tbuckley/cabot-search huggingface dataset:
Multi-institutional, prospective, randomized, double-blind, placebo-controlled phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine to prevent recurrence in high-risk melanoma patients: A subgroup analysis.
Authors: Robert Connor Chick, Mark B. Faries, Diane F. Hale, Phillip M. Kemp Bohan, Annelies Hickerson, Timothy J. Vreeland, John William Myers, Jessica L. Cindass, Tommy A. Brown, John Robert Hyngstrom, James W. Jakub, Jeffrey J. Sussman, Adam C. Berger, Montaser F. Shaheen, G. Travis Clifton, Thomas Wagner, George Earl Peoples
Journal: Journal of Clinical Oncology (2020)

63 Background: A novel vaccine strategy may prevent recurrence in high-risk melanoma patients (pts). The TLPLDC vaccine uses yeast cell wall particles (YCWP) to load tumor lysate into autologous dendritic cells (DC). In this phase IIb trial of TLPLDC vs. placebo in resected stage III/IV pts, TLPLDC increased 24 month (mo) disease free survival (DFS) in the per treatment (PT) population. Here, we present a 24mo DFS subgroup analysis and estimated overall 36mo DFS. Methods: Disease-free pts were randomized 2:1 to the TLPLDC vaccine vs. unloaded YCWP+DC at 0, 1, 2, 6, 12, and 18mo. The protocol was amended to allow concurrent adjuvant checkpoint inhibitor (CPI) therapy once approved. The pre-specified PT population included only pts completing the primary vaccine/placebo series (PVS) at 6 mo. Kaplan-Meier estimates of DFS were used to compare treatment arms by stage (III or IV) and CPI therapy (yes/no) in the ITT and PT populations. Results: 144 pts were randomized (103 TLPLDC, 41 placebo); 98 pts (66 TLPLDC, 32 placebo) completed the PVS. There were no clinicopathologic differences between treatment groups. There was no difference in 24mo DFS in stage III pts (n = 112), but in stage IV pts (n = 32), the 24mo DFS was 44% vs 0% (TLPLDC vs placebo) (p = 0.41) in ITT and 73.3% vs. 0% (HR 0.14, p = 0.002) in PT. Stage IV pts were more likely to receive CPI than stage III pts (50% vs. 30%, p = 0.003). There was no difference in 24mo DFS for pts who did not receive CPI (n = 102), but in pts who received CPI (n = 42), the 24mo DFS was 49.3% vs. 31.3% (p = 0.71) in ITT and 68.8% vs. 41.7% (HR 0.46, p = 0.28) in PT, showing a trend toward improved DFS in pts who completed the PVS and received CPI (n = 31). Overall, the 36mo estimated DFS was 34.2% vs. 21.6% (p = 0.89) for ITT and 56.9% vs. 27.9% (p = 0.021) for PT. Conclusions: The TLPLDC vaccine improved DFS in patients completing the PVS at 24 and 36 mos, particularly in the resected stage IV subset. The apparent synergistic effect with TLPLDC + CPI will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI vs. CPI alone in resected stage IV melanoma pts. Clinical trial information: NCT02301611.
Hepatocyte-derived intrahepatic cholangiocarcinoma requires Yap and Sox9: A clinical and preclinical analysis.
Authors: Satdarshan Monga, Sungjin Ko, Laura Molina, Junyan Tao, Aatur D. Singhi, Aaron Bell
Journal: Journal of Clinical Oncology (2020)

