tbuckley/cabot-search huggingface dataset:
Assessment of tumor mutation burden from &gt;60,000 clinical cancer patients using comprehensive genomic profiling.
Authors: Garrett Michael Frampton, David Fabrizio, Zachary Rockow Chalmers, Jeffrey S. Ross, Douglas Buckner Johnson, Christine Marie Lovly, Jeffrey Alan Sosman, Vincent A. Miller, Phil Stephens
Journal: Journal of Clinical Oncology (2016)

11558 Background: Tumor mutation burden (TMB), as measured by whole exome sequencing, has been shown to strongly correlate with objective responses to immune checkpoint inhibition (ICI), in several tumor types. Consequently, the ability to accurately measure TMB, in a clinical setting, may guide patient treatment decisions. We investigate whether TMB can be accurately measured using a comprehensize genomic profiling (CGP) assay targeting several hundred cancer genes (~1.25 Mb). We also describe the landscape of TMB observed from > 60,000 advanced clinical cancer specimens, across > 400 cancer types. Methods: CGP by hybridization capture and high-coverage sequencing (median > 500x) of the full coding regions from 236 or 315 cancer-related genes was performed. Base substitutions, indels, copy number alterations and gene fusion/rearrangements were assessed. TMB was calculated as the number of somatic, coding, base sub. and indel alterations, excluding known driver mutations, per megabase of genome examined. This metric correlates with response to anti-PD-1 in melanoma. Results: We validate that targeted sequencing of 1.25 Mb does provide an accurate measurement of genome-wide TMB. We describe the spectrum of TMB observed across a diversity of tumor types. Lower grade and pediatric malignancies tend to have the lowest TMB ( < 1 mut/MB), while epithelial cancers, associated with environmental DNA damage, were most highly mutated ( > 10 mut/MB). Mutations in mismatch-repair genes (MSH2, MSH6, MLH1, PMS2 and RAD50), DNA replication genes (POLD1, POLE) and TP53BP1 were associated with > 2x increases in TMB, though some specimens with high TMB lacked identifiable causative alterations. Several tumor types, in which ICI are not yet approved, had many cases with high TMB ( > 20 mut/MB), including intestinal type stomach adenocarcinoma (20%), and uterine endometrial adenocarcinoma (16%). Conclusions: These data demonstrate that TMB can be accurately assessed using a clinically available CGP assay, allowing assessment for current patients. Examining the landscape of TMB across a diversity of tumor types provides new data to expand the population that can potentially benefit from immunotherapy.
Abstract 10979: Impairment of Autophagic Flux in Doxorubicin Cardiotoxicity and Its Restoration and Improvement of Cardiac Function by Prior Starvation
Authors: Tomonori Kawaguchi, Genzou Takemura, Hiromitsu Kanamori, Akiko Tsujimoto, Kazuko Goto, Atsushi Ogino, Toshiaki Takeyama, Takatomo Watanabe, Kentaro Morishita, Masanori Kawasaki, Takako Fujiwara, Hisayoshi Fujiwara, Atsushi Mikami, Shinya Minatoguchi
Journal: Circulation (2012)

Active autophagy has recently been reported in doxorubicin-induced cardiotoxicity, of which pathophysiological role we here investigated. Acute cardiotoxicity was induced in green fluorescent prote...
Effect of gene expression profile (GEP) testing on clinical management in 19% of consecutively treated patients with stage IB/IIA melanoma at a single institution.
Authors: Lynn Thacher Dengel, Alexandra W. Hickman, Craig L. Slingluff
Journal: Journal of Clinical Oncology (2017)

