people have suffered and died, making the need for a treatment of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) more crucial than ever.

Materials and methods: The authors carried out a search in PubMed, ClinicalTrials.gov and New England Journal of Medicine (NEJM) for COVID-19 to provide information on the most promising treatments against SARS-CoV-2.

Results: Possible COVID-19 agents with promising efficacy and favorable safety profile were identified. The results support the combination of copper, N-acetylcysteine (NAC), colchicine and nitric oxide (NO) with candidate antiviral agents, remdesivir or EIDD-2801, as a treatment for patients positive for SARS-CoV-2.

Conclusion: The authors propose to study the effects of the combination of copper, NAC, colchicine, NO and currently used experimental antiviral agents, remdesivir or EIDD-2801, as a potential treatment scheme for SARS-COV-2.

Keywords: COVID-19; EIDD-2801; N-acetylcysteine (NAC); copper; remdesivir (RDV); review; treatment.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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30
Review In Vivo
. 2020 Jun;34(3 Suppl):1593-1596. doi: 10.21873/invivo.11948.
Oral Methioninase for Covid-19 Methionine-restriction Therapy
Robert M Hoffman 1, Qinghong Han 2
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PMID: 32503816 DOI: 10.21873/invivo.11948
Abstract
The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.

Keywords: Coronavirus; Covid-19; RNA genome; S-adenosylmethionine; SARs-CoV-2; methioninase; methionine restriction; methylation; methyltransferase.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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31
Review In Vivo
. 2020 Jun;34(3 Suppl):1613-1617. doi: 10.21873/invivo.11951.
Coronavirus Disease (COVID-19): A Machine Learning Bibliometric Analysis
Francesca DE Felice 1, Antonella Polimeni 2
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PMID: 32503819 DOI: 10.21873/invivo.11951
Abstract
Background/aim: To evaluate the research trends in coronavirus disease (COVID-19).

Materials and methods: A bibliometric analysis was performed using a machine learning bibliometric methodology. Information regarding publication outputs, countries, institutions, journals, keywords, funding and citation counts was retrieved from Scopus database.

Results: A total of 1883 eligible papers were returned. An exponential increase in the COVID-19 publications occurred in the last months. As expected, China produced the majority of articles, followed by the United States of America, the United Kingdom and Italy. There is greater collaboration between highly contributing authors and institutions. The "BMJ" published the highest number of papers (n=129) and "The Lancet" had the most citations (n=1439). The most ubiquitous topic was COVID-19 clinical features.

Conclusion: This bibliometric analysis presents the most influential references related to COVID-19 during this time and could be useful to improve understanding and management of COVID-19.

Keywords: COVID-19; bibliometric analysis; coronavirus; machine learning; management.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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32
Review In Vivo
. 2020 Jun;34(3 Suppl):1589-1592. doi: 10.21873/invivo.11947.
Role of Interleukin-6 in Lung Complications in Patients With COVID-19: Therapeutic Implications
Karel Smetana Jr 1 2, Jan Brábek 3 4
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PMID: 32503815 DOI: 10.21873/invivo.11947
Abstract
COVID-19 is viral respiratory infection with frequently fatal lung complications in the elderly or in people with serious comorbidities. Lung destruction appears to be associated with a cytokine storm related to an increased level of interleukin-6 (IL6). Therapeutic targeting of the interleukin-6 signaling pathway can attenuate such a cytokine storm and can be beneficial for patients with COVID-19 in danger of pulmonary failure. This article demonstrates the importance of IL6 in progression of disease and the possibility of inhibition of IL6 signaling in COVID-19 therapy.

Keywords: COVID-19 therapy; IL6; SARS-CoV-2; cytokine storm; lung failure; review.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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33
In Vivo
. Jul-Aug 2020;34(4):1739-1747. doi: 10.21873/invivo.11967.
Association of Leukocyte Telomere Length and Genes Involved in Its Regulation With Oral Carcinoma
Zaneta Jumatovaite 1, Albertas Kriauciunas 2, Alvita Vilkeviciute 3, Greta Gedvilaite 3, Vykintas Liutkevicius 4, Virgilijus Uloza 4, Alina Smalinskiene 5, Rasa Liutkeviciene 3
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PMID: 32606142 DOI: 10.21873/invivo.11967
Abstract
Background/aim: This study aimed to determine the relationship between the relative leukocyte telomere length (RLTL) and gene polymorphisms involved in its regulation with the occurrence of oral squamous cell carcinoma (OSCC).

Patients and methods: Patients with OSCC and healthy subjects were examined. Genotyping and RLTL measurement were carried out using rPCR.

