Cancer Letters

Organoid technology in cancer precision medicine Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Xinyi Xia, Fei Li, Juan He, Rebiguli Aji, Dong Gao Abstract Organoid technology has been remarkably improved over the last decade. Various organoids have been derived from different types of tissues and recapitulate their organ-specific gene expression signatures, particular tissue spatial structures and functions of their original tissue. The patient-derived organoids (PDOs) have been used to elucidate crucial scientific questions, including the relationships between genetic/epigenetic alterations and drug responses, cell plasticity during disease progressions, and mechanisms of drug resistances. With the great expectations, PDOs will be widely used to facilitate the personalized medical decisions, which have the potential to profoundly improve patient outcomes. In this review, we will discuss the developmental details, current achievements, applications and challenges of organoid technology in precision cancer medicine.

Vps4A mediates the localization and exosome release of β-catenin to inhibit epithelial-mesenchymal transition in hepatocellular carcinoma Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Qingfang Han, Lihong Lv, Jinxing Wei, Xin Lei, Haoming Lin, Guolin Li, Jun Cao, Jiyan Xie, Weibang Yang, Shaobin Wu, Jia You, Jing Lu, Peiqing Liu, Jun Min Abstract We previously reported that Vps4A acted as a tumor suppressor by influencing the microRNA profiles of exosomes and their parental cells in hepatocellular carcinoma (HCC). However, the underlying mechanism and if Vps4A contributes to sorting proteins into exosomes are not well known. Here, we performed mass spectrometry analysis of the immunoprecipitated Vps4A complex and confirmed that Vps4A was associated with β-catenin and CHMP4B. Through this interaction, Vps4A promoted the plasma membrane (PM) localization and exosome release of β-catenin. Silencing Vps4A or CHMP4B decreased the PM localization and exosome sorting of β-catenin. Vps4A overexpression decreased β-catenin signaling pathway and inhibited epithelial-mesenchymal transition (EMT) and motility of HCC cells. And, silencing Vps4A or CHMP4B promoted EMT in HCC. Furthermore, the expression of Vps4A was significantly related to that of several EMT markers in HCC tissues and the level of exosomal β-catenin in patients with metastatic HCC was significantly lower compared to that of control patients. In conclusion, through the interaction with CHMP4B and β-catenin, Vps4A regulates the PM localization and exosome sorting of β-catenin, consequently decreases β-catenin signaling, and thereby inhibits EMT and metastasis in HCC.

Combined Bcl-2/Src inhibition synergize to deplete stem-like breast cancer cells Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Qi Sun, Yufen Wang, Jay S. Desgrosellier Abstract Breast cancer cells with stem cell properties play an important role in tumor progression and thus are key targets for therapy. Here, we show that combined Bcl-2/Src inhibition synergize to deplete stem-like cells. While Src inhibition increases pro-apoptotic PUMA, we find that a significant amount interacts with Bcl-2 and Bcl-xL, promoting resistance to cell death. Consistent with this, the clinically-approved Bcl-2 selective drug venetoclax was sufficient to overcome resistance by preventing PUMA/Bcl-2 binding, enhancing apoptosis. This effect was specific to stem-like breast cancer cells as there was no effect on luminal or basal-like cell types. In contrast, the Mcl-1 inhibitor S63845 potently targeted basal-like, but not stem-like cells, highlighting dependency on distinct sentinel Bcl-2 family members. Our findings reveal Bcl-2/Src inhibition as a superior therapy to target stemness, providing a foundation for a potential personalized strategy to reduce breast cancer progression.

Interferon regulatory factor-1 reverses chemoresistance by downregulating the expression of P-glycoprotein in gastric cancer Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Jingsheng Yuan, Zhijie Yin, Lulu Tan, Wenzhong Zhu, Kaixiong Tao, Guobing Wang, Wenjia Shi, Jinbo Gao Abstract The emergence of multiple drug resistance (MDR) is the main cause of chemotherapy failure in gastric cancer. In this study, to generate MDR gastric cancer cell lines, we exposed MKN45 and AGS gastric cancer cells to cisplatin, fluorouracil, and adriamycin. Through transcriptome sequencing, we found that interferon regulatory factor-1 (IRF-1) was expressed at significantly lower levels in the MDR cell lines than in the parental cell lines. We then established stable clones of MKN45 and SGC7901 cells with a doxycycline-inducible IRF-1 expression system and confirmed that IRF-1 overexpression efficiently reversed the MDR. Further analyses indicated that IRF-1 suppresses P-glycoprotein (P-gp) expression in vitro and in vivo, leading to an increase in chemotherapy drug retention. The results showed that IRF-1 bound to the promoter regions of P-gp gene and inhibited P-gp transcription. IFN-γ induced IRF-1-mediated downregulation of P-gp in gastric cancer cells. Finally, we demonstrated that the clinical correlation between IRF-1 and P-gp expression and that IRF-1 serves as an independent prognostic factor for patients with gastric cancer. We conclude that IRF-1 reverses the MDR trait of gastric cancer by downregulating P-gp, and this mechanism has potential treatment implications and is clinically actionable.

BIRC5 is a target for molecular imaging and detection of human pancreatic cancer Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Shi-He Liu, Yeahwa Hong, Stephen Markowiak, Robbi Sanchez, Justin Creeden, John Nemunaitis, Andrea Kalinoski, James Willey, Paul Erhardt, Jason Lee, Michael van Dam, F. Charles Brunicardi Abstract Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer mortality with a dismal overall survival rate and an urgent need for detection of minute tumors. Current diagnostic modalities have high sensitivity and specificity for larger tumors, but not for minute PDAC. In this study, we test the feasibility of a precision diagnostic platform for detecting and localizing minute human PDAC in mice. This platform includes: 1) defining BIRC5 as an early PDAC-upregulated gene and utilizing an enhanced BIRC5 super-promoter to drive expression of dual Gaussia luciferase (GLuc) and sr39 thymidine kinase (sr39TK) reporter genes exponentially and specifically in PDAC; 2) utilizing a genetically-engineered AAV2RGD to ensure targeted delivery of GLuc and sr39TK specifically to PDAC; 3) using serologic GLuc and sr39TK microPET/CT imaging to detect and localize minute human PDAC in mice. The study demonstrates feasibility of a precision diagnostic platform using an integrated technology through a multiple-stage amplification strategy of dual reporter genes to enhance the specificity and sensitivity of detection and localization of minute PDAC tumors and currently undetectable disease.

Tumor vasculature remodeling by radiation therapy increases doxorubicin distribution and efficacy Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Vincent Potiron, Karen Clément-Colmou, Emmanuel Jouglar, Manon Pietri, Sophie Chiavassa, Grégory Delpon, François Paris, Stéphane Supiot Abstract The tumor microenvironment regulates cancer initiation, progression and response to treatment. In particular, the immature tumor vasculature may impede drugs from reaching tumor cells at a lethal concentration. We and others have shown that radiation therapy (RT) induces pericyte recruitment, resembling vascular normalization. Here, we asked whether radiation-induced vascular remodeling translates into improved tissue distribution and efficacy of chemotherapy. First, RT induced vascular remodeling, accompanied by decreased hypoxia and/or increased Hoechst perfusion in prostate PC3 and LNCaP and Lewis lung carcinoma. These results were independent of the RT regimen, respectively 10 × 2 Gy and 2 × 12 Gy, suggesting a common effect. Next, using doxorubicin as a fluorescent reporter, we observed that RT improves intra-tumoral chemotherapy distribution. These effects were not hindered by anti-angiogenic sunitinib. Moreover, sub-optimal doses of doxorubicin had almost no effect alone, but significantly delayed tumor growth after RT. These data demonstrate that RT favors the efficacy of chemotherapy by improving tissue distribution, and could be an alternative chemosensitizing strategy.

PD-1/PD-L1 blockade in paediatric cancers: What does the future hold? Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Julia Moreno-Vicente, Stephen A. Beers, Juliet C. Gray Abstract Checkpoint blockade (CPB) immunotherapy has shown unprecedented success in a wide range of adult malignancies, and is increasingly being employed in the treatment of advanced cancers. However, the experience in the paediatric population remains limited and the small number of single agent studies reported have shown disappointing response rates. Paediatric cancers offer unique challenges that can hinder the translation of CPB into the paediatric clinic, and combinational therapies are likely to be needed to achieve therapeutic success. As the number of paediatric trials using CPB rapidly increases, understanding the challenges that these agents may encounter in this population is of special significance to allow the design of optimal combinatorial strategies for each tumour type. Here, we offer an overview of the unique biological and immunological features of paediatric cancers as compared to adult malignancies, and how these might impact the overall success of CPB in the paediatric population. We review the growing body of pre-clinical and clinical experiences to date, and discuss future strategies involving the combination of CPB with traditionally used therapies (chemotherapy and radiotherapy) or with other newly developed immunotherapies.