582 Background: Intrahepatic cholangiocarcinoma (ICC) is a liver tumor of increasing incidence and devastating prognosis. WGS and WES have identified numerous molecular pathways and fusions in ICC. Recent studies have also suggested hepatocyte as a cell source in a subset of ICCs, especially those associated with chronic liver insult such as non-alcoholic steatohepatitis (NASH) or primary sclerosing cholangitis (PSC). Methods: Since co-expression of myristoylated AKT (myrAKT) &amp; Notch intracellular domain (NICD) in hepatocytes using sleeping beauty transposon/transposase-based hydrodynamic tail vein injection (SB-HTVI) lead to ICC, we initiated a comprehensive analysis of mechanism of ICC development in patients and in this preclinical model. Results: Over 90% of CC samples exhibited high levels of nuclear SOX9 &amp; YAP, in addition to a significant positivity for pAKT in ICCs as compared to extrahepatic CC. We also identified upregulation of p-AKT, SOX9 &amp; YAP in hepatocytes of patients with PSC and NASH. This was also seen in many murine models of cholestatic injury and NASH. While co-expression of myrAKT+NICD led to hepatocyte-derived ICC, conditional deletion of either Yap or Sox9 significantly delayed and almost completely abrogated ICC development. While Yap deletion impaired the initial HC-to-BEC fate conversion, Sox9 elimination had no such effect on reprograming. Interestingly, following deletion of either Yap or Sox9 we observed a few AKT/NICD-driven ICC tumors expressing either Sox9 or Yap but not both. This also occurred in a small subset of human CC tumors which may be Sox9+Yap- (4%) or Sox9-Yap+ (3.7%), showing that deletion of Yap or Sox9 is not sufficient to completely abrogate ICC development. We finally demonstrated that conditional deletion of both Yap &amp; Sox9 completely blocked development of ICC tumors in the myrAKT+NICD model. Conclusions: Thus, we show that cholestatic injury or NASH in humans and mice induces hepatocyte-to-cholangiocyte reprograming to increase the risk of ICC development. We also provide evidence for critical but distinct roles of Yap and Sox9 in ICC development and demonstrate the therapeutic potential of targeting these factors for treatment of subsets of ICC.
Identifying strategies to address obstacles to optimal integration of cancer immunotherapies in the community.
Authors: Latha Shivakumar, Christine B. Weldon, Ali McBride, Igor Puzanov, Joanne Riemer, Matthew R. Zibelman, Leigh Boehmer
Journal: Journal of Clinical Oncology (2020)

96 Background: Evolving indications for immuno-oncology (IO) therapies in cancer pose a significant challenge to community clinicians around the practical issues that must be addressed to implement these therapies safely and effectively. The Association of Community Cancer Centers (ACCC) initiated a quality improvement (QI) research study to assess the impact of educational interventions targeting the multidisciplinary cancer care team on evidence-based integration of IO therapy. Methods: The QI study collected baseline data from 100 patients initiating IO therapy between Dec 2017-Apr 2018 at two community cancer centers on co-morbidities, immune-related adverse events (irAEs), laboratory tests, ER visits and hospitalizations, patient education, and adherence. The advisory committee analyzed this data to identify practice gaps and designed educational interventions to address these gaps. After clinicians at both centers completed the educational interventions, data was collected from 100 patients initiating IO therapy between Jan 2019-Apr2019 and compared using Fisher’s exact test. We also conducted staff surveys before and after participating in the interventions. Results: Offering ACCC-created IO wallet cards to patients was a recommended intervention but only one site adopted this. The site that used the wallet cards had a statistically significant reduction in hospitalization rates compared to the other site (38% vs 70%, p = 0.0024). Respondents to the practice surveys reported an increase in handing out patient education materials following participation in the interventions. They also reported an improved understanding of strategies to manage patients with co-morbidities, management of irAEs, patient education and engagement, interprofessional communication, and coordination with non-oncology specialists. Conclusions: Community cancer center directed educational interventions are feasible and may improve clinician understanding, comfort, and attitudes with the integration of emerging IO agents. Administering wallet cards to patients at the beginning of IO therapy may decrease the risk of hospitalization and warrants further investigation in larger studies.
Endoscopic versus surgical resection for mucosal esophageal squamous cell carcinoma: Treatment outcomes and factors affecting survival.
Authors: Ga Hee Kim, Ho June Song, Hee Kyong Na, Ji Yong Ahn, Jeong Hoon Lee, Kee Wook Jung, Do Hoon Kim, Kee Don Choi, Gin Hyug Lee, Hwoon-Yong Jung
Journal: Journal of Clinical Oncology (2020)