Results: The OSCC group had longer telomeres than controls (p=0.001). Minor allele T at TERF1rs1545827 may increase RLTL shortening (p=0.047). TNKS2rs10509639 A/G and A/G+G/G genotypes were associated with a 2.6-fold increased odd (p=0.012) and a 2.4-fold increased odd (p=0.019) of RLTL elongation compared to A/A genotype. The A/G genotype was associated with a 2.6-fold increased odd (p=0.011) compared to the A/A+G/G genotypes. Each G allele was associated with a 2.1-fold increased odd of longer RLTL (p=0.036).

Conclusion: Longer telomeres were found in patients with OSCC than in controls. The TERF1 rs1545827 and the TNKS2 rs10509639 polymorphisms were associated with an increase in RLTL.

Keywords: Relative leukocyte telomere length; gene polymorphisms; oral squamous cell carcinoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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34
In Vivo
. Jul-Aug 2020;34(4):2073-2078. doi: 10.21873/invivo.12010.
Radical Hysterectomy for Cervical Cancer in Patients With Uterine Prolapse
Nicolae Bacalbasa 1 2 3, Ioana Halmaciu 4, Dragos Cretoiu 5 6, Cristian Balalau 5 7, Camelia Diaconu 5 8, Laura Iliescu 5 8, Gabriel Gorecki 9 10, Ciprian Bolca 11, Adrian Neacsu 5 12, Irina Balescu 13
Affiliations expand
PMID: 32606185 DOI: 10.21873/invivo.12010
Abstract
Background/aim: Association between cervical cancer and uterine prolapse represents a scarce eventuality. This is a case series of 11 patients diagnosed with different stages of cervical cancer in association with uterine prolapse.

Patients and methods: Between 2014 and 2020, 11 patients were diagnosed with cervical cancer on prolapsed uterine cervix.

Results: The mean age of patients at the time of uterine cervix diagnosis was 68 years. In six cases, the first intent treatment was surgery, while in the remaining five cases it consisted of radio-chemotherapy, followed by radical surgery. The perioperative and postoperative outcomes were compared to those reported in a similar series of patients diagnosed in similar stages of the disease, but in the absence of uterine prolapse, no significant differences being encountered.

Conclusion: Although it represents an unusual situation, malignant transformation of the uterine cervix might be encountered even in cases presenting uterine prolapse. In such cases, the therapeutic strategy should be tailored according to the stage of the disease.

Keywords: Cervical cancer; therapeutic strategy; uterine prolapse.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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35
In Vivo
. Jul-Aug 2020;34(4):1797-1803. doi: 10.21873/invivo.11974.
Ultrasonographic Follow-up of the Multistep Protocol for Prostate Cancer Induction in Wistar Rats
Ana I Faustino-Rocha 1 2, Fernanda Seixas 3 4, Rita Ferreira 5, Jessica Silva 3, Maria J Pires 2 3, Margarida Fardilha 6, MÁrio Ginja # 2 3, Paula A Oliveira # 2 3
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PMID: 32606149 DOI: 10.21873/invivo.11974
Abstract
Aim: This work intended to improve the knowledge of the rat model of prostate cancer (PCa) by ultrasonographic monitoring.

Materials and methods: Male Wistar rats were divided into control (n=8) and PCa (n=14) groups. PCa development was induced in the PCa group through the sequential administration of the anti-androgenic drug flutamide, testosterone propionate and the carcinogenic N-methyl-N-nitrosourea. The prostate was evaluated by ultrasonography at five timepoints along 49 weeks of the experimental protocol. Ventral prostate lobes were observed in all ultrasonographic examinations.

Results: The ventral prostate area of the control group increased gradually between the first and the last ultrasonographic examination. The ventral prostate area of PCa groups decreased due to flutamide administration and increased after androgen and carcinogen administration. The area of the dorsal prostate lobe increased between the fourth and the fifth ultrasonographic examination. In the last ultrasonographic examination, hypoechoic and anechoic lesions were observed in the PCa group.

Conclusion: To our knowledge, this is the first study presenting a follow-up of rat prostatic dimensions by ultrasonography. Ultrasonography is a feasible approach for prostate cancer monitoring in experimental models.

Keywords: Carcinogenesis; prostate; rodent; ultrasonography.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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36
In Vivo
. Jul-Aug 2020;34(4):1857-1862. doi: 10.21873/invivo.11980.
Osteogenic Evaluation of Hydroxyapatite Scaffold Loaded With Dexamethasone in Femoral Drill Holes
Min-Ho Park # 1, Seok Jin Jang # 2, Seok Hwa Choi 3
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PMID: 32606155 DOI: 10.21873/invivo.11980
Abstract
Background/aim: Many cases of bone damage are due to trauma and metabolic diseases. This study aimed to evaluate bone regeneration into a porous hydroxyapatite (HA) scaffold using dexamethasone (DM)-loaded polymeric microspheres.