A tRNA fragment, 5′-tiRNAVal, suppresses the Wnt/β-catenin signaling pathway by targeting FZD3 in breast cancer Publication date: 10 August 2019 Source: Cancer Letters, Volume 457 Author(s): Dongping Mo, Pan Jiang, Yining Yang, Xuelian Mao, Xuyan Tan, Xun Tang, Da Wei, Bing Li, Xiaoming Wang, Li Tang, Feng Yan Abstract tRNA-derived fragments offer a recently identified group of non-coding single-stranded RNAs that are often as abundant as microRNAs in cancer cells and play important roles in carcinogenesis. However, the biological functions of them in breast cancer are still unclear. Hence, we focused on investigating whether tiRNAs could play a key role in the progression of breast cancer. We have identified 5′-tiRNAVal with significantly low expression in breast cancer tissues. The down-regulation of serum 5′-tiRNAVal was positively correlated with stage progression and lymph node metastasis. Overexpression of 5′-tiRNAVal suppressed cells malignant activities. FZD3 was confirmed to be a direct target of 5′-tiRNAVal in breast cancer. In addition, FZD3, β-Catenin, c-myc and cyclinD1 levels in 5′-tiRNAVal overexpressing cells were downregulated while APC was inversely upregulated. Moreover, 5′-tiRNAVal inhibited the FZD3-mediated Wnt/β-Catenin signaling pathway in breast cancer cells. Finally, 5′-tiRNAVal levels differentiated breast cancer from healthy controls with a sensitivity of 90.0% and specificity of 62.7%. This is the first study to show that 5′-tiRNAVal as a new tumor-suppressor through inhibition of FZD3/Wnt/β-Catenin signaling pathway, which could be as a potential diagnostic biomarker for breast cancer.

Management of immune related adverse events induced by immune checkpoint inhibition Publication date: 1 August 2019 Source: Cancer Letters, Volume 456 Author(s): Andreas Teufel, Tianzuo Zhan, Nicolai Härtel, Jan Bornschein, Matthias P. Ebert, Nadine Schulte Abstract In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy and these drugs have already become essential for the treatment of various non-curable tumors. Compared to conventional chemotherapy or tyrosine kinase inhibitors, ICIs generally exhibit a favorable side effect profile further promoting their increasing prescription rate. However, increasing use of these substance made clear that ICI induced activation of the immune system may also lead to immune-related adverse events (irAEs). Common irAEs are dermatological, gastrointestinal, or endocrine side effects but further tissue types and organ systems may also be affected. A detailed knowledge of these potential side effects is important as early recognition is the key to successful treatment, reversibility of organ dysfunction and in some cases even prevention of fatal outcome. In more severe irAEs, immunosuppression may be necessary to cope with these side effects. To increase awareness of irAEs and support immediate and successful management, we provide a comprehensive review on most common irAEs of ICIs, their diagnosis, and treatment.

Immune checkpoint modulators in cancer immunotherapy: Recent advances and combination rationales Publication date: 1 August 2019 Source: Cancer Letters, Volume 456 Author(s): Li Fan, Yue Li, Jia-Yu Chen, Yong-Fa Zheng, Xi-Ming Xu Abstract As a new hallmark of cancer, immune surveillance evading plays a critical role in carcinogenesis. Through modulating the immune checkpoints, immune cells in tumor microenvironment can be harnessed to battle cancer cells. In recent years, the administration of anti-CTLA or/and anti-PD-1/L1 antibody has exhibited unexpected antitumor effect in multiple types of cancer, motivating the researchers to find more potential immune checkpoints as clinical targets. A wealth of clinical trials have been done to evaluate the safety and efficacy of monotherapy or combination therapy with immune checkpoint modulators. However, there still exist problems such as low response rate and adverse events in the clinical, which in turn leads us to the basic study. The better understanding of the crosstalk between the immune cells and the cancer cells within the microenvironment may inspire us new ideas for cancer treatment. In this review, we mainly summarize the recent advances in application of immune checkpoint modulators and the combination rationales, and discuss the problems existing in the precision therapy with immune checkpoint modulators.

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

A positive attitude causes a chain reaction of positive thoughts, events and outcomes.

Μέσω

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

Cancer Research, Statistics, Treatment

Love in the time of cancer Vikas Talreja Cancer Research, Statistics, and Treatment 2018 1(2):75-77

Hypersensitivity reactions to paclitaxel with a modified dexamethasone intravenous premedication regimen Vanita Noronha, Deborah Enting, Ravi Thippeswamy, Amit Joshi, Vijay Maruti Patil, Kumar Prabhash Cancer Research, Statistics, and Treatment 2018 1(2):78-83 Background: The conventional paclitaxel premedication regimen consists of two oral dexamethasone doses of 20 mg each taken 12 h and 6 h before paclitaxel administration. For the sake of convenience, the premedication regimen has been modified with a single dose of dexamethasone administered intravenously 30–60 min before paclitaxel, omitting the oral doses. We assessed the rate of hypersensitivity reactions (HSRs) when a modified dexamethasone regimen was used. Materials and Methods: This was an observational prospective cohort study in patients receiving paclitaxel chemotherapy. We recorded demographics, prior history of allergy and comorbidities, diagnosis, chemotherapy regimen with schedule, details of HSRs, and details of rechallenge. Descriptive analysis and simple percentages were performed. Results: Between February 2011 and May 2011, 310 patients received 495 cycles of paclitaxel chemotherapy. The median age was 50 years, 77% of patients were female. Sixty-nine percent of patients had breast and gynecologic malignancies. Forty-four percent of patients were chemonaive. Sixty-eight percent of the paclitaxel cycles were once-in-3-week regimens; the remaining 32% were once a week. In all the paclitaxel cycles, a modified premedication regimen was administered. The dose of intravenous dexamethasone was 0 (n = 20), 8 mg (n = 210), 12 mg (n = 1), 16 mg (n = 56), and 20 mg (n = 163). The incidence of HSRs was 1.6%, with 1.2% incidence of severe hypersensitivity. No patient required hospitalization for the management of hypersensitivity. Three patients were rechallenged with paclitaxel after the development of hypersensitivity; all tolerated rechallenge without further infusion reactions. Conclusion: A modified dexamethasone premedication regimen is a safe and convenient option with a low risk of hypersensitivity.

Hypothyroidism post-chemoradiation on outcomes in head-and-neck cancer Vijay M Patil, Vanita Noronha, Amit Joshi, Tanmoy Kumar Mandal, Atanu Bhattacharjee, Alok Goel, Vikas Talreja, Arun Chandrasekharan, Nikhil Pande, Anant Ramaswamy, Kumar Prabhash Cancer Research, Statistics, and Treatment 2018 1(2):84-91 Background: Hypothyroidism is a known side effect of head-and-neck cancer treatment and might improve outcomes. However, whether the development of hypothyroidism or maintaining a hypothyroid state remains a factor is unclear. Methods: Once-a-week versus once-every-3-weeks cisplatin chemoradiation in locally advanced head and neck cancer was a Phase III open-label, noninferiority randomized study conducted by our group in the Medical Oncology Department of Tata Memorial Hospital, Mumbai, India. The database of this study was assessed for this analysis. Hypothyroidism was defined as a serum thyroid-stimulating hormone (TSH) level of above 5 uIU/ml. Duration of hypothyroidism was defined as cumulative duration in days postrandomization that the patient spent in hypothyroid state before progression. The relationship between duration of hypothyroidism (continuous variable) and peak TSH values and outcomes (locoregional failure [LRF] rate, progression-free survival [PFS], and overall survival [OS]) were analyzed. Results: Higher duration of time spent in a hypothyroid state had a favorable impact on PFS (HR: 0.996, 95% CI: 0.994–0.999, P = 0.007), and OS (HR: 0.995, 95% CI: 0.991–0.999, P = 0.016). This favorable impact on LRF (HR: 0.963, 95% CI: 0.929–0.997, P = 0.034), PFS (HR: 0.996, 95% CI: 0.993–0.999, P = 0.005), and OS (HR: 0.993, 95% CI: 0.987–0.999, P = 0.022) was confirmed on multivariate analysis too. Peak TSH value between 30 and 40 uIU/ml provided the maximum benefit for LRF with HR of 4.76 (standard error (SE) of HR as 0.627, P = 0.01). Conclusion: A longer duration and higher state of hypothyroidism (TSH – 30–40 Iu/ml) provided the maximum improvement in outcomes, this is an interesting hypothesis which needs to be confirmed with more studies.