368 Background: Mucosal esophageal squamous cell carcinoma (T1a EC) is treated with endoscopic (ER) or surgical resection (SR). The data regarding prognosis of T1a EC and the associated factors are still lacking. This study aimed to compare the treatment outcomes of T1a EC in ER and SR groups, and to investigate the factors affecting long-term survival. Methods: We retrieved data for 263 patients with T1a EC who underwent ER (n = 200) or SR (n = 63). Relevant clinical and tumor-specific parameters were reviewed. Underlying comorbidity was scored using Charlson co-morbidity index (CCI). Significant factors affecting survival were determined by Cox regression analysis. Results: The mean age of the patients was 64.5±8.0 years. During a mean follow-up of 54.4±20.4 months, the 5-year overall survival (OS) of all T1a EC patients was 85.7% (86.8% in ER and 82.4% in SR group; p = 0.631). In multivariate analysis, CCI was a significant factor affecting survival (p &lt; 0.001). The 5-year OS was 60.2% in patients with CCI &gt; 2 and 88.2% in patients with CCI ≤2 (p &lt; 0.001). The 5-year cumulative incidence of primary EC recurrence was 1.9% and metachronous EC recurrence was 15.1% in ER group (0% in SR group). Incidence of subsequent second primary cancers was 9% in ER and 9.5% in SR. The 5-year cumulative incidences of all cases of cancer recurrence in ER and SR groups were 27.5% and 10.8%, respectively (p = 0.037). The procedure-related adverse events occurred in 10.0% in ER and 41.3% in SR (p &lt; 0.001). Among the 24 (12.0%) and 10 (15.9%) deaths in ER and SR group, respectively, primary EC-specific death was not reported. The major causes of death were second primary cancers in ER group (75%), and post-operative complications or organ failure in SR group (70%). Conclusions: Long-term survival was excellent in patients undergoing ER or SR for T1a EC. The prognosis of T1a EC was significantly associated with underlying comorbidity. Attention should be paid to metachronous cancer recurrence in ER group and operation-related adverse events in SR group.
Molecular profiling of immunoglobulin heavy-chain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients
Authors: Alejandro Medina, Cristina Jiménez, M. Eugenia Sarasquete, Marcos González, M. Carmen Chillón, Ana Balanzategui, Isabel Prieto-Conde, María García-Álvarez, Noemí Puig, Verónica González-Calle, Miguel Alcoceba, Isabel Cuenca, Santiago Barrio, Fernando Escalante, Norma C. Gutiérrez, Mercedes Gironella, Miguel T. Hernández, Anna Sureda, Albert Oriol, Joan Bladé, Juan-José Lahuerta, Jesús F. San Miguel, María-Victoria Mateos, Joaquín Martínez-López, María-José Calasanz, Ramón García-Sanz
Journal: Blood Cancer Journal (2020)

Abstract Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavy-chain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3 , IGHD2 and IGHD3 , as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361−0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation ≥7% (HR: 0.291, 95% CI: 0.137−0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers.
Waist circumference as a vital sign in clinical practice: a Consensus Statement from the IAS and ICCR Working Group on Visceral Obesity
Authors: Robert Ross, Ian J. Neeland, Shizuya Yamashita, Iris Shai, Jaap Seidell, Paolo Magni, Raul D. Santos, Benoit Arsenault, Ada Cuevas, Frank B. Hu, Bruce A. Griffin, Alberto Zambon, Philip Barter, Jean-Charles Fruchart, Robert H. Eckel, Yuji Matsuzawa, Jean-Pierre Després
Journal: Nature Reviews Endocrinology (2020)

Abstract Despite decades of unequivocal evidence that waist circumference provides both independent and additive information to BMI for predicting morbidity and risk of death, this measurement is not routinely obtained in clinical practice. This Consensus Statement proposes that measurements of waist circumference afford practitioners with an important opportunity to improve the management and health of patients. We argue that BMI alone is not sufficient to properly assess or manage the cardiometabolic risk associated with increased adiposity in adults and provide a thorough review of the evidence that will empower health practitioners and professional societies to routinely include waist circumference in the evaluation and management of patients with overweight or obesity. We recommend that decreases in waist circumference are a critically important treatment target for reducing adverse health risks for both men and women. Moreover, we describe evidence that clinically relevant reductions in waist circumference can be achieved by routine, moderate-intensity exercise and/or dietary interventions. We identify gaps in the knowledge, including the refinement of waist circumference threshold values for a given BMI category, to optimize obesity risk stratification across age, sex and ethnicity. We recommend that health professionals are trained to properly perform this simple measurement and consider it as an important ‘vital sign’ in clinical practice.
Conversion gastrectomy for stage IV unresectable gastric cancer: A retrospective cohort study.
Authors: Tamotsu Sagawa, Yasushi Sato, Kyoko Hamaguchi, Masahiro Hirakawa, Hiroyuki Nagashima, Eriko Waga, Koshi Fujikawa, Yasuo Takahashi
Journal: Journal of Clinical Oncology (2020)