e21080 Background: A 31-GEP test is predictive of metastasis in cutaneous melanoma. We hypothesized that GEP testing would “upgrade” surveillance to routine imaging in at least 16% of stage IB/IIA patients, similar to the upgrade rate from sentinel node biopsy. Methods: A GEP score was obtained for consecutive patients with Stage IB/IIA melanoma treated between 6/2014-6/2016. A retrospective review of a prospectively collected database was performed. Results: 67 patients with Stage IB/IIA melanoma met inclusion criteria. In four cases, a GEP result was not available. Of the 63 tested cases, 68% were Stage IB (N = 43), and 32% were Stage IIA (N = 20). A high-risk result was seen in 12% of stage IB (5/43) and 42% of stage IIA (8/19) patients. Insurance denied coverage of scans in 1/13 patients with a high-risk GEP result. The remaining 12 Stage IB/IIA patients with high-risk scores were “upgraded” to high-intensity surveillance. With a median follow-up of 14 months, 1/13 patients with a high-risk GEP result developed distant metastases 21 months after diagnosis of a Stage IIA melanoma. Conclusions: Results from this retrospective single institution study show that GEP testing altered patient management in 19% of Stage IB/IIA patients. Early detection in 1/13 patients with high-risk scores in this series supports further investigation into stratifying traditionally low-risk patients by GEP testing.
Cancer genomics-based screening of new therapeutic targets and biomarkers for esophageal cancer.
Authors: Yataro Daigo, Atsushi Takano, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2020)

e16514 Background: Since the number of esophageal cancer patients who show objective response to standard therapies is still small, development of new anti-cancer agents with minimum risk of adverse events and highly precise molecular biomarkers is eagerly awaited. Methods: We have been screening novel therapeutic targets and their companion diagnostics for esophageal cancers as follows; i) To identify up-regulated genes in esophageal cancers by the gene expression profile analysis, ii) To verify the candidate genes for their low expression in normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 265 esophageal cancers, and iv) To verify their function for the growth of the esophageal cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate oncoproteins and selected a metyltransferase ESOC1 (esophageal cancer-associated oncoprotein 1). Immunohistochemical analysis revealed that ESOC1 positivity was observed in 68.5% of esophageal cancers and associated with tumor size. Moreover ESOC1 expression was an independent prognostic factor for esophageal cancer patients. Suppression of ESOC1 expression by its siRNAs inhibited growth of esophageal cancer cell lines. Introduction of ESOC1 increased the growth activity of mammalian cells, suggesting that ESOC1 is likely to be a prognostic biomarker and therapeutic target for esophageal cancers. Conclusions: Cancer genomics-based approach could be useful for the development of new cancer biomarkers as well as therapeutic targets for small molecules, antibodies, nucleic acid drugs, and immunotherapies.
Frequency of secondary malignancies (SM) in patients with large granular lymphocytic leukemia (LGLL): A single institutional experience.
Authors: Leidy Lismeri Isenalumhe, Magali Van den Bergh, Emilie Wang, Braydon Schaible, Zhenjun Ma, Ling Zhang, Lubomir Sokol
Journal: Journal of Clinical Oncology (2017)

7542 Background: Large granular lymphocyte (LGL) disorders represent a spectrum of aberrant T-cell or natural killer cell lymphocytic proliferations. LGLL is classically associated with autoimmune conditions and bone marrow (BM) failure disorders. SM has been reported in association with LGLL in about 10%. The aim of this study is to evaluate the impact of SM on the clinical course of LGLL. Methods: This is a retrospective study of LGLL patients (pts) evaluated at Moffitt Cancer Center between January 1995 and May 2016. The diagnostic clinico-pathological criteria consisted of LGL count &gt; 0.5 k/μL with T-cell receptor gene rearrangement. Lower absolute number of clonal circulating LGLs with characteristic immunophenotype associated with BM involvement, cytopenias, splenomegaly and/or associated symptoms were also diagnostic. Pts with myelodysplastic syndrome were excluded. Survival analysis was performed using the Kaplan-Meier method with log-rank test. Chi-square and T-test were used to analyze association among various variables. Significant P-value was considered &lt; 0.05. Results: Out of 668 screened pts with LGL expansions in peripheral blood, 261 met criteria for LGLL. SM were present in 44% (116/261) of LGLL pts, of which 38% were hematological and 80% arose prior to onset of LGLL. Most common solid SM included skin cancer (14%), prostate cancer (12%), and breast cancer (12%), while most common hematological SM consisted of non-Hodgkin lymphoma (17%) and chronic leukemia (14%). 5-year overall survival (OS) for all LGLL pts was 75% and 10-year OS 63%. There was a statistically significant difference in 5-year OS between LGLL pts with SM compared to without (p = 0.049), but no difference between both groups in median OS or 10-year OS. Pts diagnosed with SM prior to LGLL had worse 5-year OS (p = 0.031) and 10-year OS (p = 0.05) compared to all other LGLL pts. Conclusions: This study showed that the frequency of SM is higher than previously described, especially with onset prior to diagnosis of LGLL. Even though median age of LGLL is around 60 years, it appears that age itself cannot explain this phenomenon. Our results suggest that having a SM is a poor prognostic factor in LGLL patients.
Rationing policy will do far more harm than good
Authors: Nick Mann
Journal: BMJ (2018)