Materials and methods: Four adult dogs were used to evaluate the in vivo performance of DM-loaded microspheres immobilized on the surfaces of porous HA scaffolds. Two 5-mm drill holes were created in both the left and right femurs of each dog. The experimental groups included a control group (drill holes filled with HA scaffold alone), a DM 20 group (holes filled with DM-loaded HA scaffold with 20 mg DM per scaffold), and a DM 100 group (hole filled with DM-loaded HA scaffold with 100 mg DM per scaffold). Resulting bone volume percentages and bone mineral densities were calculated by examing micro-computed tomographic (CT) images.

Results: The DM-loaded HA scaffold groups showed a gradual periosteal reaction two weeks after insertion of the HA scaffold into the femoral drill holes. Four weeks after HA scaffold insertion, the periosteal reaction in the femoral drill holes became denser. Eight weeks after insertion of DM-loaded HA scaffolds, clear images of the scaffold were observed in micro-CT images of the femoral drill hole. The DM 100 group had better bone healing tendencies (bone mineral density, bone mass, trabecular volume, bone surface, and trabecular thickness) than the DM 20 group.

Conclusion: DM-loaded HA scaffolds are suitable platforms for distributing bioactive molecules during osteogenesis in femoral drill holes.

Keywords: Dexamethasone; drill bit; hydroxyapatite; osteogenesis; scaffold.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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37
In Vivo
. Jul-Aug 2020;34(4):2159-2162. doi: 10.21873/invivo.12023.
A Case of Metastatic Iris Tumor Observed With Anterior Segment Optical Coherence Tomography Before and After Radiation Therapy
Mizuho Mitamura 1 2, Satoru Kase 3, Yuka Suimon 1, Takako Ito 1, Susumu Ishida 1
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PMID: 32606198 DOI: 10.21873/invivo.12023
Abstract
Background/aim: Metastatic iris tumors are relatively rare entities that are often treated with radiation therapy; however, it remains difficult to evaluate the effectiveness of treatment. Anterior segment optical coherence tomography (AS-OCT) provides high-resolution cross-sectional images with no dye injection, and may thus be useful for evaluating iris tumors. Herein, we report a case of metastatic iris tumor examined with AS-OCT before and after radiation therapy.

Case report: A 56-year-old Japanese woman complained of ocular hyperemia and pain in her right eye, and was referred to our hospital because of uveitis and an iris mass. One year before the initial visit, the patient was diagnosed with lung adenocarcinoma, and treated with chemotherapy. She also underwent radiation therapy 4 months ago due to multiple bone metastases. Slit-lamp microscopy revealed a 2×2 mm elevated lesion with partial depigmentation on the lower iris. AS-OCT examination revealed that the mass was located in the iris stroma with an irregular anterior surface. Based on fine needle aspiration cytology, she was diagnosed with metastatic iris tumor derived from lung adenocarcinoma, leading to local radiotherapy. Seven months later, AS-OCT showed shrinkage and atrophy of the iris tumor with peripheral anterior synechia formation.

Conclusion: We report a case of cytology-proven metastatic iris tumor observed with AS-OCT before and after radiation therapy. This study highlights the potential usefulness of AS-OCT for monitoring changes in tumor size and configuration following radiotherapy.

Keywords: Iris tumor; anterior segment optical coherence tomography; aspiration cytology; iris metastasis.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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38
Review In Vivo
. 2020 Jun;34(3 Suppl):1597-1602. doi: 10.21873/invivo.11949.
Potential Antiviral Drugs for SARS-Cov-2 Treatment: Preclinical Findings and Ongoing Clinical Research
Sabrina Bimonte # 1, Anna Crispo # 2, Alfonso Amore 3, Egidio Celentano 2, Arturo Cuomo 4, Marco Cascella 4
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PMID: 32503817 DOI: 10.21873/invivo.11949
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), initially termed 2019-new CoV (2019-nCoV), is a novel coronavirus responsible for the severe respiratory illness currently ongoing worldwide from the beginning of December 2019. This beta gene virus, very close to bat coronaviruses (bat-CoV-RaTG13) and bat-SL-CoVZC45, causes a severe disease, similar to those caused by Middle East respiratory syndrome (MERS)-CoV and SARS-CoV viruses, featured by low to moderate mortality rate. Unfortunately, the antiviral drugs commonly used in clinical practice to treat viral infections, are not applicable to SARS-Cov-2 and no vaccine is available. Thus, it is extremely necessary to identify new drugs suitable for the treatment of the 2019-nCoV outbreak. Different preclinical studies conducted on other coronaviruses suggested that promising clinical outcomes for 2019-nCoV should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs. Moreover, clinical trials with these suitable drugs should be performed on patients affected by SARS-Cov-2 to prove their efficacy and safety. Finally, a very promising therapeutic drug, tocilizumab, is discussed; it is currently used to treat patients presenting COVID-19 pneumonia. Herein, we recapitulate these experimental studies to highlight the use of antiviral drugs for the treatment of SARS-Cov-2 disease.

