tbuckley/cabot-search huggingface dataset:
Mutational profiling of resected intrahepatic cholangiocarcinoma.
Authors: Linda Ma Pak, Debra Goldman, Mithat Gonen, Peter J. Allen, Vinod P. Balachandran, Michael Ian D'Angelica, Ronald P. DeMatteo, T. Peter Kingham, Amber Simpson, Jaclyn Frances Hechtman, Efsevia Vakiani, Carlie S. Sigel, Maeve Aine Lowery, William R. Jarnagin
Journal: Journal of Clinical Oncology (2017)

e15675 Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive neoplasm with increasing incidence and mortality. Resection is the only potential curative treatment and is associated with 5-year survival up to 44%. The objective of this study was to characterize the mutational landscape of patients with ICC undergoing resection and to identify potential prognostic genetic markers that may be unique to these patients. Methods: Sixty-six resected ICC tumor specimens were assessed for genetic alterations using next-generation sequencing of 410 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). We identified the gene alterations occurring with greatest frequency and grouped mutations by known cancer pathways and families, such as RAS-MAPK pathway, mTOR pathway, Notch signaling pathway, chromatin-remodeling gene family, and DNA repair gene family. Overall survival (OS) was calculated from time of resection until death and disease-free survival (DFS) was calculated from resection until recurrence or death. Kaplan Meier 5-year estimates and the log-rank test were used to evaluate the associations with OS and DFS, adjusted for multiple comparisons with false discovery rate (FDR) correction. Results: The median age of all patients was 65 years (range 29-87 years). Majority of tumors were T1 (24/66, 36%) or T2 (35/66, 53%), and of moderate differentiation (46/66, 70%). Lymphovascular invasion, perineural invasion, and periductal infiltration were present in 34 (52%), 20 (30%), and 8 (12%) patients, respectively. The median number of genetic alterations per tumor was 3 (range 0-26). The most common genetic alterations were PBRM1 (16/66, 24%), IDH1 (15/66, 23%), ARID1A (14/66, 21%) and TP53 (8/66, 12%). FGFR2 fusion mutations (5/66, 8%) were relatively rare. The median OS for all patients was 53.4 months (95%CI: 43.0-79.3 months) and median DFS was 17.4 months (95%CI: 10.4-32.6 months). None of the gene alterations or pathways were associated with OS (p = 0.29-0.84) or DFS (p = 0.23-0.65). Conclusions: In this cohort of resected ICC patients, genetic alterations or alterations within gene families, by themselves, did not stratify risk of disease recurrence or death.
When to treat Kaposi’s Sarcoma? Paclitaxel survival benefit on classic versus AIDS/HIV-related subtypes.
Authors: Eduardo Eyzaguirre, Daniel Enriquez, Gabriel Antonio De la Cruz Ku, Victor Castro, Zaida Morante, Natalia Valdiviezo, Diana Portillo, Luis Ernesto Cuellar Ponce de León, Luis Mas, Henry Leonidas Gomez
Journal: Journal of Clinical Oncology (2017)