NHS England’s list of restricted procedures normalises denying patients effective treatments.1 Shifting between pretexts of “clinically obsolete” and “too expensive,” it is the antithesis of a sensible, pragmatic response to planning provision for the population in an artificially constrained budget. Clinical commissioning groups’ rationing of hip and knee surgery—effective and cost effective procedures—alongside redundant or cosmetic procedures, creates a …
Resource consumption and financial burden of cancer patients.
Authors: Nicholas George Zaorsky, John Lin, Djibril Ba, Ivan Nikiforov, Joel E Segel, Heath B. Mackley, Guodong Liu, Doug Leslie
Journal: Journal of Clinical Oncology (2018)

e18913 Background: We aim to characterize resource consumption and financial burden of cancer patients. Methods: The MarketScan database was used to summarize expenditures reimbursed to the provider for care, consisting of the amount paid by insurance companies and patient’s out-of-pocket (copay and deductible) payments. For the year 2014, the top 15 cancers with highest incidence were identified by ICD-9 codes; the top 20 Current Procedural Terminology (CPT) codes associated with each were characterized. CPT codes were split by subtype, including hospital care, radiology, lab, pathology, drugs/anesthesia, cardiac, critical care, and surgery. Results: There were 1,299,126 payments totaling $235,138,732. The median total cost for all procedures per cancer diagnosis was $9,466,790 (interquartile range [IQR]: $6,441,970 - $23,218,373), median number of procedures of 29,782 (IQR 49,158 – 99,960). The median per patient reimbursed costs was $3,724 (IQR $2,249 – 5,607). Lung cancer patients had the greatest number of procedures (2,214,159, totaling $26,349,128). The costliest cancers were those of the breast ($48,997,931), followed by prostate ($38,696,423); the plurality of financial burden for these two cancers came from prostatectomy ($17,694,508, average of $2,003/procedure), and breast reconstruction ($13,143,220, average of $2,018/procedure). Hospital care codes (e.g. inpatient consults) contributed to the plurality of cost ($65,142,514 total for 617,366, at an average of $140 per code). Surgical procedures had the 3rd highest total cost, $58,655,598, but the highest cost per procedure at $1246. The procedures used in the greatest number of cancers (typically consults, lab tests, radiological procedures) contributed to the lowest cost per cancer (IQR $100-200); in contrast, procedures used in the least number of cancers (surgical procedures, drugs/anesthesia) had the highest cost per code (IQR $490 – $1,700). Conclusions: Cancer patients consumed an exorbitant number of resources, associated with a large financial burden, with large differences seen among different cancer subtypes. The predominant source of financial burden comes from complex disease-specific surgical procedures.
Reversing resistance to PD-1 blockade by combination of talimogene laherparepvec (T-VEC) with pembrolizumab (pembro) in advanced melanoma patients following progression on a prior PD-1 inhibitor: SWOG S1607 (NCT#02965716).
Authors: Siwen Hu-Lieskovan, James Moon, Danae Campos, Kenneth F. Grossmann, Jeffrey Alan Sosman, Christopher W. Ryan, Michael Wu, Antoni Ribas
Journal: Journal of Clinical Oncology (2018)

TPS9603 Background: A significant number of patients do not respond to PD-1/L1 blockade because there are no pre-existing tumor antigen-specific T-cells in their tumors ready to attack the cancer. We hypothesize that this lack of sufficient immune activation can be addressed by a combination therapy with an immune activating oncolytic virus such as T-VEC. Intralesional administration of T-VEC, a modified herpes simplex virus type-1, can selectively replicate in tumor tissue and stimulate a local and systemic antitumor immune response. Methods: This is a Phase 2 study of T-VEC plus pembro in patients with advanced melanoma whose disease progressed after prior therapy with a PD-1/L1 inhibitor. The primary endpoint is durable response rate. Secondary objectives include objective response rate in the injected, non-visceral non-injected and visceral lesions, progression free survival, overall survival and toxicity. Translational objectives include difference in T-cell infiltrate in responding vs non-responding tumors. Key eligibility criteria include unresectable melanoma; anti-PD-1/L1 based therapy must be the immediate previous line of treatment within 56 days prior to registration; no confirmed partial or complete response to prior anti-PD1 agents; Zubrod performance status 0-2; no active brain metastases; no history of autoimmune disease or toxicity requiring steroids; and adequate organ function. Subjects in cohort A must have at least one measurable visceral lesion; in cohort B subjects must not have visceral lesion. Subjects will receive intratumoral injection of T-VEC 1 million PFU/ml for cycle 1 followed by 100 million PFU/ml from cycle 2 to 36 (one cycle equals 21 days). Pembro 200mg IV will be given every 21 days. Tumor biopsy and research blood are taken at baseline and while on treatment at Day 28 (both injected and non-injected lesions). Tumor assessments are performed every 12 weeks, and treatment is continued while clinical benefit persists for up to 2 years. A total of 36 subjects will be enrolled in cohort A and 25 subjects in cohort B, with a Simon 2 stage design. Clinical trial information: NCT02965716.
Management of hyperhidrosis in secondary care
Authors: R. Wade, A. Llewellyn, J. Jones-Diette, K. Wright, S. Rice, A.M. Layton, N.J. Levell, D. Craig, N. Woolacott
Journal: British Journal of Dermatology (2018)

Hyperhidrosis is uncontrollable excessive sweating, which occurs at rest, regardless of temperature. It can have a major impact on people's quality of life. Primary hyperhidrosis is thought to affect at least 1% of the UK population. There is considerable variation in the availability of treatments in specialist care. This systematic review from the UK assessed the effectiveness of treatments used in specialist care for patients with hyperhidrosis. A comprehensive search was undertaken to find relevant studies of hyperhidrosis treatments. The quality of the studies was assessed. Patient advisors contributed to the interpretation of the results. Fifty studies were included in the review, most were small and of poor quality. The treatments assessed were iontophoresis, botulinum toxin injections, anticholinergic medications, curettage and other technologies that damage the sweat gland. Some studies assessing botulinum toxin injections for hyperhidrosis of the armpit were pooled together to estimate average effects. Our review found that there was moderate quality evidence that botulinum toxin injections reduce symptoms of armpit hyperhidrosis in the short and medium term (up to 16 weeks), compared with placebo (no treatment). There was weak but consistent evidence of some benefit from using iontophoresis for hyperhidrosis of the hands. Evidence for other interventions was of low or very low quality. Overall, the evidence for the effectiveness of treatments for primary hyperhidrosis is limited and few firm conclusions can be drawn. However, there is moderate quality evidence to support the use of botulinum toxin injections in clinical practice. A well conducted, adequately powered, randomised controlled trial of botulinum toxin injections compared with iontophoresis (which is the current standard treatment in many dermatology units for palmar hyperhidrosis, which affects the palms of the hands) for palmar hyperhidrosis may be warranted.
PreB cells are moving on
Authors: Dhaval Dixit, Susan R. Schwab
Journal: The Journal of Experimental Medicine (2018)

In this issue of JEM, Fistonich et al. (https://doi.org/10.1084/jem.20180778) address how the bone marrow microenvironment supports diverse lineages through multiple developmental stages. Differential motility between pro- and preB cells results in differential IL-7 exposure, and, intriguingly, stromal cells respond to abnormal B cells by reducing Il7.
Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels to predict efficacy of bevacizumab in metastatic colorectal cancer patients receiving first-line chemotherapy.
Authors: Mitsukuni Suenaga, Shu Cao, Wu Zhang, Yan Ning, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Marta Schirripa, Roel Gopez, Elizabeth Melendez, Shivani Soni, Afsaneh Barzi, Toshiharu Yamaguchi, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2017)