Health-related quality of life in patients with multiple myeloma on novel agents: Report from a tertiary cancer center in rural India Vineetha Raghavan, Avaronnan Manuprasad, PB Sajeev Kumar, Zoheb Raj, Praveen Kumar Shenoy, Chandran K Nair Cancer Research, Statistics, and Treatment 2018 1(2):92-95 Background: Multiple myeloma is a disease where health-related quality of life (HRQoL) is an important treatment end point. There are limited quality of life data of patients on novel antimyeloma agents, especially from developing countries. Methods: All adult patients diagnosed with multiple myeloma who were on novel agents for a period of at least one year and attended our clinic between July 15, 2015 and July 30, 2015 were included in the study. They were asked to fill local language versions of European Organization for Research and Treatment of Cancer Questionnaire Core 30 (EORTC QLQ-C30), supplemented by the myeloma-specific module, and the outcomes were analyzed. Mean scores of the study population were compared with EORTC reference values. A higher score for a functional domain indicates a higher level of functioning, whereas a higher symptom score indicates a higher symptomatic burden. Results: Of the total 64 patients, median age was 60 years and 60% (n = 38) were females. Median duration from diagnosis was 23 months (12–92 months). Mean QoL score for global quality of life was 55.3 and was comparable to the reference score. Our patients had significantly lower physical function score and higher financial strain compared to the reference population. The most common symptom was pain (60%), and the most common adverse effect was peripheral neuropathy (60%). Sixty-five percent of the patients were worried about future health and 42% about dying. Conclusion: Our patients with multiple myeloma have lower HRQoL compared to the reference population in many domains, despite being on novel agents.

The enemy within J Barrett Cancer Research, Statistics, and Treatment 2018 1(2):96-97

Systemic treatment options in bladder cancer Rahul Ravind, Kumar Prabhash, Amit Joshi, Vijay Patil, Vanita Noronha Cancer Research, Statistics, and Treatment 2018 1(2):98-109 Since the 1980's, with the advent of MVAC (methotrexate, cisplatin, vinblastine, adriamycin) the role of chemotherapy for bladder cancer was defined. Since then, multiple chemotherapy regimens have been used and the field of chemotherapy has reached a therapeutic plateau. In the last decade, there have been recent updates in the systemic options used in bladder cancer. Early stage disease is managed with cystectomy. The role of neoadjuvant chemotherapy is well established and the trimodality approach for bladder preservation is widely being practiced worldwide. With the advent of immunotherapy, the survival pattern has changed in patients with metastatic disease, and still, more research work needs to be done. Here we aim to review all the latest trends in the systemic treatment options of bladder cancer.

Prevalence of tobacco use among school-going adolescents in India: A systematic review of the literature B Kumara Raja, V N Kavitha Devi Cancer Research, Statistics, and Treatment 2018 1(2):110-115 Individuals who initiate tobacco use during adolescence are likely to continue the use into adulthood, and this constitutes a major risk factor for premature death. The purpose of this study was to systematically review existing literature on the prevalence of tobacco use among school-going adolescents in India. Records were searched from the various databases such as PubMed, PubMed Central, Cochrane Library, Embase, and Google Scholar for studies published from 2000 to 2018. A total of 20 studies with a total population of 50, 390 were reviewed. The prevalence of tobacco smoking among school-going adolescents ranged from 5.9% to 49%. The common risk factor for tobacco usage among school-going adolescents was found to be peer pressure. Parents' smoking behavior, family conflict, stress, and curiosity were also found to be additional risk factors. The prevalence of tobacco usage among school-going adolescents was found to be high. These findings emphasize the need for formulating strict tobacco control policies at school premises.

Modified dose dexamethasone premedication for paclitaxel use Sharada Mailankody Cancer Research, Statistics, and Treatment 2018 1(2):116-117

Treatment-induced hypothyroidism in head-and-neck cancer – Is it a crystal ball? Tarun Puri Cancer Research, Statistics, and Treatment 2018 1(2):118-120

Current treatment landscape and emerging management options for extremity sarcoma Siddharth Turkar Cancer Research, Statistics, and Treatment 2018 1(2):121-138 Malignant tumors of extremity are mostly of mesenchymal origin and arise from bone or extraskeletal soft tissue. Combination chemotherapy has greatly increased the survival of non-metastatic localized osteosarcoma and Ewing's sarcoma; however, there is conflicting evidence regarding the role of neoadjuvant and adjuvant chemotherapy in soft tissue sarcoma due to the rarity and heterogeneous population. Despite intensive multimodal therapy and valiant efforts, most of the patients with relapsed and metastatic sarcoma will succumb to their disease. Molecular studies like next-generation sequencing have revealed various targetable biomarkers which can be further explored in the therapeutic landscape with specific targeted therapies. We reviewed all ongoing and completed clinical trials involving chemotherapy, targeted therapy, and immunotherapy valid for patients with extremity sarcoma. We present the current viable therapeutic options for such a cohort of patients in routine clinical practice.

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

Cancer Genetics

FANCM, RAD1, CHEK1 and TP53I3 act as BRCA-like tumor suppressors and are mutated in hereditary ovarian cancer Publication date: Available online 9 May 2019 Source: Cancer Genetics Author(s): Jaime L. Lopes, Sophia Chaudhry, Guilherme S. Lopes, Nancy K. Levin, Michael A. Tainsky Abstract Although 25% of ovarian cancer cases are due to inherited factors, most of the genetic risk remains unexplained. We previously identified candidate genes through germline whole exome sequencing of BRCA1/BRCA2negative ovarian cancer patients with familial risk. Here, we performed functional assessment to determine whether they act as BRCA-like tumor suppressors. Seven candidate risk genes were targeted by siRNA for mRNA depletion followed by functional assays for clonogenic survival, cytotoxicity to DNA damaging agents, and involvement in homologous recombination repair. BRCA1 and BRCA1 were targeted as standards for loss of function outcome. Knockdown of various candidate genes led to tumor suppressor phenotypes also observed in BRCA1/BRCA2 deficient cells. Deficiency of CHEK1, FANCM and TP53I3 led to reduced homologous recombination repair efficiency. Knockdown of RAD1, CHEK1 or FANCM led to a decrease in cellular viability and cells deficient in CHEK1, RAD1 or TP53I3 displayed increased sensitivity to cisplatin. Functional studies of candidate genes identified by whole exome sequencing complements bioinformatics techniques and aid the implication of novel risk loci. The results of this study suggest that genes found mutated in hereditary ovarian cancer, FANCM, RAD1, CHEK1 and TP53I3, act as BRCA-like tumor suppressors.

Somatic mutation panels: Time to clear their names Publication date: Available online 26 April 2019 Source: Cancer Genetics Author(s): Amy M. Trottier, Marcela Cavalcante de Andrade Silva, Zejuan Li, Lucy A. Godley Abstract With improvements in DNA sequencing technologies and the consequent reduction in costs, next generation sequencing is being utilized increasingly in panel-based testing to perform molecular profiling of tumors. Such tumor-based panels are often referred to as 'somatic' panels, but this term is misleading and should not be used, since not all DNA variants within a tumor are somatic in nature. Every cell in a person's body contains that person's germline DNA, including tumor cells. Moreover, tumor samples are invariably contaminated with blood, a tissue that can contain somatic mutations itself in a process now called clonal hematopoiesis. Differentiating between germline variants or tumor-associated somatic mutations versus clonal hematopoiesis can be challenging. In this review, we address how to interpret the results of somatic mutation panels, how to differentiate between germline and truly somatic events, and discuss the importance of this distinction.

Outcomes of disease-specific next-generation sequencing gene panel testing in adolescents and young adults with colorectal cancer Publication date: Available online 26 April 2019 Source: Cancer Genetics Author(s): Maureen E. Mork, Andrea Rodriguez, Sarah A. Bannon, Patrick M. Lynch, Miguel A. Rodriguez-Bigas, Selvi Thirumurthi, Y. Nancy You, Eduardo Vilar Abstract Purpose Adolescents and young adults with colorectal cancer (CRC) have attracted recent attention, with a hereditary syndrome identified in one-third of patients diagnosed ≤ 35. We aimed to study this population to determine if a CRC-specific gene panel increased the yield of testing. Methods Patients with CRC ≤ 35 evaluated from 05/2014–11/2017 were identified from the genetic counseling database. Records were reviewed for personal/family history and genetic counseling outcomes. Results One hundred forty-three patients with CRC ≤ 35 were included. One hundred four (72.7%) underwent CRC panel testing. Thirty-nine (27.2%) had syndrome-directed testing, declined, or were lost to follow-up. Forty-two patients had a genetic syndrome (29.4%). Twenty-four of the 42 hereditary patients (57.1%) were identified via syndrome-directed testing. Mutations identified via panel testing were consistent with patient personal/family history. Thirty-three patients had at least one variant of uncertain significance. Conclusion Hereditary syndromes were identified in 29.4% of patients. Panel testing in patients without a phenotype did not increase diagnostic yield, but identified variants in one-third. Disease-specific panel testing is of low yield in young patients without a suggestive personal/family history. Testing broader panels may increase the yield of mutation pick-up in this population, although at the expense of identifying variants.

Uptake of genetic testing for germline BRCA1/2 pathogenic variants in a predominantly Hispanic population Publication date: Available online 24 April 2019 Source: Cancer Genetics Author(s): Julia E. McGuinness, Meghna S. Trivedi, Thomas Silverman, Awilda Marte, Jennie Mata, Rita Kukafka, Katherine D. Crew Abstract Genetic counseling is under-utilized in women who meet family history criteria for BRCA1 and BRCA2 (BRCA1/2) testing, particularly among racial/ethnic minorities. We evaluated the uptake of BRCA1/2 genetic testing among women presenting for screening mammography in a predominantly Hispanic, low-income population of Washington Heights in New York City. We administered the Six-Point Scale (SPS) to women presenting for screening mammography at Columbia University Irving Medical Center (CUIMC) in the Washington Heights neighborhood of New York, NY. The SPS is a family history screener to determine eligibility for BRCA1/2 genetic testing based upon U.S. Preventive Services Task Force (USPSTF) guidelines that has been validated in low-income, multiethnic populations. Among women who underwent screening mammography at CUIMC between November 2014 and June 2016, 3,055 completed the SPS family history screener. Participants were predominantly Hispanic (76.7%), and 12% met family history criteria for BRCA1/2 testing, of whom <5% had previously undergone testing. In a multiethnic population, a significant proportion met family history criteria for BRCA1/2 testing, but uptake of genetic testing was low. Such underutilization of BRCA1/2 genetic testing among minorities further underscores the need to develop programs to engage high-risk women from underrepresented populations in genetic testing services.

Retrotransposon elements among initial sites of hepatitis B virus integration into human genome in the HepG2-NTCP cell infection model Publication date: Available online 24 April 2019 Source: Cancer Genetics Author(s): Ranjit Chauhan, Yoshimi Shimizu, Koichi Watashi, Takaji Wakita, Masayoshi Fukasawa, Tomasz I Michalak Abstract Integration of hepatitis B virus (HBV) DNA into host's genome is evident in all stages and models of HBV infection. Investigations of the initial virus-host junctions have been just recently initiated since their nature may promote liver oncogenesis immediately following infection. We examined the time-frame and host sites at which HBV integrates in HepG2 cells overexpressing sodium taurocholate co-transporting polypeptide (NTCP) receptor mediating HBV entry. HepG2-NTCP cells were analyzed from 15 min to 13 days post-infection (p.i.). The results showed that except for 15 min p.i., HBV-host integrations were detected at all time points thereafter. At 30 min p.i., virus junctions with retrotransposon SINE and with neuroblastoma breakpoint family member 1 gene were detected. At one-hour p.i., HBV integration with retrotransposon THE-1B-LTR was identified, while virus insertions into proline-rich protein and protein kinase cGMP-dependent type 1 encoding genes were found at 3 h p.i. Fusion with runt-related transcription factor 1 was detected at 24 h p.i. and merges with 9 different genes at 13 day p.i. The data showed that retrotransposon elements are frequent among first-hit sites of HBV insertion. This may suggest a mechanism by which HBV DNA may spread across host's genome from earliest stages of infection.

Circulating cell-free DNA integrity as a diagnostic and prognostic marker for breast and prostate cancers Publication date: Available online 23 April 2019 Source: Cancer Genetics Author(s): Benjamin Arko-Boham, Nii Ayite Aryee, Richard Michael Blay, Ewurama Dedea Ampadu Owusu, Emmanuel Ayitey Tagoe, Eshirow-Sam Doris Shackie, Ama Boatemaa Debrah, Nii Armah Adu-Aryee Abstract Background Cancer incidence and its related mortality is rising and is currently the second leading cause of death globally. In Africa, breast and prostate cancer in females and males, respectively, are the worst globally. However, biomarkers for their early detection and prognosis are not well developed. This study sought to investigate circulating cell-free DNA (ccfDNA) integrity and its potential utility as diagnostic and/or prognostic biomarker. Circulating cell-free DNA (ccfDNA) is degraded DNA fragments released into the blood plasma. In healthy individuals, the source of ccfDNA is solely apoptosis, producing evenly sized shorter DNA fragments. In cancer patients, however, necrosis produces uneven longer cell-free DNA fragments in addition to the shorter fragments originating from apoptosis. DNA integrity, expressed as the ratio of longer fragments to total DNA, may be clinically useful for the detection of breast and prostate cancer progression. Methods Sixty-four (64) females, consisting of 32 breast cancer patients and 32 controls, and 61 males (31 prostate cancer patients and 30 controls) were included in the study. Each participant donated 5 ml peripheral blood from which sera were separated. Real-time qPCR was performed on the sera to quantify ALU 115 and 247 levels, and DNA integrity (ALU247/ALU115) determined. Results & Conclusion ALU species 115 and 247 levels in serum were elevated in breast and prostate cancer patients compared to their counterpart healthy controls. DNA integrity was higher in prostate cancer patients than in the control, but in breast cancer patients was lower compared to their controls. In prostate but not in breast cancers, DNA integrity increased with disease severity and higher staging.

Prevalence and characteristics of likely-somatic variants in cancer susceptibility genes among individuals who had hereditary pan-cancer panel testing Publication date: Available online 13 April 2019 Source: Cancer Genetics Author(s): Thomas P. Slavin, Bradford Coffee, Ryan Bernhisel, Jennifer Logan, Hannah C. Cox, Guido Marcucci, Jeffrey Weitzel, Susan L. Neuhausen, Debora Mancini-DiNardo Abstract Next-generation sequencing (NGS) hereditary pan-cancer panel testing can identify somatic variants, which exhibit lower allele frequencies than do germline variants and may confound hereditary cancer predisposition testing. This analysis examined the prevalence and characteristics of likely-somatic variants among 348,543 individuals tested using a clinical NGS hereditary pan-cancer panel. Variants showing allele frequencies between 10% and 30% were interpreted as likely somatic and identified in 753 (0.22%) individuals. They were most frequent in TP53, CHEK2 and ATM, commonly as C-to-T transitions. Among individuals who carried a likely-somatic variant and reported no personal cancer history, 54.2% (78/144) carried a variant in TP53, CHEK2 or ATM. With a reported cancer history, this percentage increased to 81.1% (494/609), predominantly in CHEK2and TP53. Their presence was associated with age (OR=3.1, 95% CI 2.5, 3.7; p<0.001) and personal history of cancer (OR=3.3, 95% CI 2.7, 4.0; p<0.001), particularly ovarian cancer. Germline ATM pathogenic variant carriers showed significant enrichment of likely-somatic variants (OR=2.8, 95% CI 1.6, 4.9; p = 0.005), regardless of cancer status. The appearance of likely-somatic variants is consistent with clonal hematopoiesis, possibly influenced by cancer treatment. These findings highlight the precision required of diagnostic laboratories to deliver accurate germline testing results.

A comparison of survival analysis methods for cancer gene expression RNA-Sequencing data Publication date: Available online 12 April 2019 Source: Cancer Genetics Author(s): Pichai Raman, Samuel Zimmerman, Komal S. Rathi, Laurence de Torrenté, Mahdi Sarmady, Chao Wu, Jeremy Leipzig, Deanne M. Taylor, Aydin Tozeren, Jessica C. Mar Abstract Identifying genetic biomarkers of patient survival remains a major goal of large-scale cancer profiling studies. Using gene expression data to predict the outcome of a patient's tumor makes biomarker discovery a compelling tool for improving patient care. As genomic technologies expand, multiple data types may serve as informative biomarkers, and bioinformatic strategies have evolved around these different applications. For categorical variables such as a gene's mutation status, biomarker identification to predict survival time is straightforward. However, for continuous variables like gene expression, the available methods generate highly-variable results, and studies on best practices are lacking. We investigated the performance of eight methods that deal specifically with continuous data. K-means, Cox regression, concordance index, D-index, 25th-75th percentile split, median-split, distribution-based splitting, and KaplanScan were applied to four RNA-sequencing (RNA-seq) datasets from the Cancer Genome Atlas. The reliability of the eight methods was assessed by splitting each dataset into two groups and comparing the overlap of results. Gene sets that had been identified from the literature for a specific tumor type served as positive controls to assess the accuracy of each biomarker using receiver operating characteristic (ROC) curves. Artificial RNA-Seq data were generated to test the robustness of these methods under fixed levels of gene expression noise. Our results show that methods based on dichotomizing tend to have consistently poor performance while C-index, D-index and k-means perform well in most settings. Overall, the Cox regression method had the strongest performance based on tests of accuracy, reliability, and robustness.

Prognostic significance of CDC25C in lung adenocarcinoma: An analysis of TCGA data Publication date: April 2019 Source: Cancer Genetics, Volumes 233–234 Author(s): Zengfei Xia, Wen Ou-yang, Ting Hu, Ketao Du Abstract Objective Cell division cycle 25C (CDC25C) is involved in the regulation of the G2/M phase transition and is associated with various cancers, including non-small cell lung cancer. We evaluated its prognostic value in lung adenocarcinoma (LUAD) based on data from The Cancer Genome Atlas (TCGA). Methods Kruskal–Wallis test, Wilcoxon signed-rank test, and logistic regression were used to evaluate relationships between clinical-pathologic features and CDC25C expression. Cox regression analyses and the Kaplan–Meier method were used to evaluate factors contributing to prognosis. Gene set enrichment analysis (GSEA) was performed. Results High CDC25C expression in LUAD was associated with a high tumor extent (odds ratio (OR) = 2.23 (1.52–3.29), P < 0.001), regional lymph node invasion (OR = 2.18 (1.48–3.22), P < 0.001), OR = advanced stage (OR = 2.47 (1.72–3.59), P < 0.001), and poor status (OR = 1.87 (1.19–2.96), P = 0.007). A univariate analysis showed that high CDC25C expression is associated with a short overall survival (OS) (HR: 1.873; 95% CI: 1.385–2.535; P < 0.001) and poor progression-free survival (HR: 1.503; 95% CI: 1.173–1.926; P = 0.0012). In a multivariate analysis, high CDC25C expression was associated with poor OS (HR = 2.193; CI: 1.394–3.452, P = 0.001). GSEA showed the enrichment of cell cycle, apoptosis, p53-dependent G1 DNA damage response, S-phase, mitotic M-M G1 phases, and FA-mediated cell death in the CDC25C high-expression phenotype. Conclusions CDC25C predicts poor prognosis in LUAD and may function in cell cycle regulation and FAS-mediated apoptosis.

Aberrant methylation status of SPG20 promoter in hepatocellular carcinoma: A potential tumor metastasis biomarker Publication date: April 2019 Source: Cancer Genetics, Volumes 233–234 Author(s): Lifeng He, Xiaoxiao Fan, Yirun Li, Bin Cui, Zhaoqi Shi, Daizhan Zhou, Hui Lin Abstract Purpose The aim of this study is to analyze the methylation levels of SPG20 promotor region and explore the association between the methylation levels and clinical features in hepatocellular carcinoma (HCC). Materials and methods We collected paired of HCC and adjacent non-cancerous tissues (ANT) from 160 HCC patients and analyze the methylation levels through MassARRAY Analyzer 4. The statistical calculations were performed using SPSS version 22.0. Real-time-quantification PCR was performed to assess expression levels of SPG20 in HCC cell lines. Wound healing assay and transwell assay was used to measure cell migration capacity. Result We found that mean methylation level of SPG20 in tumor tissues was significantly higher than that in ANT (7.3% vs. 16.2%, P<0.0013). There was a significantly negative correlation between expression level and methylation level of SPG20 (P<0.01). In addition, the methylation levels in HCC were correlated with age and HBV infection. Meanwhile, micro-satellite tumors (P = 0.016) and tumor number (P = 0.018) was found significantly associated with increased methylation levels of several CpG sites and the mean levels of SPG20 promotor in ANT. In addtion, the capacity of cell migration was significantly enhanced in SPG20 knock-down HCC cells. Conclusion The hypermethylation status of SPG20 gene promoter is significantly associated with intra-hepatic metastasis and contribute to HCC metastasis.

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

Oral Oncology

A new CT dynamic maneuver "Mouth Opened with Tongue Extended" can improve the clinical TNM staging of oral cavity and oropharynx squamous cell carcinomas Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Guillaume Bron, Ugo Scemama, Virginie Villes, Nicolas Fakhry, Sebastien Salas, Christophe Chagnaud, David Bendahan, Arthur Varoquaux Abstract Objectives Cross sectional imaging is mandatory for oral cavity and oropharynx head and neck squamous cell carcinoma's (ooSCC) local extension and TNM staging. However a complex anatomy and frequent dental metallic artifacts make it difficult. This study assesses the clinical benefit of "Mouth Open with Tongue Extended" dynamic maneuver at CT (CTmote) as compared to the conventional CT (CTconv) and MRI. Material Retrospectively, 58 patients with histologically proven ooSCC (oral cavity: 34; oropharynx: 24) were included in the study. All had endoscopy with biopsies, MRI, CTconv and an CTmote acquisitions. Data were splitted in 3 datasets and 2 independent radiologists performed readings blindly. Gold standard was pTNM in 31% of cases; otherwise cTNM obtained at multidisciplinary team meeting with endoscopy and mapping biopsies were used. Results CTmote was feasible for all patients including those already treated by surgery or radiotherapy. Exact TNM staging was obtained in 68%, 83%, 83% for CTconv, CTmote and MRI respectively. The best exam ratings at paired wise comparisons were 3%, 47%, 50% for CTconv, CTmote and MRI respectively. CTmote and MRI observer agreements, image quality and confidence ratings, were comparable and higher compared to CTconv (p < 0.001). Conclusions CTmote improves oral cavity and oropharynx tumour stage assessment compared to CTconv with performances close to those of MRI examination. In clinical practice, combining both CT with MOTE maneuver and MRI seems to be the optimal imaging strategy for local staging. Graphical abstract

Comparisons of clinical and functional outcomes of different reconstructive methods for the hypopharyngeal defect Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Song I. Park, Sung Yong Choi, Chung-Hwan Baek, Young-Ik Son, Han-Sin Jeong, Man Ki Chung Abstract Background To compare clinical and functional outcomes of different reconstructive options for a hypopharyngeal defect after head and neck cancer surgery. Methods We retrospectively analyzed 127 cases who had undergone hypopharyngeal reconstruction, as either pedicled (25 cases), fasciocutaneous free flap (FCFF) (41 cases) or visceral flap (61 cases). Results Overall incidence of flap compromise was 10.2% (13 cases), and there were no statistically significant factors associated with flap compromise. Fistula or stenosis occurred in 36.2% (46 patients) and 23.6% (30 patients), respectively. Salvage surgery increased the risk of fistula formation (OR 2.93, 95% CI 1.32–6.52, p < 0.01), whereas FCFF showed a protective effect for stenosis, compared to pedicled flap (OR 0.09, 95% CI 0.01–0.47, p < 0.01). Conclusion Outcomes of hypopharynx reconstruction can be successful if different flap options are used appropriately according to the type of defect and previous treatment history of the patient.

Novel application of the Clavien-Dindo classification system and the comprehensive complications index® in microvascular free tissue transfer to the head and neck Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Julian Jakob Ebner, Tarun Mehra, Thomas Gander, Paul Schumann, Harald Essig, Daniel Zweifel, Martin Rücker, Ksenjia Slankamenac, Martin Lanzer

The high stakes of head and neck surgery following radiation and chemotherapy – An assessment of complications and survival Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Ramez Philips, Nolan Seim, Anna Marcinow, James Rocco, Amit Agrawal, Enver Ozer, Ricardo Carrau, Stephen Kang, Matthew Old Abstract Objectives To investigate variables that predict medical and surgical complications in patients undergoing salvage surgery after primary organ-preserving therapy for head and neck cancer and to investigate the effect of complications on 5-year overall survival. Materials and methods A retrospective study was conducted on patients undergoing salvage surgery after primary organ-preserving therapy for head and neck cancer at a tertiary institution from 2006 to 2011. Multivariable regression analysis was used to assess association between independent variables and medical and surgical complications. A Kaplan-Meier survival curve was plotted to assess effect of surgical and medical complications on 5-year overall survival. Results One hundred thirty-six patients undergoing salvage surgery after primary organ-preservation surgery met inclusion criteria. Surgical complications occurred in 68/136 (50.0%) of patients. After adjusting for confounders, young age and history of hypothyroidism were significant predictors of surgical complications (p < 0.05). Medical complications occurred in 37/136 (27.2%) of patients. After adjusting for confounders, older age and history of hepatic disease were significant predictors of having a medical complication (p < 0.05). Patients with no complications had better overall survival than patients with medical complications (p = 0.009). There was no difference in overall survival between patients without complications and patients with surgical complications only (p = 0.259). Conclusion Risk factors for medical and surgical complications include history of hypothyroidism, liver disease, and age. Survival outcomes are not affected by surgical complications but are significantly affected by medical complications highlighting the importance of personalized patient care and medical co-management.

Time to recurrence and patient survival in recurrent oral squamous cell carcinoma Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Annelies Weckx, Maximilian Riekert, Andrea Grandoch, Volker Schick, Joachim E. Zöller, Matthias Kreppel Abstract Objectives Tumour relapse remains one of the major problems in managing oral squamous cell carcinoma (OSCC) with mortality rates of up to 92%. Early recurrences have a worse prognosis than late relapses. However, few has been written about the influence of clinicopathological parameters on the timing of recurrence and the patient survival. Materials and methods Retrospective chart review of 159 patients with an OSCC recurrent disease. Exclusion criteria were neoadjuvant chemoradiotherapy, follow-up <6 weeks, perioperative death, second primaries and inadequate information on clinicopathological parameters. Statistical analysis was performed using univariate and multivariate analysis. Results A significant correlation was found in the χ2-analysis between the timing of recurrence and the margin status (p = 0.020), lymph node ratio (p = 0.030) and grading (p = 0.003) of the primary tumour. In the multivariate survival analysis, the timing of recurrence (p < 0.001), margin status of the primary tumour (p = 0.023), presence of extracapsular spread in the primary tumour (p = 0.003) and performance of a salvage treatment (p < 0.001) were shown to be independent risk factors for overall survival. Conclusion For patients with a recurrent OSCC, the time to recurrence, margin status, extracapsular spread and the performance of a salvage treatment are independent prognostic factors for overall survival. Furthermore, a significant association exists between the moment of recurrence and the lymph node ratio, the margin status and grading of the primary tumour. This knowledge can allow for the development of individualised surveillance programs and like this, an earlier diagnosis and better second treatment chance in the case of a recurrence.

Upfront PET/CT affects management decisions in patients with recurrent head and neck squamous cell carcinoma Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Max Rohde, Anne L. Nielsen, Jørgen Johansen, Jens A. Sørensen, Anabel Diaz, Manan Pareek, Jon T. Asmussen, Oke Gerke, Anders Thomassen, Niels Gyldenkerne, Helle Døssing, Kristine Bjørndal, Poul Flemming Høilund-Carlsen, Christian Godballe Abstract Purpose To compare multidisciplinary team conference (MDTC) decisions regarding treatment intent based on either chest X-ray + MRI of the head and neck (CXR/MRI) or 18F-FDG-PET/CT (PET/CT) in patients with recurrent head and neck squamous cell carcinoma (HNSCC). Methods Prospective blinded cohort study based on paired data. Consecutive patients with suspected recurrent HNSCC were invited to participate. All included patients underwent CXR/MRI and PET/CT before diagnostic biopsy. An ordinary MDTC using all available imaging data was conducted as per standard practice. After at least three months (to eliminate recall bias in the team), the first project MDTC, based on either CXR/MRI or PET/CT, was conducted, and the tumor board made conclusions regarding treatment. After an additional three months, a second project MDTC was conducted using the complementary imaging strategy. The separate treatment strategies were compared using McNemar's test. Results A total of 110 patients (90 males and 20 females, median age 66 years, range 40–87) were included. The initial primary tumor originated from the pharynx in 56 (51%) patients, oral cavity in 17 (15%) patients, and larynx in 37 (34%) patients. Based on CXR/MRI, 87 patients (79%) were recommended curative treatment and 23 (21%) palliative treatment. Based on PET/CT, the MDTC decided that 52 (47%) patients were suitable for curative treatment and 58 (53%) for palliative treatment. The absolute difference of 32% was statistically significant (95% CI: 22–42%, p < 0.001). Conclusions PET/CT affected MDTC decisions in patients with recurrent HNSCC towards less curative and more palliative treatment.

Gender disparities in head and neck cancer chemotherapy clinical trials participation and treatment Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Liliya Benchetrit, Sina J. Torabi, Janet P. Tate, Saral Mehra, Heather A. Osborn, Melissa R. Young, Barbara Burtness, Benjamin L. Judson Abstract Objectives To characterize the representation of women in clinical trials directing the National Comprehensive Cancer Network (NCCN) guidelines for chemotherapy use in head and neck squamous cell carcinoma (HNSCC), as well as the relationship between gender and chemotherapy administration in the definitive treatment of HNSCC in the United States. Methods A review of all HNSCC chemotherapy clinical trials cited by the 2018 NCCN guidelines was performed. Sex-based proportions were compared with the corresponding proportions in the general U.S. population of patients with HNSCC between 1985 and 2015, derived from the Surveillance, Epidemiology, and End Results (SEER) program. A second analysis using the National Cancer Database (NCDB), identified 63,544 adult patients diagnosed with stages III-IVB HNSCC between 2004 and 2014 and treated with definitive radiotherapy or chemoradiotherapy. Univariable and multivariable logistic regression analyses were used to identify predictors of chemotherapy administration. Results While women comprised 26.2% of U.S. patients with HNSCC between 1985 and 2015, they comprised only 17.0% of patients analyzed in U.S. NCCN-cited chemotherapy clinical trials between 1985 and 2017. On multivariable analysis, women had decreased odds of receiving chemotherapy (Odds Ratio [OR]: 0.875; 95% Confidence Interval [CI]: 0.821–0.931; p < 0.001). Conclusion Women are underrepresented in HNSCC chemotherapy clinical trials cited by the national guidelines. Additionally, women are less likely than men to receive definitive chemoradiotherapy as oppose to definitive radiotherapy. Reasons for these disparities warrant further investigation as well as re-evaluation of eligibility criteria and enrollment strategies, in order to improve relevance of clinical trials to women with HNSCC.

Corrigendum to "Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma" [Oral Oncol. 86 (2018) 278–287] Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): D.J. Hartman, F.S. Ahmed, R.L. Ferris, D.L. Rimm, L. Pantanowitz

Concurrent oropharyngeal squamous cell carcinomas in couples Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): Prashanth Panta, Mukund Seshadri

Human papillomavirus (HPV) vaccine and HPV-related head and neck cancer: What's next? Publication date: June 2019 Source: Oral Oncology, Volume 93 Author(s): F. De Felice, A. Polimeni, V. Tombolini

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

Bronchology

Leptin as a local inflammatory marker in chronic obstructive pulmonary disease acute exacerbation Hossam H Masoud, Ahmed M Abd El-Hafeez, Mohamed S Ismail, Naef G Baharetha Egyptian Journal of Bronchology 2019 13(2):139-147 Background Chronic obstructive pulmonary disease (COPD) is a disease of chronic inflammation affecting the lungs. Leptin is a pleiotropic cytokine thought to play a role in host inflammatory response. Aim This study aimed to investigate the role of leptin in sputum and serum as an inflammatory marker in acute exacerbation of COPD (AECOPD). Patients and methods Twenty patients with stable COPD, 20 patients with AECOPD, and 12 controls were included in this study. All participants were males. BMI, routine laboratory investigations, sputum and serum leptin levels, serum tumor necrosis factor (TNF-α), and C-reactive protein (CRP) levels were measured twice in patients with AECOPD (initially and after 7 days of management) and only once in stable patients and controls. Results In patients with patients with AECOPD, there were significant differences between sputum leptin and serum TNF-α, CRP, and leptin levels before and after treatment. Sputum leptin and serum CRP levels were significantly higher in the AECOPD group than other groups. Additionally, serum TNF-α levels were significantly higher in patients with AECOPD than the controls. Insignificant correlation was found between AECOPD and stable groups regarding serum leptin and TNF-α levels. Conclusion The present study highlights the role of leptin hormone as a local inflammatory marker in COPD acute exacerbation either in the sputum or the serum, together with serum TNF-α and CRP. These markers could be useful indicators of COPD acute exacerbation and its response to treatment.

Metabolic syndrome; frequency and its relationship with variable parameters in chronic obstructive pulmonary disease Azza Farag Said El-toney, Bahaa Ibrahim Mohamed, Emad Allam Abd-Elnaeem, Alaa Shaban Ismail Egyptian Journal of Bronchology 2019 13(2):148-154 Background Chronic obstructive pulmonary disease (COPD) has many extrapulmonary comorbidities, and metabolic syndrome (MetS) is one of them. Scant data are available on MetS in Egyptian patients with COPD. Objective The purpose of the current research was to determine the frequency and clinical characteristics of MetS among Egyptian patients with stable COPD. Patients and methods A prospective study including 70 (64 males and six females) patients with stable COPD was conducted. Clinical assessment, pulmonary function, and other laboratory studies were performed. Results MetS was present in 31 patients with COPD (44.3%). BMI and high-sensitivity C-reactive protein were significantly higher in patients with COPD with MetS than those without MetS (P=0.02 and 0.01, respectively). Age of the patients, duration of COPD, grade of dyspnea, and pulmonary function tests had no significant difference between those with MetS versus those without it. There was a significant negative correlation between plasma triglyceride level, as the only one of the variables of MetS, and some of parameters of pulmonary function test. Conclusion MetS is relatively frequent among patients with COPD. Plasma triglyceride level is the only parameter of MetS to have a significant correlation with pulmonary function tests. Apart from BMI and high-sensitivity C-reactive protein, no other parameter among patients with COPD has a significant relationship with MetS.

The role of medical thoracoscopic lung biopsy in diagnosis of diffuse parenchymal lung diseases Magdy M Omar, Ahmad S Alhalafawy, Nashwa M Emara, Mohammad A.E El-Mahdy, Etemad Abdelsalam Egyptian Journal of Bronchology 2019 13(2):155-161 Background Interstitial lung disease in the immunocompetent patient is often a difficult challenge for the clinician, especially when no diagnostic clues are present. A clear diagnosis confirmed by biopsy allows clinicians and patients to discuss fully the implications of the disease. Aim The aim was to evaluate the role of medical thoracoscopic lung biopsy in diagnosis of patients with diffuse parenchymal lung diseases. Patients and methods The study included 15 patients with diffuse parenchymal lung diseases of unknown etiology. They had undergone full history taking, complete clinical examination, ventilatory function tests (spirometry), arterial blood gases analysis, high-resolution computed tomography chest, coagulation profile, platelet count, collagen profile, and thoracoscopic lung biopsy by medical thoracoscopy for histopathologic examination. Follow-up of the patients in the inpatient unit was done by chest radiography and clinical evaluation. Results The pathological diagnosis of cases was six (40%) patients with extrinsic allergic alveolitis, five (33.3%) patients with malignancy, three patients with idiopathic interstitial pneumonias, one (6.7%) patient with tuberculosis, and one (6.7%) patient with sarcoidosis. Regarding complications, one (6.7%) patient had pneumothorax after intercostal tube (ICT) removal, and three (20%) patients had subcutaneous emphysema. The duration of the ICT drainage was 3.1±2.6 days. There was no wound infection, no bleeding, no persistent air leak after more than 24 h (Hs) from ICT insertion, no respiratory failure requiring ICU admission, and no mortality in the study sample. Conclusion Thoracoscopic lung biopsy by medical thoracoscopy is useful in diagnosis of cases with diffuse parenchymal lung diseases of unknown etiology when lung biopsy is needed for accurate diagnosis. The procedure is safe. The procedure carries some complications that are not life threatening and can be minimized by good selection of patients.

Thoracoscopic pleural cryobiopsy versus conventional forceps biopsy in diagnosis of exudative pleural effusion of unknown etiology Randa S.E Muhammad, Sabah A.M Hussein, Mohammad F Mohammad, Marwa M Ahmed, Gehad A Ali Egyptian Journal of Bronchology 2019 13(2):162-169 Background Rigid forceps is commonly used for pleural biopsies during medical thoracoscopy in undiagnosed pleural effusion, and recently, the use of cryoprobe for pleural biopsies was encouraged, as the procedure is effective and safe. Objective This study compared between rigid forceps and cryoprobe pleural biopsies regarding biopsy characteristics, diagnostic yield, and tissue viability in patients with undiagnosed exudative pleural effusion who underwent medical thoracoscopy. Patients and methods A total of 30 patients with undiagnosed exudative pleural effusion were selected for medical thoracoscopy, and pleural biopsies were taken by rigid forceps and cryoprobe in the same setting. All biopsies were processed for histopathology examination. Results Of the 30 patients, 18 (60%) were males and 12 (40%) were females, with mean age of 51.03 years. The most frequent diagnosis was mesothelioma (43.3%) followed by chronic nonspecific inflammation (23.3%), metastatic carcinoma (16.6%) and tuberculosis (16.6%). Biopsies of rigid forceps (mean: 0.8193 cm2) were larger than cryoprobe (mean: 0.3377 cm2) but with less depth. Tissue viability of cryoprobe biopsies was better than rigid forceps biopsies, and the diagnostic yield of both techniques was the same. Conclusion Cryobiopsies obtained during medical thoracoscopy is technically feasible and safe with high diagnostic value. Biopsies of cryoprobe were smaller than that of rigid forceps but were deeper and with better preserved cellular architecture. These results will encourage the use of cryotechnique for diagnosis of undiagnosed exudative pleural effusion.

Assessment of gradient between partial pressure of arterial carbon dioxide and end-tidal carbon dioxide in acute respiratory distress syndrome Fatmaalzahraa S Abdalrazik, Mohamed O Elghonemi Egyptian Journal of Bronchology 2019 13(2):170-175 Context End-tidal carbon dioxide (EtCO2) is used as a noninvasive bedside test to assess the adequacy of ventilation and physiologic dead space in mechanically ventilated patients. The gradient difference between EtCO2 and partial pressure of arterial carbon dioxide (PaCO2) is directly related to an increase in the physiologic dead space. Aim The aim of this study was to evaluate the role of measuring the gradient between EtCO2 and PaCO2 in adults with acute respiratory distress (ARDS). Settings and design This was a prospective consecutive enrollment study. Patients and methods Overall, 51 cases were recruited after the diagnosis of ARDS was made according to the Berlin definition. Patients were mechanically ventilated as per the lung-protective protocol. Daily arterial blood gases were collected and for every sample, the EtCO2 value was collected electronically by capnography using an endotracheal tube for the first 5 days. Results Cases were classified into survivors and nonsurvivors: 26 cases were because of extrapulmonary causes and 25 cases were because of pulmonary causes. The mean value of the APACHE II score for all cases on admission was 21.6. The mean length of ICU stay was 12.7 days. For all study cases, PaO2/FiO2 was the lowest at day 1 and the highest at day 5. We found a significant negative correlation between PaO2/FiO2 and the gradient at days 2, 4, and day 5, and a significant positive correlation between the gradient on admission and the APACHE II score (r=0.4, P≤0.05). Nonsurvivors had a significantly higher gradient and lower EtCO2 and PaO2/FiO2 levels at all time intervals, whereas PaCO2 alone was found to be nonsignificant. Conclusion In ARDS, EtCO2 and gradient are reliable indicators of severity.

Postintensive care syndrome in mechanically ventilated patients secondary to respiratory disorders Mohammed A Agha, Mahmoud M El-Habashy, Mohammed S Abdelshafy Egyptian Journal of Bronchology 2019 13(2):176-183 Background Patients admitted to ICU, especially those who are mechanically ventilated, are under the effects of many clinical, therapeutic, and emotional stress factors that usually lead to different physical, psychological, and cognitive disabilities. These acquired disabilities are called postintensive care syndrome (PICS). Objective the aim was to detect any component of PICS in mechanically ventilated patients at respiratory ICU (RICU) after being discharged from ICU. Patients and methods All recruited patients were assessed at three time points: first during admission to RICU, where all clinical and laboratory data were recorded; second following discharge from RICU, and third following 1 month of discharge from hospital. During the second and third points, cognitive, psychological, and physical components of PICS were assessed. Results A total of 20 (50%) patients developed one or more component of PICS. There were highly significant differences between patients with and without PICS regarding age, duration of mechanical ventilation, duration of ICU admission, level PaO2, acute physiology and chronic health evaluation (APACHE) IV score, the presence of co-morbidities, and the process of weaning. There were highly significant positive correlations between age of patients, duration of mechanical ventilation and ICU stay, and the score of APACHE IV and the development of PICS, whereas there was a highly significant negative correlation regarding the level of PaO2. Conclusion Patients with respiratory disorders admitted to the RICU should be evaluated and followed up for the detection of any components of PICS especially those who are old adult, have prolonged intubation or ICU stay, have co-morbidities, high APACHE IV score, and persistent hypoxemia.

Assessment of diaphragmatic mobility by chest ultrasound in patients with chronic obstructive pulmonary disease on different modes of mechanical ventilation Adel M Saeed, Ashraf A El Maraghy, Riham H Raafat, Ahmed M Abd Elsamad Egyptian Journal of Bronchology 2019 13(2):184-190 Background Chronic obstructive pulmonary disease (COPD) is a disease characterized by airway obstruction and air trapping that is not fully reversible. The diaphragm is the principal respiratory muscle, and its dysfunction can prolong the duration of mechanical ventilation. Ultrasonography is a fast, easy, and accurate method of bedside evaluation for diaphragmatic function. In the ICU population, it can quantify normal and abnormal movements in a variety of clinical conditions. Patients and methods A prospective observational study was carried on 32 patients with COPD admitted to the respiratory ICU. Diaphragmatic excursion had been assessed by chest ultrasonography in every mode of mechanical ventilation and was correlated with weaning off mechanical ventilation and other physiological parameters. Results Of 32 patients with COPD included in the study, 24 patients were successfully weaned versus eight patients failed to be weaned off mechanical ventilation. Diaphragmatic excursions in every mode of mechanical ventilation (noninvasive, volume control, bilevel positive airway pressure, and pressure support) were higher in weaned patients with best cutoff values of 1.4, 1.3, 1.5, and 1.6 cm, respectively. Moreover, the diaphragmatic excursions were directly correlated with tidal volumes and inversely correlated with days of mechanical ventilation and rapid shallow breathing index. Conclusion Diaphragmatic displacement assessed by ultrasound is a good predictor for weaning off mechanical ventilation in patients with COPD, as it is sensitive, specific, and accurate. Diaphragmatic excursions are directly related to tidal volumes and inversely related with rapid shallow breathing index and days of mechanical ventilation.

Diaphragm ultrasound as a predictor of successful extubation from mechanical ventilation Taher Abd El Hamid El Naggar, Ibrahim A Dwedar, Eman F.A Abd-Allah Egyptian Journal of Bronchology 2019 13(2):191-195 Background Ultrasonography can be used for assessment of diaphragmatic mobility and thickness. Diaphragm is the main muscle of respiration. Rationale To predict successful extubation from mechanical ventilation. Patients and methods Forty patients were involved in the present study. They were admitted in the ICU at Abbassia Chest Hospital. They received the conventional measurements for weaning and transdiaphragmatic ultrasonography after extubation. We assessed the diaphragmatic mobility and diaphragmatic thickening fraction. All ultrasonography findings were gathered and compared with some of the usual weaning tools such as arterial blood gas and respiratory mechanics. The findings were statistically analyzed. Results Thirty-one patients revealed successful liberation from mechanical ventilation. Diaphragmatic mobility and thickening fraction showed high sensitivity and specificity compared with other weaning tools. The cutoff value was 10 mm for mobility and 30% for diaphragmatic thickening fraction. Conclusion Diaphragmatic ultrasonography can be used as a new tool for prediction of weaning process.

Serum level of carbohydrate antigen 15-3 in patients with interstitial lung diseases and its correlation with pulmonary function and high-resolution computed tomography Randa Salah El-Din Mohamed, Mahmoud Mohammed El-Batanouny, Neveen Mahmoud Amin, Rasha Abdel Razek Mahmoud, Doaa A.A Abd-Elhalim Egyptian Journal of Bronchology 2019 13(2):196-203 Background Carbohydrate antigen 15-3 (CA15-3) is a central protein core of mucin-1, a high-molecular-weight glycoprotein, found in alveolar and extrapulmonary epithelial cells that increases in interstitial lung disease. It uses antibodies against different epitopes. It is also considered a tumor marker for breast cancer. Aim The aim was to evaluate the value of CA15-3 as a biomarker in patients with interstitial lung diseases and to evaluate the correlation between CA15-3 level and radiological findings in high-resolution computed tomography (HRCT) and pulmonary function in patients with interstitial lung diseases (ILDs). Materials and methods The study was performed on 60 adult patients with ILD and 20 healthy controls. We classified the patients into three groups according to HRCT findings: group I ground glass (18 patients), group II reticulation (27 patients), and group III honeycombing (15 patients). All patients were subjected to HRCT, spirometry, collagen markers, and serum CA15-3 level evaluation. Results CA15-3 level in patients with ILD was significantly higher than control (P<0.001). CA15-3 level in reticulation and honeycombing groups was significantly higher than ground glass group, and CA15-3 level in reticulation group was significantly higher than honeycombing group (P=0.003). This may be explained by that reticulation is active fibrosis, whereas honeycombing is established fibrosis. A significant negative correlation has been noticed between CA15-3 level and forced vital capacity in the three different groups (P<0.05, r=−0.304). Conclusion The serum level of CA15-3 is strongly elevated in patients with ILD. CA15-3 is a noninvasive, nonexpensive, rapid biomarker in ILD, being proportional to the extent of lung injury.

Fayoum experience in the ultrasonographic evaluation of diffuse parenchymal lung disease Sherif Refaat Abd El Fatah, Radwa Ahmed Elhefny, Randa Ibrahim Ahmed, Doaa Mohamed Abd El Tawab Egyptian Journal of Bronchology 2019 13(2):204-213 Objective Chest ultrasound has many uses, both diagnostic and interventional. It may be used for the diagnosis of multiple pleural diseases (pleural effusion, pleural masses, and pneumothorax). It is also used in the diagnosis of diseases caused by lung parenchymal lesions, such as neoplasms, pulmonary embolism, pneumonia, and lung abscesses. Aim This study aimed to evaluate the sonographic features of diffuse parenchymal lung disease (DPLD). Design This was a prospective study. Setting The study was carried out at Fayoum University Hospital in Egypt during the period spanning from January 2017 to June 2017. Patients and methods This study included 120 participants. Sixty of them were diagnosed as having DPLD. For the diagnosis of these cases, we need a full medical history, a detailed clinical examination, spirometry, 6 min walk test, arterial blood gases’ analysis, high-resolution computed tomography, and chest ultrasound. The other 60 were studied as controls. Statistical analysis The data were collected and coded to facilitate data manipulation, and they were double entered into Microsoft Access; the data analysis was performed by using SPSS software, version 18 in Windows 7. The simple descriptive analysis was carried out in the form of numbers and percentages for qualitative data and arithmetic means as central tendency measurement, SDs as measure of dispersion for the quantitative parametric data and the inferential statistic test. Results There was a female predominance with a wide range of age. Most of the cases were nonsmokers, breeding birds, and exposed to biomass. All cases had diffuse bilateral B-lines. There was a negative relation between the Warrick score on the one hand and the B-line number, PaO2, 6 min walk test, and forced vital capacity on the other hand. In contrast, a positive relation was demonstrated between the Warrick score and B-line distance and pleural thickness. Most of the studied patients (71.6%) had irregular and thickened pleura and (51.6%) had an abolished lung sliding. Conclusion Chest ultrasound has a significant role in the diagnosis of DPLD and also in estimating the severity of the disease according to the number and the distance between B-lines. Multiple B-lines in the combination of thickened and irregular pleural line are highly suggestive of DPLD.

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