11077 Background: Kaposi’s Sarcoma (KS) is a angioproliferative disease related to AIDS/HIV (AIDS-KS) or not (Classic, CKS). Treatment options are limited in low-income countries where taxanes represent a cost-effective alternative. Our aim was to compare overall response (ORR) of paclitaxel and progression free survival (PFS) and overall survival (OS) between KS subtypes. Methods: We reviewed 203 medical records from pts diagnosed between 2002-2014 at the Instituto Nacional de Enfermedades Neoplasicas (Peru). Survival differences were calculated by log-rank test in the univariate analysis and Cox regression analysis for prognostic factors. Results: From 203 pts, 85 had CKS and 118 AIDS-CK. Mean age was 67 and 36years in CKS and AIDS-KS, respectively. Most pts were males (84.7%), coinfections as tuberculosis (11.9%) were more frequent in AIDS-CK. In CKS pts, 80% debuted with localized elevated lesions at lower limbs, 16% were resected, 48% received RT and 29% paclitaxel. Among AIDS-KS, 37% had poor risk, 22% were diagnosed concurrently to HIV infection. 76.9% had generalized lesions with origin at lower limbs, 50.5% had +ve nodes and 19% visceral disease. 25.8% had Zubrod &gt; 2 and mean neutrophil to lymphocyte ratio (NLR) was 3.5, CD4 count was lower in pts with recently diagnosis of AIDS/HIV (166 vs 268, p = 0.039) and no differences were noted on viral load (mean 233 411). 77.1% of AIDS-KS pts received ART and 56.8% paclitaxel. In AIDS-KS ORR was 77%(CR:52%, PR:22%) versus 86% in CKS (CR:43%, PR:43%). At 4.3year median follow-up, 3-year PFS and OS was 71% and 75% in AIDS-CK, while CKS had 78% and 79%, respectively. Paclitaxel was associated with better survival among AIDS-KS patients (PFS HR:0.41, 95%CI:0.2-0.7, p = 0.004 and OS HR: 0.37, 95%CI:0.1-0.7, p = 0.007), patients with Zubrod≤2 had more survival benefit. There was not survival benefit in CKS pts. At multivariate analysis, ART and paclitaxel were associated with favorable PFS and OS, while higher NLR and poorer status performance to worse outcomes in AIDS-KS pts. Conclusions: Paclitaxel is an effective alternative treatment for AIDS-KS, there was not survival benefit in CKS patients. Poorer status performance and higher NLR were associated to worse prognosis.
Meaningful changes in quality of life (QoL) in patients with gastric cancer: Exploratory analyses from RAINBOW and REGARD.
Authors: Ian Chau, Charles S. Fuchs, Atsushi Ohtsu, Astra M. Liepa, Zhanglin Lin Cui, Yanzhi Hsu, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2017)

4047 Background: EORTC QLQ-C30 is a well-established QoL instrument for cancer patients (pts), but there is limited information for gastric cancer. To identify priority domains and describe meaningful changes, we explored data from 2 randomized ramucirumab phase 3 trials in pts with previously treated gastric or gastroesophageal junction cancer. Methods: Pts completed QLQ-C30 v3.0 at baseline and Q6W while on study. Data from all treatment arms were pooled (N=1020). Changes from baseline in QoL domains were compared by best overall response (BOR) and ECOG performance status (PS) using analysis of covariance. Odds ratios (ORs) for BOR and PS outcome groups per QoL unit (point) change were estimated by cumulative logit regression modeling, with OR≤0.85 considered meaningful. Results: Changes from baseline in QoL domains were significantly associated with BOR and PS outcomes (Table). ORs for BOR and PS outcomes for these domains were statistically significant (p&lt;0.05) and suggested changes of 10-15 points predict clinical outcomes. Conclusions: QLQ-C30 is sensitive to clinical outcomes in advanced gastric cancer patients, particularly in global QoL, functional status and disease symptoms of fatigue, pain, and appetite loss. These analyses can inform trial designs and interpretation of results. [Table: see text]
Institutional cohort study of HIV-positive patients with lung cancer: Implications for screening?
Authors: Shirin Attarian, Aditi Puri Singh, Christopher Su, Missak Haigentz, Haiying Cheng, Vipul Pareek, Mindy Ginsberg, Xiaoling Guo, Balazs Halmos
Journal: Journal of Clinical Oncology (2018)