298 Background: Stage IV Gastric cancer (GC) is a heterogeneous biological condition with a mixture of distant metastases, including hematologic, lymph nodal and/or peritoneal. In the recent classification introduced by Yoshida et al with the proposal to identify objective principles for conversion surgery, stage IV GC patients were subdivided into 4 new categories. In this study, we retrospectively investigated the efficacy of conversion gastrectomy for stage IV GC patients, with particular focus on the Yoshida’s classification. Methods: A retrospective, single center cohort study was performed in patients who had undergone conversion gastrectomy between 2005 and 2018. Data were extracted from Hokkaido Cancer Center database including all metastatic gastric cancer patients submitted to surgery. Only stage IV unresectable tumors/metastases which became resectable after chemotherapy were included in this analysis. Results: Forty-two resected stage IV GC patients were included in this analysis. Median overall survival (OS) was 40.0 months and 1-, 3- and 5-year survivals were 92.9, 70.7 and 57.7%, respectively. Univariate analysis among the patients with conversion gastrectomy identified macroscopic type, clinical response to 1st line therapy, pathological tumor depth, pathological nodal stage, R0 resection as significant prognostic factors. The MSTs of the patients with conversion gastrectomy for each category were 50.1 months for category 1, 46.6 months for category 2, 22.7 months for category 3 and 17.2 months for category 4. Conclusions: Unresectable stage IV GC patients could benefit from radical surgery after chemotherapy and achieve long survivals. Adequate selection of stage IV GC patients for conversion therapy may be an important role.
Retrospective review of delayed adverse events secondary to treatment with a smooth, cohesive 20-mg/mL hyaluronic acid filler in 4500 patients
Authors: Shannon Humphrey, Derek H. Jones, Jean D. Carruthers, Alastair Carruthers, Katie Beleznay, Naissan Wesley, Jeanette M. Black, Sherri Vanderveen, Ardalan Minokadeh
Journal: Journal of the American Academy of Dermatology (2020)
A pilot study of liposomal irinotecan plus 5-FU/LV combined with paricalcitol in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy.
Authors: Patrick Grierson, Andrea Wang-Gillam, Haeseong Park, Katrina Pedersen, Benjamin R. Tan, Manik A. Amin, Rama Suresh, Nikolaos Trikalinos, Jingxia Liu
Journal: Journal of Clinical Oncology (2020)

TPS793 Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death by 2030, and is characterized by resistance to chemo- and radiotherapy and a highly fibrotic tumor microenvironment. Front-line therapies for advanced PDAC include FOLFIRINOX and gemcitabine/nab-paclitaxel with median overall survival ranging from 8.5 to 11 months. After progression on gemcitabine-containing therapy, 5-FU/LV/liposomal irinotecan is a standard second-line option, however outcomes are still poor. Retrospective studies demonstrate superior survival of advanced PDAC in patients with high serum levels of 25(OH) vitamin D. Notably, the PDAC tumor microenvironment is enriched in cancer-associated fibroblasts that favorably respond to vitamin D, prolonging survival in combination with chemotherapy in mouse models. Furthermore, vitamin D suppresses catabolism of irinotecan in gastrointestinal cancer cells, potentiating its efficacy. Therefore, we are conducing an investigator-initiated study of 5FU/LV/liposomal irinotecan with paricalcitol as second-line therapy in advanced PDAC. Methods: This is a pilot study of 5FU/LV/liposomal irinotecan combined with paricalcitol in patients with advanced PDAC progressed on gemcitabine-based therapy. All patients receive liposomal irinotecan, LV, 5-FU and paricalcitol. Liposomal irinotecan is given at 70 mg/m 2 IV over 90 minutes, LV at 400 mg/m 2 IV over 30 minutes, and 5-FU at 2400 mg/m 2 continuous IV infusion over 46 hours, on Day 1 of each 14-day cycle. Paricalcitol IV infusion will precede the above, given according to assigned cohort (75 mcg weekly or 7 mcg/kg weekly). The primary objective of this study is to determine the tolerability between two different dose levels of paricalcitol added to the combination regimen of 5-FU/LV/liposomal irinotecan in patients with advanced PDAC. Secondary objectives are measures of efficacy (ORR, PFS, OS, CA19-9 biochemical response rate). Clinical trial information: NCT03883919.
Early progression (progr) in patients (pts) with metastatic pancreatic cancer (mPaC) and a germline BRCA mutation (gBRCAm): Phase III POLO trial of olaparib (O) versus placebo (P).
Authors: Teresa Macarulla, Hedy L. Kindler, Pascal Hammel, Michele Reni, Eric Van Cutsem, Michael J. Hall, Joon Oh Park, Daniel Hochhauser, Dirk Arnold, Do-Youn Oh, Anke C. Reinacher-Schick, Giampaolo Tortora, Hana Algül, Eileen Mary O'Reilly, David McGuinness, Karen Cui, Katia Schlienger, Gershon Y. Locker, Talia Golan
Journal: Journal of Clinical Oncology (2020)

750 Background: In POLO (NCT02184195), maintenance O was associated with significant progr-free survival benefit vs P in pts with a gBRCAm and mPaC (Golan NEJM 2019). Early progr or death (within 4 months [m]) occurs in ~35−45% of pts on standard-of-care first-line (1L) chemotherapy for mPaC (Conroy NEJM 2011; von Hoff NEJM 2013); however, predictive factors are currently unknown and early progr has not been addressed in the maintenance setting. We examined factors potentially associated with early progr in POLO. Methods: Following ≥16 weeks of 1L platinum-based chemotherapy (PBC) without progr, pts were randomized to maintenance O (tablets; 300 mg bd) or P until progr or unacceptable toxicity. Early progr was defined as progr (by blinded independent central review) or death within 4 m of randomization. A stepwise logistic regression model included baseline (BL) factors age, albumin, lactate dehydrogenase (LDH), global health status (GHS) and physical functioning (PhysF) as continuous variables, and discrete variables listed in the Table. Results: 62/154 randomized pts (40%) were defined as early progressors (EP; Table). Due to missing BL data, the multivariate analysis included 127 pts (56 EPs [44%]). Lower BL PhysF score (continuous) was significantly associated with early progr ( P= 0.02); no difference for partial/complete response (PR/CR) vs stable disease (SD). Conclusions: While small sample size limited analysis power, PhysF score was the only BL factor significantly associated with early progr in pts with a gBRCAm and mPaC in the POLO trial of maintenance O vs P. Clinical trial information: NCT02184195 . [Table: see text]
BRCA mutations in metastatic colorectal cancer (mCRC) and response to chemotherapy.
Authors: Sophie Feng, Laith Al-Showbaki, Monika K. Krzyzanowska, Rebecca M. Prince, Tracy Stockley, Celeste Yu, Philippe L. Bedard, Lillian L. Siu, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2020)

235 Background: Mutations in BRCA 1/2 are typically associated with breast, ovarian, pancreatic and prostate cancers. BRCA mutations have been reported in colorectal cancer in sporadic case series. Unlike other cancers, the significance of BRCA mutations in mCRC is not known. We report the prevalence and molecular characteristics associated with BRCA 1/2 mutations in mCRC, and investigate the impact of these mutations on chemotherapy response since both oxaliplatin (OX) and irinotecan (IRI) interfere with DNA repair pathways. Methods: The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) database was queried to identify mCRC patients (pts) harbouring BRCA 1/2 mutations. BRCA 1/2 mutations were detected using panel-based next generation sequencing (NGS) on archival tumour tissue. Clinical and molecular variables were collected, together with treatment outcomes. Results: Of 279 mCRC pts within the OCTANE database as of March 2019, 9 pts with BRCA 1/2 mutations were identified (3.2%): 4 BRCA 1 and 5 BRCA 2 mutations. Each patient had a unique variant with 8/9 missense mutations and 1/9 splicing error. Allele frequency ranged from 0.11 to 0.57. RAS or BRAF mutations were present in 67%. Common co-mutations included TP53 (56%), APC (56%), TSC1 (44%), ROS1 (33%) and ATM(33%). 2 pts were mismatch repair deficient. Median age was 48.5 years (range: 31-69 years), 56% males. 5 pts presented with de novo metastatic disease. First line OX-containing chemotherapy was administered to 4 pts, and IRI to 3 pts. 2 pts did not receive chemotherapy (1 had surgery only post-adjuvant OX, and 1 immunotherapy). Overall response rate (ORR) was 71%, with all pts achieving a partial response or stable disease. The median progression-free survival was 7.5 months (range: 1.8- 31.7 months) and median overall survival 68.5 months (range: 10.5- 68.5 months) respectively. Conclusions: BRCA 1/2 mutations are present in a small subset of mCRC pts. Pts with these mutations tend to be younger at diagnosis. BRCA 1/2 mutations are associated with favourable response to first line chemotherapy. Targeting BRCA 1/2 mutations may broaden treatment options for these patients.
Former NHS director convicted of voyeurism is struck off
Authors: Clare Dyer
Journal: BMJ (2020)

Jonathan Fielden, former deputy medical director of NHS England, has been struck off the UK medical register after being convicted of voyeurism.

Fielden, who was also national director of specialised commissioning for NHS England at the time of the incident, pleaded guilty to one count of voyeurism at Luton Crown Court in February 2019.1

He admitted watching a child having a shower through a ventilation pipe for up to “15 to 20 seconds” when he was in the loft of a private home and the child was in the bathroom below. He also admitted watching for the purpose of sexual gratification.

He …