Keywords: COVID-19; SARS-Cov-2; antiviral drugs; coronaviruses; review; tocilizumab; virus.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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39
In Vivo
. Jul-Aug 2020;34(4):1981-1986. doi: 10.21873/invivo.11995.
Volume Delineation in Cervical Cancer With T2 and Diffusion-weighted MRI: Agreement on Volumes Between Observers
Consuelo Rosa 1 2, Andrea Delli Pizzi 2 3, Antonietta Augurio 4, Luciana Caravatta 4, Monica DI Tommaso 4, Erica Mincuzzi 3, Sebastiano Cinalli 5, Raffaella Basilico 3, Annamaria Porreca 6, Marta DI Nicola 7, Domenico Genovesi 4 2
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PMID: 32606170 DOI: 10.21873/invivo.11995
Abstract
Aim: To delineate cervical cancer gross tumor volume (GTV) on T2-magnetic resonance imaging (MRI) and apparent diffusion coefficient (ADC) maps, assessing volumes and inter-observer agreement between two observers.

Patients and methods: A radiologist and a radiation oncologist delineated GTV on T2 (T2GTV) and ADC (ADCGTV) sequences. Dice similarity index (DICE) and Bland-Altman analysis were used to estimated concordance.

Results: Mean T2GTV and ADCGTV volumes were 43.84±71.47 cc and 37.28±68.92 cc according to the radiologist, and 43.4±70.44 cc and 36.65±69.21 cc according to the radiation oncologist. ADC led to statistically significantly smaller volumes compared to T2. The mean DICE index was 0.86 for T2GTV and 0.84 for ADCGTV The Bland-Altman plots globally showed concordance.

Conclusion: GTV delineation was smaller in the ADC maps compared to T2-MRI, reaching an almost perfect agreement between observers. Thanks to this acceptable variability, adding functional imaging might provide more information for tumor delineation, improving reproducibility for image-guided adaptive radiotherapy.

Keywords: Cervical cancer; inter-observer agreement; magnetic resonance imaging; radiotherapy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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40
In Vivo
. Jul-Aug 2020;34(4):2057-2060. doi: 10.21873/invivo.12007.
Synchronous Bilateral Carcinoma of the Ureters. Report of a Case and a Short Discussion of the Literature
Dimitrios Sidiropoulos # 1 2, Filippos Kapogiannis # 3, Panagiota Kripouri 2, Dimitrios Filippou 2, Konstantinos Vlassis 2
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PMID: 32606182 DOI: 10.21873/invivo.12007
Abstract
Background/aim: The strategy for treatment of bilateral simultaneous renal pelvic and/or ureteral tumors has not been established and is dependent on individual decision.

Case report: We herein report the case of an elderly man who was examined for fatigue at the emergency department and subsequently diagnosed with bilateral ureteral cancer. The most common histologic type of ureteral cancer is urothelial (transitional epithelium) cancer and though it is rare, it can be synchronously present in the contralateral ureter. Computed tomography-urography (CTU) has very good results regarding diagnosis and surgical treatment and -though not preferred in our case-, it has shown promising results.

Conclusion: We believe that conservative treatment is a viable therapeutic option for simultaneous bilateral renal pelvic and/or ureteral tumors in selected patients. Yet, this treatment has seldom been performed, although standard therapy with bilateral nephroureterectomy inevitably requires the support of hemodialysis or renal transplantation.

Keywords: Bilateral cancer; comorbidities; synchronous; ureter.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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41
In Vivo
. Jul-Aug 2020;34(4):1993-1999. doi: 10.21873/invivo.11997.
Prognostic Impact of the Neoadjuvant Rectal Score as Compared With the Tumor Regression Grade and Yield Pathologic TNM Stage in Patients With Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiotherapy
Jin Ho Baek # 1, Dong Won Baek # 1, Byung Woog Kang 1, Hye Jin Kim 2, Su Yeon Park 2, Jun Seok Park 2, Gyu Seog Choi 2, Jong Gwang Kim 3
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PMID: 32606172 DOI: 10.21873/invivo.11997
Abstract
Background/aim: The present study compared the prognostic value of the yield pathologic (yp) stage, tumor regression grade (TRG), and neoadjuvant rectal (NAR) score in patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiotherapy (nCRT).