e13582 Background: Patients (Pts) with HIV are twice as likely as the general population to be diagnosed with lung cancer. We aimed to study the epidemiological, clinical and pathological characteristics of lung cancer in pts with HIV in an NCI-designated cancer center in the Bronx, a region with a high prevalence of HIV (1675/100000). Methods: In this retrospective study, we reviewed 143 charts of pts with HIV who were diagnosed with lung cancer between 9/2000 and 7/2016. Ninety-one pts with available pathology specimens were selected for the purpose of this study. Demographics, clinical and pathological characteristics were collected for all pts. We compared the age and disease stage of this pt group to the overall group of pts with lung cancer at our institution. Results: Pts with HIV and lung cancer had a mean age of 55.8 years (range 25-71), 67% were men, 45% black, and 25% Hispanic. 55% of pts reported a history of smoking (average 34 pack/year), 34% a history of illicit drug use, and 11% a history of alcohol abuse. At the time of lung cancer diagnosis, 67% of pts had stage IV disease, 33% had a CD4 count of less than 200/mcL with an average CD4 of 370/mcL, and 44% were on antiretroviral therapy (ART). Pathological review revealed that rates of adenocarcinoma, squamous cell carcinoma, small cell carcinoma/neuroendocrine tumors, large cell carcinoma and mixed/rare pathology were 51%, 19%, 15%, 2% and 13% respectively. Pts who were not on ART at the time of lung cancer diagnosis were younger than those who were on ART (p = 0.010). In comparison with the overall group of pts with lung cancer at our institution, pts with HIV were younger (mean age 68.0 vs 55.8, p = 0.014) and had a higher percentage of metastatic disease at diagnosis (49% vs 67%, p < 0.001). Conclusions: Pts with HIV were significantly younger than pts without HIV at diagnosis and a higher percentage presented with advanced disease. These findings have implications in screening recommendations for this population. The median CD4 count was 370/mcL, implying that pts do not have to be severely lymphopenic to develop lung cancer. Pts who were not on ART developed lung cancer at a younger age than those on treatment. Studies on PD-L1 and immune cells in patients with HIV and lung cancer are ongoing.
A 71-Year-Old Man With Inferior ST-Segment Elevation
Authors: Mohammad Alkhalil, Colum Owens
Journal: JAMA Cardiology (2018)

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Randomized phase II study of dual epidermal growth factor receptor inhibition with erlotinib and panitumumab with or without irinotecan as second-line therapy in patients with metastatic colorectal cancer.
Authors: Aparna Kalyan, Sheetal Mehta Kircher, Halla Sayed Nimeiri, Kari Braun Wisinski, Jason J. Suh, Michael Jones, Ali R. Lakhani, Alfred Rademaker, Mary Frances Mulcahy, Al Bowen Benson
Journal: Journal of Clinical Oncology (2016)

e15037 Background: Median PFS for second line treatment of mCRC with anti-EGFR ranges from 4.5-5.5 months. Preclinical data support the hypothesis that dual blockade of the EGFR with a monoclonal antibody, panitumumab (PAN), and a TKI, Erlotinib, enhances the anti-tumor effect of these agents. Evidence also suggests that anti-tumor effects of monoclonal antibody and EGFR TKI are non-overlapping.Irinotecan (IRI) is converted to its more active metabolite, SN-38, and is inactivated by UGT1A1. This inactivation is critical in preventing IRI induced toxicities. The MTD of erlotinib in combination with IRI is correlated to the genotype of UGT1A1. Small retrospective studies have shown that dual blockade with EGFR yielded SD in 76% of patients. Hypothesis: dual blockade of EGFR will have improved tumor response rates in the 2nd line setting. Primary Outcome: Tumor response rate. Secondary outcomes: time to disease progression, time to treatment failure and toxicity profile. Methods: The study used erlotinib at a dose of 150mg/day with IRI doses adjusted based on UGT1A1 genotype. Enrollment was into 3 arms based on the genotype of UGT1A1 with patients being randomized between Arm A & B. Arm A (genotype 6/6 or 6/7) PAN + IRI + erlotinib ; Arm B (genotype 6/6 or 6/7) PAN + Erlotinib ; Arm C (genotype 7/7) PAN + erlotinib. Patients in Arm B crossed over to Arm A at progression. Results: A total of 28 patients were enrolled, (61% males, 31% females) across the 3 arms. 2 patients were homozygous, 16/28 wildtype genotype and 10 were heteroygous. Waterfall plot for tumor best response (SD, CR or PR) was 64%. CR was 4%, PR 25% and SD of 36%. Median PFS was 3.7 months (95%CI 1.8-5.9mths) with median OS 12.1 months (95% CI 5.9-17.6mths). Incidence of grades 3 and 4 reported toxicities were 18% and 3.5%. Grade 3 dermatological toxicity was 22%; grade 3 diarrhea 9%; grade 3 hypomagnesemia 6%; grade 4 hypomagnesemia 25%. Conclusions: We could not generate enough sites to complete accrual. However, dual EGFR therapy in combination with IRI is an efficacious and safe option in the 2nd line setting warranting further evaluation. (NCT00940316, supported by Genentech) Clinical trial information: NCT00940316.
Comparison of physicians, nurses' and patients' assessment of overall symptom burden.
Authors: Shing Mirn Lee, Dawn L. Hershman, John Rowland, