tbuckley/cabot-search huggingface dataset:
<i>Pd-l1</i> gene alterations to identify a subset of diffuse large B cell lymphoma that harbor a T cell inflamed phenotype.
Authors: James K. Godfrey, Sonali M. Smith, Sravya Tumuluru, Justin Paul Kline, James McElherne, Girish Venkataraman, Riyue Bao
Journal: Journal of Clinical Oncology (2018)

7566 Background: Programmed death – ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism in cancer, and classically occurs as an adaptive response to the presence of activated T cells and interferon gamma in the tumor environment. Interestingly, a unique genetic mechanism underlying PD-L1 up-regulation has been described in a variety of lymphomas, in which the 9p24.1 chromosomal region encoding the PD-1 ligands is highly amplified. We sought to determine the incidence and immune landscape of pd-l1 gene copy number alterations (CNA) in diffuse large B cell lymphoma (DLBCL). Methods: We utilized fluorescent in situ hybridization (FISH) to identify DLBCLs harboring pd-l1 CNA, thereby enabling a characterization of the immunogenomic landscape of these lymphomas compared to those lacking pd-l1 CNA. Results: Among 95 DLBCLs analyzed, 26% harbored pd-l1 CNA (17 copy gain, 7 amplified, 1 translocation). Pd-l1 CNA were highly enriched among DLBCLs with an activated B cell phenotype (75%). PD-L1 cell surface expression was strikingly enhanced in DLBCLs with pd-l1 CNA versus those without, as assessed by PD-L1 H score. Furthermore, pd-l1 CNA DLBCLs were associated with a pronounced infiltration by T cells with a restricted T cell receptor – beta repertoire, suggesting that lymphoma antigen-specific T cells had expanded in these samples. RNA-sequencing of pd-l1 gene-altered versus non-altered DLBCLs revealed differential expression of pd-l1, as well as genes involved in T cell and cytokine signaling in the former, indicating that pd-l1 CNA DLBCLs have been subjected to host immune surveillance. Lastly, whole exome sequencing of pd-l1 gene altered versus non-altered DLBCLs is ongoing to identify potential differences in mutational loads and profiles. Conclusions: Our results indicate that pd-l1 CNA identify a unique biological subset of DLBCL that has activated an endogenous anti-lymphoma immune response, and that may be more likely to respond to checkpoint blockade therapy with anti-PD-1 antibodies. We propose that a straightforward FISH analysis for pd-l1 gene amplification may be useful as a predictive biomarker for immunotherapy responsiveness in DLBCL.
Mutation profiling of <i>TSC1</i> and <i>TSC2</i> genes in solid tumors using comprehensive NGS panel.
Authors: Yong Li, Rongrong Chen, Jun Zhao, Lingjun Zhu, Jian Xu, Fei Ma, Renhua Guo, Chunwei Xu, Wen-xian Wang, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2018)

e24244 Background: Loss of function mutation of tumor suppressor genes TSC1 or TSC2 causes Tuberous Sclerosis (TSC), a rare hamartomas syndrome. Understanding the role of mTOR signaling pathway in TSC has been a major step in identifying the therapeutic potential of mTOR inhibitors such as sirolimus and everolimus. Moreover, targeted sequencing revealed somatic TSC1 mutations in bladder cancers are correlated with everolimus sensitivity. However, the prevalence of TSC1 or TSC2 mutations in other solid tumors remains wildly unknown. Methods: We retrospectively analyzed mutation profiling of 6000 consecutive cancer patients in our institute. Somatic mutation testing was performed with hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes). Variant interpretation followed the ACMG guidelines. Results: Loss of function mutations in TSC1 or TSC2 were identified in a total of 85 patients (1.4%), as detailed in table 1. Eighty-two mutations were SNV, while 3 were copy number loss (2 in TSC1, 1 in TSC2). There were more TSC2 mutation (n = 49) than TSC1 mutation (n = 36), which was more significant in liver cancer patients (2 versus 12). Interestingly, for the 8 patients with kidney tumor, one had a germline mutation of TSC2 (p.L1548P) indicating the somatic mutation (TSC2 p.E1558*) was a second hit for this TSC patient; another one had germline MLH1 mutation (p.S702Rfs*80) but without other Lynch Syndrome symptoms or signs up to now. Conclusions: Comprehensive NGS sequencing can detect different types of TSC1 or TSC2 mutations in multiple solid tumors. This approach may be cost-effective in finding potential target for refractory cancer patients. Table 1. The prevalence of TSC1 or TSC2 mutations in solid tumors TSC1 TSC2 all lung cancer 20 20 40 liver cancer 2 12 14 colorectal cancer 5 3 8 kidney tumor 2 6 8 breast cancer 1 3 4 uterine cancer 2 1 3 biliary cancer 1 1 2 others 3 3 6 Notes: others include ovarian, urethral, pancreatic, brain, penis and soft tissue tumors.
Cardiovascular risk and the impact of self-reported physical activity in long-term testicular cancer survivors: A longitudinal study.
Authors: Hege Sagstuen Haugnes, Lene Thorsen, Roy M. Bremnes, Marianne Brydoy, Carl Wilhelm Langberg, Torgrim Tandstad, Tom Wilsgaard, Sophie Fossa
Journal: Journal of Clinical Oncology (2016)

e16048 Background: The aims were to evaluate the longitudinal development of cardiovascular (CV) risk factors and CV disease (CVD: coronary artery disease, stroke and other atherosclerotic disease) and the impact of a prolonged high physical activity level (PrPA) on CV risk in long-term testicular cancer (TC) survivors (TCS). Methods: The study includes770 men treated for unilateral TC during 1980-1994 (surgery, n = 162; radiotherapy, n = 297; chemotherapy, n = 311) with complete data from two national follow-up surveys (survey 1 (S1) 1998-2002, survey 2 (S2) 2007-2008) including physical examination, blood samples and a questionnaire regarding physical activity, smoking, medication and morbidity. Obesity was defined as BMI ≥ 30 kg/m2. Diabetes was defined as previously diagnosed diabetes or fasting serum glucose ≥ 11 mmol/l. The metabolic syndrome was defined according to the National Cholesterol Education Program criteria. PrPA was defined as self-reported high physical activity level, leading to sweating and breathlessness at least 1-2h weekly, at both S1 and S2. The impact of PrPA on CV risk factors and disease at S2 were assessed with logistic regression. Results: Median follow-up since diagnosis was 11 years at S1, and 19 years at S2. Median age at S1 and S2 were 43 and 51 years, respectively. The prevalence of obesity did not change from S1 to S2 (14.3% vs. 16.4%, p = .08), but there were significantly increased prevalences of diabetes (S1: 2.9%, S2: 7.5%, p < .001), use of antihypertensive (S1:7.5%, S2:23%, p < .001) and lipid-lowering medication (S1:1.2%, S2:15.5%, p < .001) and CVD (S1:1.4%, S2:7%, p < .001). The number of men reporting a high physical activity level had increased from 43% at S1 to 53% at S2 (p < .001), while the number of smokers decreased (S1:31%, S2:22%, p < .001). PrPA (reported by 30%) was significantly associated with decreased risks of obesity (OR 0.60, 95% CI 0.38-0.94), using antihypertensive medication (OR 0.58, 95% CI 0.39-0.88), the metabolic syndrome (OR 0.55, 95% CI 0.38-0.78), and CVD (OR 0.35, 95% CI 0.16-0.81). Conclusions: Prevalences of several CV risk factors increase during long-term follow-up among TCS. PrPA might decrease the risk of CVD.
Predictive value of the early response in locally advanced non–small cell lung cancer treated with concurrent chemoradiotherapy by 18F-alfatide RGD PET/CT.
Authors: Song Gao, Yuchun Wei, Ning Liu, Xudong Hu, Yong Huang, Wei Zhao, Wenhong Hou, Shuanghu Yuan
Journal: Journal of Clinical Oncology (2016)

e20048 Background: Integrin αvβ3 has been shown to play an important role in angiogenesis, tumor growth and progression, and it is significantly up-regulated in various types of tumor cells and the activated endothelial cells of tumor angiogenesis. Because the tripeptide sequence of Arginine-Glycine-Aspartic (RGD) can specifically bind to integrin αvβ3, RGD PET/CT can be used for imaging of integrin αvβ3 and it can help evaluate tumor neovascularization and be used for the diagnosis and treatment of malignant tumours. In this clinical study, we use a new tracer, 18F-alfatide to evaluate the predictive value of the early response by 18F-Alfatide RGD PET/CT for patients with advanced NSCLC during CCRT. Methods: 12 patients with NSCLC have underwent 18F-Alfatide RGD PET/CT examination before and during CCRT. The PET/CT parameters of maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and metabolic tumor volume (MTV) before treatment and those during treatment were obtained and the changes were calculated. These changes of PET-CT parameters were compared with the standard tumor response according to the revised Response Evaluation Criteria in Solid Tumors (RECIST) criteria (v.1.1) using the chest CT one month after CCRT. Results: 18F-Alafatide RGD PET/CT was performed successfully in all patients and no clinically significant adverse events were observed. One month after the completion of CCRT, 9 patients with a partial response of tumor (responder group) and 3 patients achieved stable disease (non-responder group). The percent changes of MTV (%ΔMTV) were significantly more pronounced in responder group than in non-responder group (47.50±5.89 vs 18.29±12.53, p < 0.001). If the %ΔMTV were decreased 30% or more during CCRT, the tumors were more likely to achieve partial response after treatment than those with less than 30% of decrease. The percent changes of SUVmax (%ΔSUVmax) or SUVmean (%ΔSUVmean) had no correlation with the tumor response after treatment. Conclusions: %ΔMTV from two serial 18F-Alfatide RGD PET/CT scans, before and during CCRT, allow prediction of the treatment response in advanced NSCLC.
Marketing e-cigarettes to kids has created an “epidemic” in US, says FDA chief
Authors: Bob Roehr
Journal: BMJ (2018)

“Nicotine isn’t a benign substance,” particularly when it comes to children and the developing brain, the commissioner of the US Food and Drug Administration, Scott Gottlieb, said in a speech to his employees on 12 September. It was the rationale for “a strong regulatory process” for e-cigarettes and other new tobacco products.

The FDA has sent letters to more than 1300 retailers of e-cigarettes seeking to restrict sales and access to tobacco products by under aged youth and has threatened fines for violations.

It also wrote to JUUL Laboratories and four other manufactures of the devices asking for a plan to tackle marketing to minors, and requested a response …
IMvigor130: A randomized, phase III study evaluating first-line (1L) atezolizumab (atezo) as monotherapy and in combination with platinum-based chemotherapy (chemo) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC).
Authors: Matt D. Galsky, Enrique Grande, Ian D. Davis, Maria De Santis, Jose Angel Arranz Arija, Eiji Kikuchi, Almut Mecke, Ann Christine Thastrom, Aristotelis Bamias
Journal: Journal of Clinical Oncology (2018)

TPS4589 Background: Platinum-based chemo is the standard of care for most pts with untreated mUC, although clinical outcomes remain poor. Atezo (anti–PD-L1) was approved in the United States, European Union and elsewhere as monotherapy in both the 1L cisplatin (cis)–ineligible and post-platinum settings based on the single-arm, Phase II IMvigor210 trial. Data from other tumor types (e.g., NSCLC and TNBC) suggest that atezo may be tolerable when combined with chemo. Here we describe IMvigor130, a Phase III trial designed to evaluate the efficacy and safety of 1L atezo given alone or in combination with platinum-based chemo vs placebo and chemo, in pts with locally advanced or mUC. Methods: Across 35 countries, IMvigor130 (NCT02807636) is enrolling ≈ 1200 pts with histologically documented advanced or mUC (T4b, any N; or any T, N2-3; M1, stage IV) of the bladder, urethra, renal pelvis or ureters who have not received prior chemo for advanced disease. Eligible pts have measurable disease (per RECIST v1.1), ECOG PS 0-2 and a tissue sample for PD-L1 testing (VENTANA SP142 IHC assay). IMvigor130 was initially designed to enroll only cis-ineligible pts but was amended to include all platinum-eligible pts. Pts are randomized 1:1:1 to: (A) atezo + chemo (gemcitabine [gem] + cis or carboplatin [carbo]), (B) atezo alone or (C) placebo + chemo at the following doses (starting day 1 of a 21-day cycle): atezo (or placebo) 1200 mg IV q3w, gem 1000 mg/m2 on days 1 and 8, carbo AUC 4.5 q3w, cis 70 mg/m2 q3w. Atezo and chemo are administered, in the absence of unacceptable toxicity, until RECIST v1.1 progressive disease. Randomization is stratified by PD-L1 status on immune cells, number of Bajorin risk factors or liver metastases and investigator's chemo choice. The co-primary endpoints are PFS and OS in Arm A vs Arm C in the ITT population and OS in Arm B vs Arm C in the ITT population. Key secondary efficacy endpoints include investigator-assessed ORR, DOR and PFS per RECIST v1.1 (for atezo vs placebo + chemo arms). Safety, biomarkers and other exploratory endpoints will also be evaluated. Clinical trial information: NCT02807636.
P05.76 Resuming treatment with immune checkpoint inhibitors in cancer patients who developed immune-related meningitis
Authors: S Cuzzubbo, R Ursu, J Mazoyer, C Belin, B Baroudjian, C Lebbe, A Carpentier
Journal: Neuro-Oncology (2018)

Immune checkpoint inhibitors (ICIs) targeting CTLA-4 (Cytotoxic T-lymphocyte associated antigen 4) and PD-1 (Programmed cell death ligand 1) constitute a promising class of cancer treatment but are associated with several immune-related disorders, including neurological syndromes. Several guidelines are available for the acute management of immune-related adverse events, but their long-term management is less clear and uniform, particularly concerning the duration of the steroid treatment and the safety of a re-introduction of ICI treatment. We collected the cases of immuno-related meningitis associated with ICIs admitted to our department. Diagnosis was defined by a (1) high count of lymphocytes (>8 cells/mm3), without bacteria or virus detection, associated or not to a high level of proteins in cerebrospinal fluid; and (2) normal brain and spine imaging. After diagnosis, patients were followed by a neurologist until 1 year after meningitis onset to better define the steroids doses and the safety of ICI reintroduction in each case. We here report 5 cases of meningitis related to ICIs. Delay of meningitis onset after ICI start was short (within 2 weeks) for 3 patients and relatively longer for the other 2 patients (7 and 13 weeks respectively). Steroid treatment was introduced in 4 patients at the dose of 1 mg/Kg, allowing a complete recovery within 2 weeks. Corticosteroids were gradually tapered until discontinuation after 1–3 months. The 5th patient spontaneously improved within 2 weeks. Given the favorable outcome, ICI drug was reintroduced in 4 patients, and none of them did show meningitis recurrence. In 2 patients, nevertheless, other severe immune-related adverse events occurred (tubulointerstitial nephritis and diffuse pneumonia) leading to the discontinuation of ICI. In both patients, ICIs was reintroduced early post discontinuation (3 and 4 weeks, vs 8 and 53 weeks in the 2 other cases). Cases of meningitis related to ICIs are rarely reported and poorly described in literature. In our cases, a steroid treatment is effective and generally necessary. ICI treatment discontinuation is not mandatory in case of isolated meningitis. However, a careful analysis of the benefit/risk ratio should be done on a case by case basis.
Genomic evolutions in the progression from lung preneoplasia to adenocarcinoma.
Authors: Xin Hu, Junya Fujimoto, Runzhe Chen, Chi-Wan Chow, Wenyong Sun, Xingzhi Song, Xizeng Mao, Paul Scheet, Humam Kadara, Carmen Behrens, Chang-jiun Wu, J. Jack Lee, Mara Antonoff, Ara A. Vaporciyan, Stephen Swisher, Jianhua Zhang, John Heymach, Ignacio Ivan Wistuba, Andrew Futreal, Jianjun Zhang
Journal: Journal of Clinical Oncology (2018)

8576 Background: Carcinogenesis may result from accumulation of genomic and epigenomic aberrations. It has been postulated that atypical adenomatous hyperplasia (AAH), the only recognized pre-neoplasia to lung adenocarcinoma (ADC) may progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive ADC. Yet the pathological definition and management of these lesions remain controversial due to lack of sufficient molecular evidences. This aim of this study is to delineate the temporal molecular carcinogenetic events and evolutionary process during the evolution from pre-neoplastic lesions to early-stage adenocarcinoma. Methods: We performed multi-regional (2-5 spatially separated regions per lesion) whole exome sequencing and reduced representation bisulfite sequencing to AAH (N = 22), AIS (N = 27), MIA (N = 54) and ADC (N = 13) from 53 patients including 39 patients presenting with multifocal disease and 23 patients carrying more than two different types of lesions. Results: Mutation burden progressively increases from AAH to AIS, then to MIA and ADC, with evidence of positive selection of non-silent mutations. APOBEC signature also progressively increases with APOBEC enrichment scores of 0.94 in AAH, 0.99 in AIS, 1.04 in MIA and 1.28 in ADC, (p = 0.011). In addition, genomic heterogeneity becomes more complex with neoplastic evolution with tumor allelic frequency-derived median Shannon index. Interestingly, aneuploidy was a common phenomenon in AIS, MIA and ADC, but not in AAH, while allelic imbalance (AI) only became prevalent in MIA and ADC, followed by structural rearrangements in ADC. Phylogenetic analysis revealed varying evolutional processes in different lesions highlighting the substantial heterogeneity even at the preneoplastic states. Conclusions: We provide molecular evidence supporting the pathological model of early lung carcinogenesis from AAH, to AIS, MIA and ADC, suggesting progressive genomic evolution at the single nucleotide level during carcinogenesis of lung ADC with macroevolution at the transition from AAH to AIS and AIS to MIA, possibly driven by ploidy change and allelic imbalance (AI), respectively.
Radioembolization for treatment of uveal melanoma hepatic metastasis: Results of a phase II, single institution, prospective trial.
Authors: Carin F. Gonsalves, David J. Eschelman, Robert D. Adamo, P. Rani Anne, Marlana M. Orloff, Takami Sato
Journal: Journal of Clinical Oncology (2018)

9535 Background: The liver is the first site of metastasis in > 90% of uveal melanoma (UM) patients. Transarterial catheter directed therapies have been used to control growth of liver tumors and prolong overall survival (OS). We report results of the first prospective, phase II trial using radioembolization ([RE] Y-90 resin microspheres) for treatment of UM hepatic metastases. Methods: Between November 2011 and January 2017, RE was performed on 24 treatment naïve patients [Group A (13 men; median age 63; range, 29 -77)] and 24 patients who progressed after immunoembolization [Group B (9 men; median age 59, range, 34-77)]. Patients received unilobar or lobar treatments separated by 3-5 weeks. Patients were followed for 1 month for acute toxicity and every 3 months for delayed toxicity (CTCAE v 3.0). MR, CT and PET imaging was obtained every 3 months to evaluate for tumor response (PFS; RECIST) and extrahepatic disease. Results: Group A: Unilobar (n = 7) or bilobar (n = 17) RE was performed (median dose, 32.6 mCi; range, 17.7-56.1). One patient was removed from the trial for incomplete lobar treatment. RE response included PR (n = 7), SD (n = 13) and PD (n = 3). Median PFS was 8.1 months (range, 3.3 - 33.7). Median OS was 18.9 months (range, 6.5 -66.9) with 4 surviving patients (range, 14.0-66.9 months). One year survival was 61%. Extrahepatic disease occurred in 17 patients (median, 6.3 months; range, 3.3 – 11.9). Group B: Unilobar (n = 5) or bilobar (n = 19) RE was performed (median dose, 35.0 mCi; range, 19.2 -50.8). RE response included PR (n = 6), SD (n = 8) and PD (n = 10). One patient withdrew from the trial. Median PFS was 4.3 months (range, 2.5 -18.6). Median OS was 19.1 months (range, 4.8-68.4) with 5 surviving patients (range, 18.6 – 68.4 months). One year survival was 70%. Extrahepatic disease occurred in 15 patients (median, 5.5 months; range 0.8-9.9). No procedure-related complications occurred. Grade 3 treatment-related toxicities included transient leukopenia (n = 2), nausea/vomiting (n = 1) and pain (n = 1). Conclusions: RE is a safe and effective treatment for UM hepatic metastases and should be considered as a treatment option for patients with and without prior transarterial catheter directed therapies. Clinical trial information: NCT01473004.
Patient reported outcomes using Internet-based tablets to inform hospice care for minority and nonminority patients with cancer.
Authors: Timothy McCurry, Yingwie Yao, Miriam O Ezenwa, Anayza Gill, Theresa Hipp, Robert Shea, Jacob Miller, Jesus Carrasco, David Shuey, Karen Frank, Nargis Nardi, Micheal Murray, Julie Glendenning, Cari Bagcus, Jessica Perez, Veronica Angulo, Marie L Suarez, Z Jim Wang, Robert E Molokie, Diana J Wilkie
Journal: Journal of Clinical Oncology (2016)

10115 Background: Unrelieved symptoms for cancer patients receiving hospice care could be influenced by lack of systematically collected PRO. Many hospice nurses now use tablets for care process documentation, but tablets are not commonly used to collect PRO. The study aim was to compare pain and symptom distress among minority and NHW hospice patients with cancer who reported their symptoms via an Internet enabled tablet with data transmitted electronically to their hospice nurses. Methods: From two hospices, we screened 2,814 cancer patients, 819 were eligible, 211 consented, and 209 completed baseline measures. In their homes, patients (mean age 68±15; 49% male; 33% African American, 46% NHW, 18% Hispanic, 3% other/unknown) used an Internet-enabled Samsung tablet to complete the valid, reliable PAINReportIt (pain intensity now, least and worst in the past 24 hours [0-10]) and Symptom Distress Scale (SDS, 0-5). Data were written to a secure server, extracted from the database, and analyzed using statistical software R. Results: Ease of tablet use was high; missing data were minimal (2.8%). Mean pain intensity scores for now, least, and worst pain in the past 24 hours were 4.7±2.7, 3.1±2.3, 7.1±2.3, respectively. The average of these pain intensity scores (API) was 5±2 and the average SDS was 2.6±.6. Patient age was negatively correlated with both API (r= -.26, p< .001) and SDS (r= -.20, p= .004). Neither API nor SDS scores differed by the patient’s gender or ethnicity. Compared to NHW, minority patients reported higher API (diff= .73, p= .01), but did not differ significantly in their reported SDS scores (diff= -.04, p= .61). Further examination of API scores showed that, controlling for hospice difference and age, Hispanics reported significantly higher API than NHW (diff= 1.00, p= .01) but the gap between African Americans and NHW was not significant (diff= .61, p= .10). Conclusions: Improvements are needed to promote comfort at the end of life, especially for Hispanics. Tablet-based PRO offers a novel way for hospice cancer patients to add their unfiltered viewpoint to their hospice record. The influence of the PROs on analgesic prescriptions and 1-week pain outcomes are under study. Clinical trial information: NCT02026115.