tbuckley/cabot-search huggingface dataset:
Clinical efficacy of cabozantinib plus nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients (pts) with chemotherapy-refractory metastatic urothelial carcinoma (mUC) either naïve (n) or refractory (r) to checkpoint inhibitor (CPI).
Authors: Rosa Nadal, Amir Mortazavi, Mark N. Stein, Sumanta K. Pal, Daniel K Lee, Howard L. Parnes, Yang-Min Ning, Lisa M. Cordes, Mohammadhadi H. Bagheri, Ryan Thompson, Christian Mayfield, Seth M. Steinberg, Paul Monk, Primo Lara, Rene Costello, Piyush K. Agarwal, Donald Bottaro, William L. Dahut, Andrea B. Apolo
Journal: Journal of Clinical Oncology (2018)

4528 Background: Preliminaryclinical activity of CaboNivo and CaboNivoIpi has been previously reported for mUC pts and other genitourinary tumors. Here, we report longer follow-up data of CaboNivo and CaboNivoIpi in pts with mUC nCPI and safety and preliminary clinical activity of CaboNivo in mUC rCPI Methods: This phase 1 dose + expansion cohorts study enrolled mUC nCPI (escalating doses of CaboNivo n = 15 and CaboNivoIpi n = 8) and mUC rCPI (Cabo40-Nivo3mg/kg n = 7) pts until progression/unacceptable toxicity. Objectives: Safety, ORR, DOR, PFS and OS. Tumors were assessed for response q8wks (RECIST 1.1). Adverse events (AEs) were graded (G) by NCI-CTCAE v4.0. Results: 30 mUC pts enrolled. Median follow-up: whole cohort: 11.9 months; mUC rCPI: 5.6 months. All G clinical AEs in ≥20% (n = 29): fatigue (83%), diarrhea (72%) and anorexia (62%); laboratory AEs: ALT elevation (55%), AST elevation (48%) and hyponatremia (48%). Common ≥G3 clinical AEs: fatigue (17%), HTN (14%), thromboembolic events (14%); laboratory AEs: lipase elevation (31%), hypophosphatemia (17%), hyponatremia (10%). Immune-related AEs 14% (n = 4): mUC nCPI: CaboNivo: G3 meningitis; G3 pneumonitis; CaboNivoIpi: G3 colitis; mUC rCPI: G2 adrenal insufficiency. For mUC nCPI CaboNivo ORR: 50% (6/12), mDOR: 24.1months(mo) [95% CI: 7.8 mo-not reached (NR)]; mPFS 24.1mo [95% CI:1.6mo-NR] & mOS: NR. For mUC nCPI CaboNivoIpi: ORR: 33% (2/6), mDOR: NR; mPFS 10.1mo [95% CI:1.6 mo-NR] & mOS: NR. For mUC rCPI CaboNivo, ORR: 28% (2/7), SD 57% (4/7) and DOR: 100% at 5mo. Conclusions: Both CaboNivo and CaboNivoIpi are safe and active in mUC nCPI pts, CaboNivo is also active in mUC pts previously treated with immunotherapy, suggesting the addition of Cabo to Nivo may aid in overcoming CPI resistance. Clinical trial information: NCT02496208.
Preference of end-of-life discussion at diagnosis in patients with advanced/recurrent cancer.
Authors: Aiko Maejima, Saran Yoshida, Shun Kudo, Hiroko Bando, Kenjiro Aogi, Eriko Tokunaga, Masayuki Furukawa, Hiroyuki Otani, Ken Shimizu, Yasunari Sakamoto, Takuji Okusaka, Tatsuya Morita, Chikako Shimizu
Journal: Journal of Clinical Oncology (2017)

e21511 Background: End-of-life discussion (EOLd) including information about incurability, prognosis, the site of death, and do-not-resuscitate (DNR) status is considered indispensable for advanced care planning (ACP). However, the preference for EOLd in cancer patients has not been elucidated. Objective: To clarify the preferences of EOLd in Japanese patients with newly diagnosed advanced or recurrent cancer. Methods: A multi-center questionnaire survey was conducted on Japanese adult patients with breast cancer, pancreatic cancer, or sarcoma, who were diagnosed as incurable within the past three months. We asked patients whether they would like to have EOLd with their physician at the time of survey. Factors related to preferences of EOLd were analyzed using chi-square or Mann-Whitney U-test. Results: For 1 year from August 2015, we distributed the questionnaire to 251 patients at five centers. Responses were obtained from 159 patients (45 males, 113 females) (response rate: 63%). The median age was 65 years (range: 29-86). 93 patients (59%) answered they would like to have EOLd, while 60 patients (38%) answered they would not. In univariate analyses, elderly patients (odds ratio [OR]: 1.03; p = 0.027), patients having worse performance status (OR: 1.988; p = 0.03), and with any physical symptoms (OR: 1.533; p = 0.044) preferred to have EOLd. On the other hand, patients who perceived “being able to sufficiently fight the disease” ( p = 0.021) and “living without being aware of the disease” ( p = 0.004) as important were reluctant to have EOLd. 114 patients (72%) answered they wanted to know their life-time prognosis. Employed patients preferred to know their prognosis (OR: 8.919; p = 0.004) while patients who had received chemotherapy did not (OR: 0.313; p = 0.009). Conclusions: Even just after the diagnosis as an incurable disease, more than half of patients with advanced cancer were willing to have EOLd with their treating physician. Patients’ preference of knowing about life-time prognosis was affected by their social and medical experience.
Veristrat based stratification of responses to immune checkpoint blockade (ICB).
Authors: Paul R. Walker, Nitika Sharma, Chipman Robert Geoffrey Stroud, Mahvish Muzaffar, Cynthia R. Cherry, Sulochana Devi Cherukuri, Teresa Parent, Jessica Hardin
Journal: Journal of Clinical Oncology (2017)

e20512 Background: Veristrat (Biodesix, Boulder, CO) is a blood based proteomic assay that is dominated by inflammatory proteins and is prognostic and predictive in metastatic NSCLC after treatment with platinum based chemotherapy (Gregorc et al, Lancet 2014). Smoldering inflammation in the tumor microenvironment regulates and escalates cancer invasion, angiogenesis and immune surveillance escape (Balkwill and Mantovani, Lancet 2001). There is preclinical evidence to suggest that the tumor microenvironment can be altered with immunomodulatory interventions (Martino et al, 2016). While immune checkpoint blockade has shown durable benefit in metastatic NSCLC, the response rates still hover around 20%. As a result, identification of predictive biomarkers are of critical importance. The predictive value of the Veristrat assay with respect to ICB is poorly defined. Methods: At our institution, 83 pts with metastatic lung cancer pts were treated with nivolumab between 6/2015 to 12/2016. The following clinicopathologic characteristics were abstracted from medical records: tumor histology, Veristrat status, no. of doses of nivolumab, irAEs and overall survival. Results: Of the 83 pts, 65 pts were found to have NSCLC. Veristrat status was available for 17/65 of these pts. Nine pts were identified to have “Veristrat good” and seven pts were “Veristrat poor”. Median number of nivolumab doses was 4. Median survival for all patients was 30 weeks. Median survival was 20 weeks for “Veristrat poor” and 26 weeks for “Veristrat good”(p = 0.68). Grade 3-4 irAEs were noted in 5/9 patients with “Veristrat good” and 5/7 patients with “Veristrat poor”. Conclusions: “Veristrat poor” pts treated with ICB have a lower median survival as compared to “Veristrat good” pts. Our study did not meet statistically significant end point due to limited sample size. Further studies are needed to identify poorly immunogenic tumors and develop novel treatment approaches to optimize outcomes. [Table: see text]
Patients should not be denied access to hip surgery
Authors: Andrew Manktelow
Journal: BMJ (2018)

Patients having to apply for exceptional funding when referred for hip surgery, which is increasingly refused, is concerning.1

Although many patients with hip arthritis are successfully managed conservatively, symptoms worsen with compromised function and increasing pain. Prolonged waiting times lead to worsening deformity, muscle wasting, and bone loss, which compromise outcomes and increase complications. Timing of referral is critical.

Anecdotally, surgeons …
Dynamic role of GTP-energy metabolism in metastasis of renal cell carcinomas: Prognosis and therapeutic applications.
Authors: Jaskirat Singh Randhawa, Hirofumi Yoshino, Takashi Kobayashi, Satoshi Kofuji, Kara Finley, Nazanin Majd, Akshiv Malhotra, Trisha Wise-Draper, Toshinari Yamasaki, Shinsuke Shibuya, Osamu Ogawa, Koichi Okumura, Atsuo Sasaki
Journal: Journal of Clinical Oncology (2016)

e16107 Background: Identification of altered metabolic pathways in metastatic renal cell carcinoma (RCC) has the potential to aid in the development of diagnosis and targeted therapies. While alterations in glucose metabolism in RCC have been previously described, it remains unknown whether other metabolic alterations could serve as prognostic indicator due to the lack of an identifying molecular marker. Methods: To identify the altered metabolic pathway in metastatic RCC, we have taken biochemical, molecular biological, bioanalytical and metabolomics analyses using renal cell carcinoma cell lines—786o and A498cell. To examine the significance of the identified gene(s), we used gene knockout approach using CRSPR/Cas9 system and pharmacological inhibition of the target. We then have taken pathological analysis using commercial available RCC specimens and Kyoto University’s cohort (in progress) Results: Our HPLC (High Performance Liquid Chromatograph) analysis showed increase in the metabolism of GTP (guanosine triphosphate), an essential energy molecule for cell proliferation, in RCC cultured cell lines, compared to primary renal epithelial cells. We found that expression of mRNA as well as protein levels of a key enzyme for GTP-metabolism elevated in metastatic RCC cells. Gene knockout study indicate that the GTP-metabolic changes is critical for cell motility of RCC. Pharmacological inhibition of the metastatic RCC-specific GTP-metabolism also suppressed the RCC’s motility. Immunohistochemical analysis showed that metastatic RCC patients increase the identified GTP metabolic enzyme. Conclusions: Our data suggest that the metastatic RCC undergo GTP-metabolic switch and this is critical for their metastatic activity. The results show that a simple immunohistochemical assay can detect this switch in GTP metabolism and potentially serves as a functional marker for metabolic reprogramming of metastatic RCC. Finally, our data suggest that alternate GTP metabolic pathway is a potential novel therapeutic target for RCC.
A stage versus stage survival analysis of small bowel and colon adenocarcinomas using the SEER database.
Authors: Maclean Harvey Thiessen, Richard M. Lee-Ying, Jose Gerard Monzon, Patricia A. Tang
Journal: Journal of Clinical Oncology (2018)

e16265 Background: Current recommendations for adjuvant chemotherapy for small bowel adenocarcinomas (SBAs) are largely based on extrapolation from colon cancer data. As a result, many stage I and stage II SBAs may not be offered adjuvant chemotherapy. This study evaluated the survival outcomes for SBAs utilizing colon adenocarcinoma as a benchmark for prognosis. Methods: Survival analysis comparing small bowel and colon adenocarcinomas was carried out using the SEER database. Cases diagnosed between 2004 and 2014 with complete demographic and staging information were included in this analysis. Results: A total of 557 small bowel and 39272 colon cancer cases were included. Compared to colon primaries, SBAs were associated with younger age (p=<.01), male gender (p=<.01), black ethnicity (p=<.01), lower rate of stage I (p=<.01) and higher rate of stage III (p=<.01) presentation. Univariate analysis demonstrated that SBAs are associated with worse outcomes compared to colon primaries of the equivalent stage (Table). Additionally, the outcomes for stage I and II SBAs were more comparable to stage III colon cancer than their equivalent colon stage. When T3 and T4 stage II SBAs were compared separately to stage III colon cases, outcomes remained worse for T4’s (HR=1.58 p=<.01), while the outcomes for the T3 subset did not statistically differ (HR=0.98 p=0.89). When age, gender, race, grade, and stage were controlled for in multivariate analysis, SBA primaries remained associated with worse survival than colon primaries (HR=1.83 p=<.01). Conclusions: Stage for stage, survival outcomes for SBAs are worse than those arising from the colon. Additional research is needed to clarify the role of adjuvant systemic therapy for SBAs, including for patients with stage I and stage II disease that may not currently be considered for chemotherapy. Primary Site Stage Small Bowel I II III IV n 40 217 202 98 Survival* (months) 46.3 61.7 46.9 22.4 Hazard Ratio of Death vs. Colon Primary p Colon I 6619 99.4 2.34 <.01 2.49 <.01 3.97 <.01 8.73 <.01 II 14110 89.9 1.59 0.09 1.69 <.01 2.70 <.01 5.68 <.01 III 12047 76.0 1.16 0.58 1.24 0.04 1.85 <.01 3.83 <.01 IV 6496 30.4 0.34 <.01 0.37 <.01 0.59 <0.01 1.24 0.06 *Median Overall Survival
A prospective analysis of germline alterations (GA) in biliary tract cancer (BTC).
Authors: Maeve Aine Lowery, Emmet Jordan, Yelena Kemel, Semanti Mukherjee, Andrea Cercek, Nancy E. Kemeny, Anna M. Varghese, Matthew Rusek, Taryn Mary Boucher, Diana Mandelker, Michael F. Berger, Ryan Ptashkin, David Michael Hyman, David Klimstra, Leonard Saltz, Eileen Mary O'Reilly, Mark E. Robson, Zsofia Kinga Stadler, Kenneth Offit, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2017)

4085 Background: The incidence of hereditary cancer predisposition syndromes in patients (pts) with BTC is unknown. Cholangiocarcinoma has been reported in pts with germline mutations in BAP1, BRCA1/2, and mismatch repair genes. These associations are poorly characterized to date and the majority of pts do not undergo clinical germline analysis (CGA). Methods: Pts with BTC were offered consent to CGA between 01/2016 and 01/2017 under an IRB approved protocol (NCT01775072). Using the MSK-IMPACT platform, 76 genes associated with hereditary cancer predisposition were analyzed for germline variants and matched tumor samples were analysed for somatic alterations in &gt; 340 genes. Demographic and clinical data were collected. Results: 78 patients were accrued: Intrahepatic = 52, extrahepatic = 13, gallbladder = 13. Median age at diagnosis was 57 years (range 21-80), 45 (58%) had a positive family history of cancer in at least one 1 st degree or two 2 nd degree relatives. 7 patients had a personal history of cancer. A pathogenic or likely pathogenic GA was identified in 16 pts (20%). (See table). Conclusions: Prospective analysis of GAs in pts with BTC, unselected by family history or age, revealed potentially actionable findings in 20% of pts. CGA in pts with BTC may benefit patients and their families in view of screening and therapeutic implications. [Table: see text]
Intravenous fosaprepitant for the prevention of chemotherapy induced vomiting in children: A double blind placebo controlled, phase III randomized trial.
Authors: Archit Joshi, Venkatraman Radhakrishnan, Jaikumar Ramamoorthy, Trivadi S. Ganesan, Swaminathan Rajaraman, Prasanth Ganesan, Manikandan Dhanushkodi, Tenali G. Sagar
Journal: Journal of Clinical Oncology (2018)

10527 Background: Fosaprepitant, is a Neurokinin-1 (NK-1) receptor antagonist, approved in adults for the prevention of vomiting associated with administration of moderately or highly emetogenic chemotherapeutic agents. The efficacy and safety of fosaprepitant in children is not known. Therefore, we conducted a phase III randomized trial to assess the safety and efficacy of fosaprepitant in children. Methods: The study was a phase III, single centre, double blind, randomized placebo controlled trial. Children aged 1-12 years with documented malignancy, who were scheduled to receive moderately or highly emetogenic chemotherapy, were randomly assigned to arm A (Fosaprepitant) or arm B (Placebo). Arm A received intravenous ondansetron (0.15 mg/kg) plus dexamethasone (0.075 mg/kg) followed by fosaprepitant (3 mg/kg) short infusion. Arm B received intravenous ondansetron (0.15 mg/kg) plus dexamethasone (0.15 mg/kg) followed by normal saline as placebo. Oral ondansetron and dexamethasone were continued for 48 hours after completion of chemotherapy. Primary end-point of the study was the proportion of patients who achieved a complete response (defined as no vomiting, no retching) during the 25–120 hours (delayed phase) after administration of fosaprepitant. Secondary end-points were proportion of patients who achieved complete response during the acute (0–24 hours) and overall phases after administration of fosaprepitant. Results: 135 patients were analyzed (68 in fosaprepitant arm and 67 in placebo arm). Complete response rates were significantly higher in fosaprepitant arm compared to placebo arm during acute phase (84% vs. 57%, p < 0.001), delayed phase (79% vs. 51 %, p < 0.001) and overall phases (69% vs. 42%, p = 0.0014). Three (4%) patients in fosaprepitant arm and fourteen (21%) patients in the placebo arm required rescue anti-emetics (p = 0.004). No fosaprepitant related grade 3-4 adverse events were observed. Conclusions: Addition of fosaprepitant to ondansetron with dexamethasone is safe and effective for the prevention of chemotherapy induced vomiting in children being treated with moderately or highly emetogenic chemotherapy. Clinical trial information: CTRI/2017/02/007925.
Anti-mitochondrial therapy in bile duct cancer.
Authors: Angela Tatiana Alistar, Boris Pasche, Bonny Morris, Rodwige Desnoyer, Ralph D'Agostino
Journal: Journal of Clinical Oncology (2017)

e15661 Background: Biliary duct carcinoma is a rare but highly fatal malignancy. The five-year survival rate for advanced bile duct cancer is 2%, per SEER data. As such, new treatment options are desperately needed. CPI-613, a novel anticancer agent that selectively inhibits mitochondrial metabolism in cancer cells, was employed in this study. Methods: This phase 1 study utilized a two-stage dose-escalation schema to determine the maximum-tolerated dose (MTD) and safety of single agent CPI-613 in patients with locally advanced or metastatic bile duct cancers. The 1st cohort enrolled 4 patients at 2300 mg/m 2 , with no dose-limiting toxicities (DLT) observed. The 2nd cohort enrolled patients at 1200 mg/m 2 /day for pre-cycle (days 1-5) and 3000 mg/m 2 on days 1 and 4 weekly for 3 weeks (28 day cycle). The 5th and 6th patient experienced a DLT. The 3rd cohort was initiated at 600 mg/m 2 pre-cycle and 3000 mg/m 2 weekly with no other DLTs observed. Results: To-date, 14 patients have been enrolled in the study. The MTD was determined at 600 mg/m 2 /day pre-cycle and 3000 mg/m 2 as per schedule. Once the MTD was determined, the cohort was expanded and, 8 patients have been treated at the MTD with no DLTs observed. Two additional patients are planned to be enrolled at this dose prior to trial completion. Of these 8 patients, 3 are still alive with 1 having prolonged survival (15 months) and the other 2 still on treatment. The most commonly observed toxicities were mild, such as anemia, anorexia, dehydration, fatigue, nausea and thrombocytopenia. Conclusions: Treatment with CPI-613 was well tolerated by patients with heavy tumor burden and refractory disease. CPI-613 has recently been shown to be well tolerated in combination with FOLFIRINOX in pancreatic cancer patients. Due to the low toxicity of CPI-613 in this study, even among highly symptomatic patients, it is anticipated that combination with other active agents is feasible in patients with advanced bile duct cancer. CPI-613 represents a novel treatment that could prove to be an exciting therapeutic alternative for patients with previously limited options and poor survival. Clinical trial information: NCT01766219.
Computer extracted measurements of intra-tumoral heterogeneity on H&amp;E stained tissue images to distinguish short term and long term survivors in patients with non-small cell lung carcinoma.
Authors: Cheng Lu, Monica Khunger, Rajat Thawani, Vamsidhar Velcheti, Anant Madabhushi
Journal: Journal of Clinical Oncology (2017)

e20052 Background: Molecular and morphologic heterogeneity is an important characteristic of cancer. This spatial and temporal tumor heterogeneity has important implications on tumor behavior and response to therapies. This study aims to evaluate the role of computer extracted features of intra-tumoral heterogeneity (ITH) from digitized whole slide H&amp;E stained images of early stage NSCLC patients treated with surgery as a prognostic marker for survival. Methods: A cohort of 89 early stage NSCLC patients treated with surgery with long term survival data were identified. 28 patients had OS&gt; 3 years from the date of definitive surgery and were defined as long term survivors and 61 patients had OS &lt; 3 years, and were defined as short term survivors. Corresponding H&amp;E stained whole mounted lung tissue images was digitally scanned and a thoracic pathologist marked the primary tumor margins on these images. Our computational approach involved determining the variance in measurements relating to nuclear size, shape, and texture across the tissue section; Each feature was then assigned a morphologic diversity score (MDS) based off the variance; the top predictive MDS features were identified via Wilcoxon Rank Sum Test and then evaluated via a quadratic classifier using 3-fold cross validation. Kaplan-Meier (KM) survival analysis was performed for the ITH features, as well as T- and N-stage. Results: The top ranked MDS features yielded a mean area under the receiver operating characteristic curve (AUC) of 0.66 in discriminating short term from long term survivors. A p=0.00657 (see Table) was obtained for KM-analysis of the ITH features. Conclusions: Computer extracted image features of ITH enabled differentiation of NSCLC patients with short and longer term survival. Large scale multi-site validation will need to be done to establish ITH measurements as a prognostic biomarker for NSCLC patients. [Table: see text]
Comparison of cooled-probe microwave and radiofrequency ablation treatment in incipient hepatocellular carcinoma: A phase III randomized controlled trial with 6-year follow-up.
Authors: Jie Yu, Ping Liang, Xiao-ling Yu, Zhi-gang Cheng, Zhi-yu Han, Fang-yi Liu
Journal: Journal of Clinical Oncology (2016)

4068 Background: According to randomized controlled trial (RCT) requirement, the therapeutic effectiveness of cooled-probe microwave ablation (MWA) versus radiofrequency ablation (RFA) on early-stage < 5cm hepatocellular carcinoma (HCC) was investigated to find a better approach for minimally invasive thermal ablation. Methods: From October 2008 to June 2015, 403 cases of biopsy-proved HCC patients were involved in a RCT study, 203 (265 nodules) cases were treated with ultrasound guided percutaneously MWA and 200 (251 nodules) cases were treated with RFA. The patients were then followed up with contrast enhanced imaging including contrast enhanced ultrasound, magnetic resonance imaging or computed tomography to evaluate treatment response prospectively, including technique effectiveness (TE), local tumor progression (LTP), intrahepatic metastases, extrahepatic metastases, complications, disease free survival(DFS) and overall survival(OS). Survival was analysed using the Kaplan–Meier method. The study has been registered in Clinical-Trials.gov and the identifier number is NCT02539212. Results: The follow-up period was 35.2 (range 2.0-81.9) months. MWA needed less applicator number, ablation session, puncture number, ablation duration and expense (P< 0.05). The TE rates were 99.6% (264/265) in MWA and 98.8% (248/251) in RFA. The 1-, 3-, 5-year LTP were 1.1%, 4.3%, 11.4% for MWA versus 2.1%, 5.8%, 19.7% for RFA, respectively(P= 0.11). The 1-, 3-, 5-year OS were 96.4%, 81.9% and 67.3% for MWA and 95.9%, 81.4% and 72.7% for RFA, respectively (P = 0.91). There was no difference in 5-year intrahepatic metastatic (P= 0.30) and extrahepatic metastatic rates(P= 0.12) between two groups. There was also no difference in major complications between MWA(3.4%) and RFA (2.5%) (P= 0.59). Conclusions: Both MWA and RFA are suitable options for early-stage HCC. MWA shared the advantages of less ablation duration, puncture, session and expense. Therefore, MWA seems a safe and promising treatment of HCC. Clinical trial information: NCT02539212.