tbuckley/cabot-search huggingface dataset:
Association between promoter hypermethylation of <i>APC, CDH13, MLH1</i> and <i>MGMT</i> genes and colorectal cancer metastasis.
Authors: Oleg Ivanovich Kit, Dmitry I. Vodolazhsky, Konstantin Vladimirovich Dvadnenko, Elena N. Oleynikova, Denis D. Oleynikov, Olga A. Bogomolova, Irina V. Mezhevova, Denis S. Kutilin, Natalya N. Timoshkina, Yaroslav S. Enin, Irina I. Efimova, Anton Pushkin
Journal: Journal of Clinical Oncology (2016)

e15066 Background: Aberrant methylation of CpG sites within promoter regions of cancer-related genes is an important epigenetic event in carcinogenesis. The frequency of methylation changes of different genes in sporadic colorectal cancer (CRC), according to various estimates, varies from 15 to 80% which allows the use of this indicator for the development of new prognostic biomarkers of CRC. Methods: Methylation was quantified at 47 CpG-sites within promoter regions of four genes (MGMT, APC, CDH13 and MLH1) in colorectal tumors and normal colorectal tissue using bisulfite pyrosequencing. 25 patients (aged 50 to 81 years, median age 59) received surgery for sporadic colorectal cancer at Rostov Research Institute of Oncology. The sample of histologically confirmed CRC included G2-G3 adenocarcinoma with 10 T3N0M0 tumors, 15 tumors with metastases to regional lymph nodes and/or distant metastases (T3-4N1-2M0-1). Results: Methylation of the MGMT, APC and CDH13 promoter regions increased by 3-5 times in 40%, 40% and 58% of tumors, respectively. 20 (80%) CRC samples showed CpG-hypermethylation of at least one gene, 4 of them (16%) were hypermethylated in all three genes (the difference in methylation level between colorectal tumors and normal tissue was significant at p < 0.01). Association between methylation status of MGMT, APC and CDH13 and metastasis development was found (χ2 = 6.52, p = 0.017). At the same time, there was no correlation of age and sex of the patients with methylation level of the investigated CpG sites in normal tissue, as well as with frequency of CpG-hypermethylation in tumor tissue. Pyrosequencing showed only one case of CpG-hypermethylation (38%) of the MLH1 promoter. Conclusions: The data on increase in methylation of promoter regions of the three genes MGMT, APC and CDH13 can be used as sensitive predictive markers of CRC progression and metastasis.
Association between promoter methylation and protein expression of tumor suppressor genes with clinical characteristics in gastric carcinoma and its effect on the biological function of gastric cancer.
Authors: Jieer Ying, Li Jingjing
Journal: Journal of Clinical Oncology (2017)

e15509 Background: Studies showed that the gene promoter methylation may be the third important mechanisms of gene expression regulation. Abnormal methylation of tumor suppressor gene can be detected in the early stage of tumor, by screening the methylation profile of gastric cancer (GC), it can provide theoretical and experimental evidence for early diagnosis, treatment and prognosis. Methods: Detecte p16, hMLH1 and CDH1 promoter methylation, the p16, hMLH1 and E-cadher expression in GC tissues and its correlation with clinicopathological features and prognosis. Detect methylation of hMLH1 promoter and mRNA expression in GC cell line and normal gastric mucosa cell line. Clone formation assay and Transwell test. Results: The methylation of hMLH1 and CDH1 in GC and adjacent tissues were statistically significant . The methylation of hMLH1 was related to alcohol , CA199 level and Borrman. The methylation of CDH1 was related to the CEA level. The methylation of hMLH1 promoter is related to OS in GC patients. The methylation of p16 and CDH1 was not related to the OS ofGC patients. The GC patients with 0 or 1 gene methylation had a better prognosis than those with 3 or 2 gene methylation. The p16, hMLH1 and E-cadherin protein expression in GC and adjacent tissues were statistically significant. The p16 protein expression was related to tumor size. The hMLH1 protein expression was related to the CA199 level and tumor size. The E-cadherin expression in GC patients with drinking history was lower than ones without drinking history. The p16, hMLH1 and E-cadherin protein expression was not related to the OS of GC patients. There was a negative correlation between hMLH1 gene methylation and its protein expression in GC. The number of clones in the control group and the experimental group were 180 ± 3 and 169 ± 6. The number of cells in the control group and the experimental group were 135 ± 4.08 and 125 ± 4.18. Conclusions: The methylation of multiple genes is associated with the prognosis, which can provide theoretical basis for accurate treatment and prognosis for GC patients.
Frequency of actionable cancer predisposing germline mutations in patients with lung cancers.
Authors: Semanti Mukherjee, Marjorie Glass Zauderer, Vignesh Ravichandran, Yelena Kemel, Diana Mandelker, Nisha Pradhan, Ahmet Zehir, Steven M. Lipkin, Preethi Srinivasan, Chaitanya Bandlamudi, Barry S. Taylor, David Randolph Jones, Liying Zhang, Michael F. Berger, David B. Solit, Mark E. Robson, Zsofia Kinga Stadler, Joseph Vijai, Kenneth Offit
Journal: Journal of Clinical Oncology (2018)

1504 Background: Most of the heritability for lung cancer, estimated at 18% in population studies, remains unexplained. Utilizing a tumor-normal screening, we determined the prevalence of clinically actionable germline cancer-susceptibility mutations in patients with lung cancer, and correlated findings with clinical, tumor associated, and family history characteristics Methods: Tumor/normal samples from lung cancer patients (pts) enrolled from 1/14 until 5/16 underwent sequencing analysis for 468 genes by MSK IMPACT [PMID: 28481359], with pathogenicity assessment for 76 cancer predisposition genes by ACMG guidelines. Selected patients with a strong family history of cancer, multiple primary tumors, or early age of diagnosis (≤50) were offered return of germline findings. As per IRB protocol, germline results were anonymized for all cases except those consenting to return of results. Frequencies of pathogenic/likely pathogenic (P/LP) germline mutations were compared to population databases. Results: 1118 pts consented to tumor-normal sequencing and 42 to return of germline findings; the median age of the two groups was 68 and 59 , respectively (p < 0.05). For the 42 pts receiving germline findings, 24% had early onset and 52% multiple cancer diagnosis, and 31% had P/LP mutations in 10 genes (3 BRCA2, 2 MEN1, 1 APC, 1 ATM, 1 BAP1, 1 BLM, 1 CHEK2, 1 FH, 1 FLCN, 1 RAD51D). Among 1118 pts, 8% had P/LP mutations in 16 genes (20 APC, 15 CHEK2, 13 MUTYH, 7 BRCA2, 6 BRCA1, 5 FH, 4 ATM, 4 FANCC, 4 RECQL4, 3 FANCA, 3 TP53, 2 RAD50, 2 RAD51C, 1 BRIP1, 1 NBN, 1 PMS2). 45% of the P/LP mutations of CHEK2, APC, MUTYH, BRCA1 were population “founder” mutations. There was no statistically significant increase in burden of these pathogenic variants in the lung cancer cases studied. The 31% prevalence of germline variants in pts enriched for family history of cancer was greater than the 8% prevalence in patients unselected for family history (p < 0.0002). Conclusions: Our preliminary findings demonstrate an increased prevalence of clinically actionable germline mutations in patients with lung cancer with either a family history of other cancers, early age at onset, or multiple cancer diagnosis, compared to unselected lung cancer patients.
Prospective assessment of tumor biopsies as part of clinical trials: Patients’ (pts) perspectives.
Authors: Sunu Lazar Cyriac, Michelle K. Wilson, Valerie Lydia Bowering, Wendy Hunt, David Gutierrez, Yeh Chen Lee, Ilaria Colombo, Luisa Bonilla, Vanessa Speers, Sangeet Ghai, Neesha C. Dhani, Marcus O. Butler, Amit M. Oza, Stephanie Lheureux
Journal: Journal of Clinical Oncology (2018)

2539 Background: Despite the increased inclusion of mandatory biopsies for clinical trials, there are scant data related to the perceptions and acceptability by pts. This study assessed the pre and post biopsy perceptions among gynecological cancer pts. Methods: A prospective study was conducted at Princess Margaret Hospital for pts with gynecological cancers. The study was approved by local ethics committee and enrolled pts planned for core tumors biopsies as part of clinical trials. A questionnaire was completed by pts prior to and 1 week post biopsy. The questionnaire assessed the Hospital Anxiety and Depression Scale (HADS), pts’ perceptions and experience. Results: 42 women completed the questionnaire at both time points. Median age was 63 years. Sites of biopsies were peritoneal nodules in 45%, liver in 24%, superficial lymphnodes (LN) in 17%, retroperitoneal LN in 7% and abdominal wall in 7%. 88% were Ultrasound guided, 8% was CT, and 4% as blind procedure. A risk threshold of less than 2% was considered acceptable for major complications, major bleeding or infection by 71%, 60% and 55% of pts, respectively. While 50% (21/42) of the pts reported that the biopsy didn’t impact their care, but helps research; only less than 10% felt it would impact their care. 71% (30/42) of the pts would allow their specimen to be used for future research. Most pts (98%) were agreeable for genetic testing of their specimen and wanted to be informed of significant findings. Table 1 shows the HADS result. The baseline score was normal in 81%. 91% (38/42) felt that the side effects and risks of biopsy were adequately explained before the procedure. One week after the biopsy, only 1 pt had major pain. 91% (38/42) of pts did not feel any embarrassment during the procedure. The majority of pts (91% [38/42]) were agreeable for a repeat biopsy for research. Table 1 Conclusions: Core biopsies for correlative studies for research purpose are well accepted and tolerated by patients. Patients were well informed and importantly willing to undergo further biopsies in the future if necessary. This is critical with the growing integration of biopsies in clinical trial design. HADS (Anxiety)(n = 42) Pre Biopsy 1 week post Biopsy Normal 34 39 Borderline abnormal 2 1 Abnormal 6 2
Trends in survival and costs among US multiple myeloma patients.
Authors: Eric M Maiese, Kristin Evans, Bong-Chul Chu, Debra E. Irwin
Journal: Journal of Clinical Oncology (2017)

8046 Background: Survival among multiple myeloma (MM) patients has improved over time, but little is known about concurrent changes in healthcare costs. This study examined trends in both survival and healthcare costs over the same time periods in US MM patients. Methods: The MarketScan Commercial and Medicare claims dataset was used to identify 5199 adult patients diagnosed with MM from Jan. 2006 to Dec. 2014. Patients had no prior evidence of cancer, were continuously enrolled for &gt;12 months prior to MM diagnosis, and were followed through the earliest event (death, end of enrollment, or end of the study period (9/30/2015)). Multivariate GLM and Cox proportional hazards models estimated healthcare costs and survival probabilities, respectively, for two time periods during which patients were diagnosed with MM (2006-2010 vs 2011-2014) while controlling for demographic and clinical characteristics. The recycled prediction method was used to calculate the incremental cost estimates between the time periods. Results: Patients diagnosed in 2011-2014 had a 35% lower risk of death compared to those diagnosed in 2006-2010 (HR [95% CI] = 0.65 [0.57-0.74]. Patients diagnosed in 2011-2014 had 18% (95% CI: 6-31%) higher all cause and 26% (95% CI: 6-50%) higher MM-related per patient per month costs compared to those diagnosed in 2006-2010 (Table). Conclusions: Among MM patients, survival has improved at a greater rate than the increase in healthcare costs. In addition to improvements in MM treatment, changes in overall disease management may have contributed to both the increased expenditures and survival improvements observed in this study. [Table: see text]
Assessment of Treatment of Refractory Granuloma Faciale With Intralesional Rituximab
Authors: Daniel Morgado-Carrasco, Priscila Giavedoni, José M. Mascaró, Pilar Iranzo
Journal: JAMA Dermatology (2018)

Granuloma faciale (GF) is a rare, benign inflammatory dermatosis of unknown cause. Some reports have suggested that it could be part of the spectrum of IgG4-related sclerosing diseases. Granuloma faciale is characterized by single or multiple red-brown nodules, most frequently occurring on the face, and it can produce severe disfigurement. Treatment is difficult, and poor outcomes are often seen. Rituximab is a monoclonal antibody against CD-20 approved by the US Food and Drug Administration for treatment of some autoimmune and tumoral diseases.To evaluate the treatment of refractory GF with intralesional rituximab.In this case series, 3 patients with biopsy-proved refractory GF who underwent treatment at a dermatology outpatient clinic of a tertiary referral hospital were evaluated. The study was conducted from August 2015 to December 2017.Doses of 0.5 to 1 mL/cm2 of intralesional rituximab, 10 mg/mL, were administered monthly for 6 months and thereafter depending on clinical response. In 2 patients, peripheral blood B-cell counts were monitored before and during treatment, and in 1 patient, only during treatment.Reduction in size of the lesions, ultrasonography evaluation, subjective improvement, and adverse events were monitored throughout the course of therapy.All 3 of the patients were men (ages from 30s to 60s). They showed a significant reduction in the size and thickness of GF both clinically and on ultrasonography evaluation. Two patients had a complete response and the third, a partial response. A reduction in peripheral blood B-cell count was observed in the 3 patients, suggesting that the action of rituximab could be systemic. No severe adverse reactions were reported.Intralesional rituximab may represent a novel and well-tolerated therapy for refractory GF.
Mismatch repair deficiency testing for immune checkpoint therapy: Immunohistochemistry vs microsatellite instability.
Authors: Sucha Sudarsanam, Forrest Blocker, Sally Agersborg, Vincent Anthony Funari, Shiping Jiang, Wayne Chen, Josette Ragheb, Vladislav Chizhevsky, Maher Albitar
Journal: Journal of Clinical Oncology (2018)

3022 Background: DNA mismatch repair deficiency (dMMR) can be tested by immunohistochemistry (IHC) or microsatellite instability (MSI). While either IHC and MSI is adequate for establishing Lynch syndrome, the relevance of discordant results in selecting patients for immune checkpoint treatment is unknown. We investigated MSI and IHC in detecting dMMR and correlated with PD-L1 expression. Methods: Community-based practice tissue samples were submitted for PD-L1 expression and dMMR by both IHC and MSI. PD-L1 testing was performed by IHC using clone 22C3, dMMR using IHC against four MMR proteins (MHL1, MSH2, MSH6, and PMS2), and MSI using PCR with five Bethesda markers. Results: Of the 396 cases tested for both PD-L1 and dMMR by IHC, 18 (4.5%) were reported dMMR positive. Of the 610 cases tested for both PD-L1 and dMMR by MSI, 27 (4.4%) were dMMR positive. The dMMR positivity was determined as having at least one MMR protein expressed at ≤ 6%. There was no statistically significant correlation between PD-L1 expression and the presence or absence of dMMR as detected by IHC. In contrast, patients with MSI had significantly higher PD-L1 positive cells when PD-L1 expression is considered as a continuous variable (P = 0.04), and at cut-offs of 5% (P = 0.003) and 10% (P = 0.004). When a cut-off point of 6% for IHC is used, 8.9% of positive cases by MSI were negative (FN) by IHC and 2.6% of MSI negative cases were positive (FP) by IHC. If a 20% cut-off for IHC is used, FP was at 4.4% but FP was at 3.6%, and if a 30% IHC cut-off is used, FP was at 3.1% and FP was at 5.7%. This difference between cut-off points was statistically significant (P = 0.0008 for 20% and P = 0.0001 for 30% cut-off). Conclusions: There is significant correlation between PD-L1 expression and dMMR as detected by MSI, but not by IHC testing. Based on this and the established association between tumor mutation burden and MSI, MSI should be considered the gold standard for dMMR testing for checkpoint blockade therapy consideration. dMMR by IHC cut-off MSI % positive % IHC FP % IHC FN Pos Neg Total by MSI by IHC 6% Pos 267 16 283 32.38 31.27 8.9 2.6 Neg 26 596 622 20% Pos 280 22 302 32.38 33.37 4.4 3.6 Neg 13 590 603 30% Pos 284 35 319 32.38 35.25 3.1 5.7 Neg 9 577 586 Total 293 612 905
Pilot study of a modified yoga program for head and neck cancer (HNC).
Authors: Barbara A. Murphy, Sujatha Yarlagadda, Mary S. Dietrich, Jie Deng, Melissa Adair, Sheila H. Ridner
Journal: Journal of Clinical Oncology (2016)

6047 Background: HNC causes late musculoskeletal impairment (MSI), physical symptoms & psychologic distress. A modified yoga intervention using poses, breath work, meditation & relaxation may improve outcomes. We conducted a wait list control study testing a modified Yoga program for HNC survivors. Primary aims: feasibility (recruitment, compliance), satisfaction, safety, MSI and need for pose modifications. Secondary aim: preliminary efficacy for range of motion (ROM), posture, pain, and psychological distress. Methods: Eligible subjects: completed therapy > 3m prior to study, cancer free, and medically cleared. Study arms: individualized yoga instruction tiw x 4 weeks then biw x 4 weeks or wait list control. Yoga was taught by a certified instructor. Fidelity Measures: home practice guide with16 poses for neck-shoulders-back, 8 week instruction plan detailing progression of poses and practices, assessment tools for the instructor to capture MSI and document pose modifications, videotaped yoga sessions and home practice diary. Demographics & treatment data captured at baseline. MSI and symptoms assessed at baseline, 4, & 8 weeks using questionnaires, posture analysis software, & measures of jaw-neck-shoulder ROM. Results: 73 patients recruited: 40 consented, 11 ineligible. Pt characteristics: median age 63.1 yrs, 62.5% male, 90% white, 32% single, 33% income < $30,000. Of 20 intervention subjects, 5 discontinued (1 recurrence, 2 medical conditions, 2 work). Median # sessions completed 19/20; median # of home practices reported: 35/36. Median program satisfaction 10/10 for 10 assessed components. No adverse events were reported. Seventeen impairments were noted: neck (80%), shoulder (67%), posture (53%), frailty/deconditioning (53%), and jaw (53%). Mean # impairments 5.27 (SD 1.97): Exploratory analysis of efficacy measures indicates potential benefit for the following: pain, anxiety and depression, and ROM. Conclusions: A modified yoga program in HNC pts is safe. Recruitment rates and satisfaction were high. Demographics of HNC pts did not limit recruitment. Significant limitations in movement requiring pose modifications were found. Preliminary efficacy data supports further yoga studies. 1R21CA173202-01A1 NIH/NCI Clinical trial information: NCT01951664.
Pembrolizumab with or without vismodegib in treating metastatic or unresectable basal cell skin cancer.
Authors: Anne Lynn S. Chang, Duy C Tran, Richard Brotherton, Sunil Reddy, A. Dimitrios Colevas
Journal: Journal of Clinical Oncology (2017)

TPS9593 Background: Basal cell carcinomas (BCCs) are the most common cancer in humans and have increased &gt; 75% in the past two decades, with &gt; 28,000 cases of advanced or metastatic diseases per year. Targeted therapy in the form of Smoothened inhibitors (SIs) are FDA approved for advanced BCC, however, over half of patients do not respond or become resistant to SI monotherapy after initial response. At this time, there are no other FDA approved drugs for advanced BCCs, however, emerging data indicates that a significant proportion of BCCs express programmed cell death ligand (PD-L)-1, suggesting potential response to PD-1 inhibition. In addition, BCCs are keratinocytic tumors, and our case series of PD-1 inhibitors against cutaneous squamous cell carcinomas, another keratinocytic tumor, have shown activity. Here, we present a proof-of-principle, phase 1b, open-label investigator initiated study of pembrolizumab for unresectable or metastatic BCC (NCT02690948). Methods: Following institutional review board approval, patients with locally advanced or metastatic BCCs who met all eligibility criteria were enrolled at a single academic center. Participants were allocated into either Arm 1 (pembrolizumab 200 mg IV every 3 weeks) or Arm 2 (pembrolizumab 200 mg IV every 3 weeks and concurrent vismodegib 150 mg by mouth daily) until disease progression or intolerable toxicity. Major inclusion criteria include individuals aged &gt; or = 18 years with histologically verified unresectable and/or metastatic BCC, and with measurable disease by Response Evaluation Criteria for Solid Tumors version 1.1. Exclusion criteria include immunosuppresion, active infection, history of pneumonitis and autoimmune disease requiring systemic treatment. The primary outcome measures are the overall response rates in Arm 1 and 2. Secondary outcome measures include incidence and severity of adverse events (AEs) as defined by the Common Terminology Criteria for Adverse Events verson 4.0, and progression free survival. This study is currently enrolling, with 10 of 26 patients accrued to date (6 of 13 in Arm 1; 4 of 13 in Arm 2), and the study stopping rule (based on first 10 enrolled patients displaying progressive disease) did not need to be deployed. Clinical trial information: NCT02690948.
Five gene predictor of genitourinary and gastrointestinal toxicity after three dimensional conformal radiotherapy (3DCRT) for localized prostate cancer.
Authors: Radmila Jankovic, Ivana Boljevic, Emina Malisic, Vesna Stankovic, Marina Nikitovic, Sinisa Radulovic
Journal: Journal of Clinical Oncology (2016)

e16584 Background: Acute and late toxicity occurs in the substantial portion of patients with prostate cancer, treated with 3DCRT. Regarding the same set of clinical/dosimetric factors, individual variability in radiation treatment response could be caused by different gene profiles. As known to be involved in cell response to radiation, five genes (SRF, RAD23B, DRAP1, TGFB1, DDX17) were chosen and their expression was correlated with specific toxicity. Methods: A total of 42 prostate cancer patients treated with 3DCRT fulfilled the following criteria: localized disease stage (T1-2), PSA level ≤ 20, Gleason score ≤ 7, Karnofsky index ≥ 80. Two dose-volume groups were defined according to the estimated risk of seminal vesicle (SV) involvement, according to the Roach formula. The first, low risk group for SV involvement was prostate group only if the risk was ≤ 15% and the second, high risk group was the prostate and seminal vesicle group if the risk was ≥ 15%. Acute and late genitourinary and gastrointestinal toxicity were graded according to EORTC scoring scale. Gene expression was measured by quantitive Real-Time PCR. Statistical analysis was performed using Wilcoxon’s rank sum test; p < 0.05 was considered significant. Results: According to gastrointestinal acute, as well as late toxicity, all patients were divided in two groups: the first was comprised of patients experiencing no toxicity whereas the second group was having toxicities grades 1-3. The same was done for acute and late genitourinary toxicities. Expression levels of all five examined genes failed to reach any significant correlation neither with acute nor late genitourinary and gastrointestinal toxicities. However, the comparison of gene expression levels between low and high risk group, revealed significantly lower DDX17 levels in high risk group (p = 0.0185). Furthermore, correlation with tumor characteristics showed lower DDX17 levels in patients with T2 compared to T1 tumors. Conclusions: Proposed five gene panel failed to predict acute and late genitourinary toxicities. Neverthless, DDX17 gene, involved in DNA repair process, emerges as a possible biomarker of more agresive form of the disease.