Patients and methods: For the assessment of tumor regression, the Dworak grading system was used. The NAR score was calculated using the following equation: (5ypN-3[cT-ypT]+12)2÷9.61.

Results: In univariate analysis, the NAR score and ypTNM stage were significantly associated with DFS [hazard ratio (HR)=2.514, p<0.001 and HR=3.200, p<0.001] and OS (HR=2.292, p=0.001 and HR=2.859, p<0.001), whereas the TRG was significantly associated with only DFS (HR=2.008, p=0.017). In multivariate analysis, the ypTNM stage was the only independent prognostic factor for DFS (HR=3.796, p<0.001) and OS (HR=3.591, p=0.0034).

Conclusion: Only the ypTNM stage was significantly associated with survival outcomes in multivariate analysis, suggesting that it is the most powerful prognostic factor of nCRT in patients with LARC.

Keywords: Rectal neoplasms; neoadjuvant therapy; neoplasm staging; prognosis.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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42
In Vivo
. Jul-Aug 2020;34(4):1749-1758. doi: 10.21873/invivo.11968.
A Feasibility Study for 3D-printed Poly(methyl Methacrylate)-Resin Tracheostomy Tube Using a Hamster Cheek Pouch Model
Harry Jung 1, Ji Seung Lee 2, Jun Ho Lee 3, Ki Joon Park 3, Jae Jun Lee 4, Hae Sang Park 5 3
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PMID: 32606143 DOI: 10.21873/invivo.11968
Abstract
Background/aim: A three-dimensional (3D) printed tracheostomy tube has potential application for patients who require a specialized tube. The aim of this study was to evaluate the characteristics of various 3D printing materials and determine their use in producing 3D-printed tracheostomy tube.

Materials and methods: Mechanical, chemical, and microbiological in vivo changes in the scaffolds were analyzed using a hamster cheek pouch (HCP) model.

Results: The poly methyl methacylate (PMMA)-resin showed superior pre- and post-insertion mechanical properties and a relatively consistent lower biofilm formation compared with other scaffolds. PMMA-resin was successfully 3D-printed with dimensional accuracy without a support system. The use of a 3D-printed PMMA tracheostomy tube in a rabbit trachea showed no definite signs of infection, allergy or foreign body reaction.

Conclusion: PMMA-resin can be proposed as an alternative for a 3D-printed tracheostomy tube material. In addition, we suggest HCPs as an in vivo model for evaluating indwelling medical devices.

Keywords: 3D printing; hamster; resin; tracheostomy; tube.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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43
In Vivo
. Jul-Aug 2020;34(4):1759-1764. doi: 10.21873/invivo.11969.
Interaction of Interleukin-16 Genotypes With Betel Quid Chewing Behavior on Oral Cancer in Taiwan
Liang-Chun Shih # 1 2 3, Wen-Shin Chang # 1 2, Hsu-Tung Lee # 4 5, Yun-Chi Wang 1 2, Zhi-Hong Wang 6, Che-Yi Chao 6, Chien-Chih Yu 2 7, Hui-Yi Lin 7, Te-Chun Shen 2, Chien-Chung Kuo 8, Chia-Wen Tsai 9 2, DA-Tian Bau 9 2 10
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PMID: 32606144 DOI: 10.21873/invivo.11969
Abstract
Background/aim: Interleukin-16 (IL-16) is reported to play an important role in inflammation, carcinogenesis and tumoricidal processes, however, the contribution of IL-16 genotype to oral carcinogenesis is still largely unrevealed. Thus, the study aimed to investigate the contribution of IL-16 genotypes to Taiwan oral cancer risk.

Materials and methods: The genotypes of IL-16 rs4778889, rs11556218, and rs4072111 were revealed among 958 oral cancer cases and 958 control subjects by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP).

Results: First, the distributions of genotypic (p=0.0004) and allelic (p=0.0001) frequencies of IL-16 rs11556218 were significantly different between the case and control groups. In detail, the frequencies of IL-16 rs11556218 TG and GG were 28.1 and 5.8%, respectively, among oral cancer patients, significantly higher compared to those among controls (25.0% and 2.7%, respectively). Second, no difference was observed regarding IL-16 rs4778889 or IL-16 rs4072111. Last, there was a synergistic effect of betel quid chewing behavior and risky IL-16 rs11556218 genotype on oral cancer risk.