11564 Background: Early VEGF-A reduction by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BV). CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in CCL5/CCR5 pathway will predict outcomes in metastatic colorectal cancer (mCRC) patients (pts) receiving BV in first-line setting. Methods: Genomic DNA was extracted from 215 samples of three independent cohorts: 61 pts receiving FOLFOX+BV (median age 60 yrs, median follow-up 39.2 mos); 83 pts receiving FOLFOX (median age 61 yrs, median follow-up 57.6 mos); 71 pts receiving FOLFOX/XELOX+BV as exploratory for serum biochemistry assay (median age 60 yrs, median follow-up 28.9 mos). Single nucleotide polymorphisms of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Serum VEGF-A levels at baseline and day 14 were measured using ELISA. Results: In univariate analysis for the FOLFOX cohort, pts with the CCL5 rs2280789 G/G variant or any CCR5 rs1799988 T allele had shorter overall survival (OS) compared to the those with any A allele or the C/C variant (18.7 vs. 29.4 mos, HR 1.93, 95%CI: 1.05−3.53 P= 0.025; 22.0 vs. 31.2 mos, HR 1.74, 95%CI: 0.98-3.90, P= 0.055). The trend remained in multivariable analysis ( P= 0.090 and P= 0.026). The differences were not confirmed in the FOLFOX+BV cohort. Pts with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and OS when receiving FOLFOX+BV than FOLFOX (PFS: 19.8 vs. 11.0 mos, HR: 0.44, 95%CI: 0.25-0.78, P= 0.002; OS: 41.8 vs. 21.1 mos, HR: 0.43, 95%CI: 0.24-0.77, P= 0.002); pts carrying any CCR5 rs1799988 T allele had longer PFS and OS ( P= 0.025 and P= 0.008, respectively). No significant difference was shown in pts with either A/A or C/C variant. In the exploratory cohort, any CCL5 rs2280789 G allele was associated with higher VEGF-A levels at baseline and greater decrease of VEGF-A levels at day 14 compared with the A/A variant. Conclusions: CCL5 and CCR5 impact the angiogenic environment. Our data suggest the genotypes may identify specific populations who benefit from BV-based chemotherapy in first-line treatment for mCRC.
Use of radiation in high risk population with non melanoma skin cancer at a rural cancer center.
Authors: Shikha Prakash, Sanjay Emandi, Sucharu Prakash
Journal: Journal of Clinical Oncology (2018)

e21613 Background: Radiotherapy in Non melanoma skin cancer (NMSC) can be employed adjuvantly, primarily, or for recurrence. We investigated tumor and host characteristics affecting treatment outcome, and patterns of failure according to treatment modality of patients with NMSC in a rural setting. Methods: We retrospectively studied 274 cases of NMSC referred to a rural Cancer Center between 2010 and 2017. The effect of age, sex, immunosuppression, histology, size, location, and radiation modality (Brachytherapy, Electrons, Photons) on prognosis were evaluated. Results: The median age was 75 with a male to female ratio of 2.5:1. 56% of patients had basal cell carcinoma (BCC), and 44% had squamous cell (SCC). 83% received radiation as primary treatment, 6% adjuvantly, and 11% for recurrence. 88% of cancers were located in the head/neck area. 38% were stage T2 or greater. HDR Ir 192 brachytherapy was used to treat 56% of the cancers, Electron Beam 34%, and Photons 10%. Majority of patients experienced grade 1 radiodermatitis. 21% of patients had an underlying immunosuppressed state at diagnosis. Median follow up duration was 2 years. The overall local recurrence rate was 9.5%, with median time to recurrence of 22 months. The recurrence rate was 11.7% in SCC vs 7.8% in BCC (p = 0.348). The recurrence rate was higher in scalp lesions (21%) as compared to other sites (p > 0.05). Recurrence rate among immunosuppressed was 16%, and recurrence among T2/T3/T4 lesions was 15% (p > 0.05). Recurrence rate was 11% in Electron treated cancers vs 7% in those treated with HDR (p > 0.05). Conclusions: This is the largest series of Radiation (Brachytherapy and Electron Beam) to treat NMSC at a rural center. Radiation provided excellent local control and cosmesis in a relatively high risk population (large tumor, elderly, immunocompromised, recurrent). SCC histology and scalp location correlated with higher rates of treatment failure but not statistically significant. Similarly, tumor size and radiation modality, did not correlate with recurrence. Immunosuppression was a risk factor for development of skin cancer, but not recurrence. Radiation can be offered as an effective treatment to patients with NMSC in rural areas, to provide quality care close to home.