Conclusion: The study indicates that the IL-16 rs11556218 G allele synergistically interacts with betel quid chewing behavior, contributing to increased risk of oral cancer in Taiwanese.

Keywords: Betel quid chewing; Taiwan; genotype; interleukin-16; oral cancer; single nucleotide polymorphism.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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44
In Vivo
. Jul-Aug 2020;34(4):1987-1992. doi: 10.21873/invivo.11996.
Laparoscopic Total Gastrectomy for Remnant Gastric Cancer: A Single-institution Experience and Systematic Literature Review
Mitsuhiko Ota 1, Masahiko Ikebe 2, Yuki Shin 2, Masaki Kagawa 2, Yohei Mano 3, Tomonori Nakanoko 2, Yuichiro Nakashima 2, Hideo Uehara 2, Masahiko Sugiyama 2, Tomohiro Iguchi 3, Keishi Sugimachi 3, Manabu Yamamoto 4, Masaru Morita 2, Yasushi Toh 2
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PMID: 32606171 DOI: 10.21873/invivo.11996
Abstract
Background/aim: The safety and efficacy of laparoscopic total gastrectomy (LTG) for remnant gastric cancer (RGC) remains unclear. The purpose of this study was to compare the clinical outcomes of LTG with open total gastrectomy (OTG) for RGC.

Patients and methods: Twenty-two patients who underwent total gastrectomy for RGC were enrolled in this study.

Results: LTG was carried out in seven patients, and OTG was performed in the remaining 15 patients. The mean operation time in the LTG group was longer than that in the OTG group. The estimated blood loss in the LTG group was less than that in the OTG group. No cases in the LTG group required open conversion. Postoperatively, the first meal and defecation were earlier in the LTG group than in the OTG group. The overall survival rates of the two groups were comparable.

Conclusion: Laparoscopic total gastrectomy is a feasible surgical option for RGC.

Keywords: Laparoscopic total gastrectomy; remnant gastric cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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45
Multicenter Study In Vivo
. 2020 Jun;34(3 Suppl):1685-1694. doi: 10.21873/invivo.11962.
The Effect of Coronavirus (COVID-19) on Breast Cancer Teamwork: A Multicentric Survey
Gianluca Vanni 1, Marco Materazzo 2, Francesca Santori 1, Marco Pellicciaro 1, Maria Costesta 1, Paolo Orsaria 3, Francesca Cattadori 4, Chiara Adriana Pistolese 5, Tommaso Perretta 5, Marcello Chiocchi 5, Rosaria Meucci 1 5, Feliciana Lamacchia 5, Massimo Assogna 1, Jonathan Caspi 1, Alessandra Vittoria Granai 1, Adriano DE Majo 1, Agostino Chiaravalloti 6 7, Maria Rolando D'Angelillo 8, Rosaria Barbarino 8, Sara Ingallinella 1, Ljuba Morando 1, Stefania Dalli 1, Ilaria Portarena 9, Vittorio Altomare 3, Giovanni Tazzioli 10, Oreste Claudio Buonomo 1
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PMID: 32503830 DOI: 10.21873/invivo.11962
Abstract
Background/aim: Despite the large amount of clinical data available of Coronavirus-19 (COVID-19), not many studies have been conducted about the psychological toll on Health Care Workers (HCWs).

Patients and methods: In this multicentric descriptive study, surveys were distributed among 4 different Breast Cancer Centers (BCC). BCCs were distinguished according to COVID-19 tertiary care hospital (COVID/No-COVID) and district prevalence (DP) (High vs. Low). DASS-21 score, PSS score and demographic data (age, sex, work) were evaluated.

Results: A total of 51 HCWs were analyzed in the study. Age, work and sex did not demonstrate statistically significant values. Statistically significant distribution was found between DASS-21-stress score and COVID/No-COVID (p=0.043). No difference was found in the remaining DASS-21 and PSS scores, dividing the HCWs according to COVID-19-hospital and DP.

Conclusion: Working in a COVID-19-hospital represents a factor that negatively affects psychosocial well-being. However, DP seems not to affect the psychosocial well-being of BCC HCWs. During the outbreak, psychological support for low risk HCWs should be provided regardless DP.

Keywords: COVID-19; DASS-21; PSS; SARS-SOV-2; anxiety; breast cancer; heath care workers; multicentric study; psychological well-being; score.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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46
Observational Study In Vivo
. 2020 Jun;34(3 Suppl):1667-1673. doi: 10.21873/invivo.11959.
Breast Cancer Surgery During the COVID-19 Pandemic: An Observational Clinical Study of the Breast Surgery Clinic at Ospedale Policlinico San Martino - Genoa, Italy
Piero Fregatti 1 2, Marco Gipponi 3, Maria Giacchino 1, Marco Sparavigna 1, Federica Murelli 1 2, Maria Luisa Toni 4, Maria Teresa Calabrò 4, Lina Orsino 4, Daniele Friedman 1 2
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PMID: 32503827 DOI: 10.21873/invivo.11959
Abstract
Background: COVID-19 pandemic required a marked re-allocation of healthcare resources, including at Breast Units. A patient-tailored program was developed to assess its efficacy regarding prevention of COVID-19 infection among patients with breast cancer undergoing surgery and healthcare workers (HCWs).

Patients and methods: From March 9th to April 9th 2020, 91 patients were selected for elective surgery by means of: i) Pre-hospital screening aimed at avoiding hospitalization of symptomatic or suspicious COVID-19 patients, and ii) prioritisation of surgical procedure according to specific disease features.

Results: Eighty-five patients (93.4%) were fit for surgery, while five patients (5.5%) were temporarily excluded through 'telephone triage'; another two patients were excluded at in-hospital triage. A total of 71 out of 85 patients (83.5%) were diagnosed with invasive cancer, most of whom were undergoing breast-conserving surgery (61 out of 85 patients, 71.8%). The mean in-hospital stay was 2.2 days (SD=0.7 days). After hospital discharge, no patient needed re-admission due to post-operative complications; moreover, no COVID-19 infection among patients or HCWs was detected.

Conclusion: Safe breast cancer surgery was accomplished for both patients and HCWs by means of a careful preoperative selection of patients and in-hospital preventative measures. This screening program can be transferred to high-volume Breast Units and it may be useful in implementing European Community recommendations for prevention of COVID-19 infection.

Keywords: COVID-19; breast cancer; clinical management.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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47
In Vivo
. Jul-Aug 2020;34(4):2021-2027. doi: 10.21873/invivo.12001.
The Number of Harvested LNs Is an Independent Prognostic Factor in Lymph Node Metastasis-negative Patients Who Received Curative Esophagectomy
Toru Aoyama # 1, Yosuke Atsumi # 2, Shinnosuke Kawahara 2, Hiroshi Tamagawa 2, Ayako Tamagawa 2, Yukio Maezawa 2 3, Kazuki Kano 2, Masaaki Murakawa 2, Keisuke Kazama 2, Masakatsu Numata 2, Takashi Oshima 2 4, Norio Yukawa 2, Munetaka Masuda 2, Yasushi Rino 2
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PMID: 32606176 DOI: 10.21873/invivo.12001
Abstract
Background/aim: The aim of the present study was to evaluate the optimal number of harvested LNs (LNs) in patients who were LN metastasis-negative after curative esophagectomy for esophageal cancer.

Patients and methods: Sixty-one patients who underwent curative surgery for esophageal cancer between 2005 and 2017 and diagnosed as lymph node metastasis-negative were included in this study.

Results: The 5-year overall survival rates were 27.8% for 0-20 harvested LNs, 35.7% for 21-30 harvested LNs, 79.4% for 31-40 harvested LNs, and 85.2% for ≥41 harvested LNs. Thirty harvested LNs was regarded as the optimal critical point of classification, considering the 5-year OS rate. The number of harvested LNs was selected as a significant prognostic factor in both univariate and multivariate analyses. The respective 3- and 5-year OS rates were 50.3% and 36.7% for <30 harvested LNs and 82.4% and 82.4% for ≥30 harvested LNs (p=0.003).

Conclusion: Thirty or more harvested LNs was a significant prognostic factor in patients with metastasis-negative LNs after curative esophagectomy for esophageal cancer. Therefore, the number of harvested LNs might be useful for predicting the LN metastasis status in esophageal cancer.

Keywords: Esophageal cancer; lymph node; recurrence; survival.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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48
In Vivo
. Jul-Aug 2020;34(4):1883-1892. doi: 10.21873/invivo.11984.
Salvage Photon or Proton Radiotherapy for Oligo-recurrence in Regional Lymph Nodes After Surgery for Non-small Cell Lung Cancer
Masatoshi Nakamura 1, Kayoko Ohnishi 2, Hitoshi Ishikawa 1, Kensuke Nakazawa 3, Toshihiro Shiozawa 3, Toshiyuki Okumura 1, Ikuo Sekine 4, Yukio Sato 5, Nobuyuki Hizawa 3, Hideyuki Sakurai 1
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PMID: 32606159 DOI: 10.21873/invivo.11984
Abstract
Background/aim: To evaluate the outcome of definitive salvage radiotherapy (RT) in non-small cell lung cancer (NSCLC) patients with oligo-recurrence in regional lymph nodes after surgery.

Patients and methods: Between January 2003 and December 2016, 33 patients with NSCLC were reviewed from radiotherapy database at our hospital. All patients received photon or proton salvage RT for metastases in the regional lymph nodes.

Results: The median follow-up from salvage RT was 35.2 (range=5.9-89.6) months. Recurrences occurred in 18 (55%) patients, and the 3-year overall and progression-free survival rates were 63.8% and 45.1%, respectively. Regional and local control improved patients' survival and these control rates were increased by use of concurrent chemotherapy (p=0.039) and proton RT (p=0.084). No grade 4 acute or late non-hematologic toxicities were observed.

Conclusion: Salvage RT is an effective treatment for NSCLC patients with oligo-recurrence at regional lymph nodes.

Keywords: Radiotherapy; lymph node metastasis; non-small cell lung cancer; oligo-recurrence.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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49
In Vivo
. Jul-Aug 2020;34(4):2015-2019. doi: 10.21873/invivo.12000.
Occurrence of Residual Cancer Within Re-excisions After Subcutaneous Mastectomy of Invasive Breast Cancer and Ductal Carcinoma In Situ - A Retrospective Analysis
Caroline Pahmeyer 1, Anika Schablack 2, Dominik Ratiu 2, Fabinshy Thangarajah 2, Sebastian Ludwig 2, Berthold Gruettner 2, Peter Mallmann 2, Wolfram Malter 2, Mathias Warm 3, Christian Eichler 2
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PMID: 32606175 DOI: 10.21873/invivo.12000
Abstract
Background/aim: Surgical margin status remains an important determinant for recurrence of invasive breast cancer and ductal carcinoma in situ. We compared the number of positive margins in initial histology with rates of residual tumor in re-excision specimens. Furthermore, we analysed cost-effectiveness of re-excisions.

Patients and methods: 101 patients treated with secondary surgery were included. The first group underwent breast conserving surgery and secondary mastectomy. The second group was primarily treated with subcutaneous mastectomy followed by secondary surgery.

Results: Within the first group, 22.7% did not show residual tumor in the re-excision specimen. Of the second group, 54.3% had no residual tumor. Consequentially 45.7% needed a re-excision to achieve R0 status. Cost-effectiveness was determined as secondary endpoint. If a patient needs a secondary mastectomy the hospital gains 602,65€ in comparison to a primary breast conserving operation.

Conclusion: In every second patient who had first received a subcutaneous mastectomy, no tumor could be detected in the secondary operation despite a previous R1 status.

Keywords: Subcutaneous mastectomy; re-excisions; residual cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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50
In Vivo
. Jul-Aug 2020;34(4):2113-2118. doi: 10.21873/invivo.12016.
A Monocentric Retrospective Observational Study of Comorbidities in Patients Affected by Autoimmune Bullous Diseases
Martina Ferranti 1, Giulia Gobbo 1, Giulia Tadiotto Cicogna 1, Mauro Alaibac 2
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PMID: 32606191 DOI: 10.21873/invivo.12016
Abstract
Background/aim: Autoimmune bullous diseases (AIBDs) of the skin and mucosae include a heterogeneous group of chronic diseases, which could be associated with various comorbidities. The purpose of this study was to evaluate the comorbidity profiles of patients affected by AIBDs, who referred to the Dermatological Clinic of Padua from December 2015 to June 2018.

Patients and methods: A monocentric retrospective observational study was conducted on 157 patients with diagnosis of AIBDs. Patients' comorbidities were investigated during the periodic visits of follow-up and through the analysis of computerized medical records.

Results: Among the 157 patients, 40 (25.5%) were diagnosed with PV, 15 (9.6%) with PF, and 102 (64.9%) with BP. Nine different comorbidities were observed, but only two of these were statistically significantly associated with BP: type 2 diabetes (p=0.0142) and neuropsychiatric disorders (p=0.015).

Conclusion: BP is statistically significantly associated with type 2 diabetes mellitus and neuropsychiatric diseases. The correlation with neuropsychiatric pathologies is interesting for the possible bidirectional role in their etiology. The association with type 2 diabetes mellitus could suggest more caution in the administration of systemic corticosteroids, especially in elderly patients.

Keywords: AIBDs; autoimmune bullous diseases; bullous pemphigoid; comorbidities; neuropsychiatric diseases; pemphigus; type 2 diabetes mellitus.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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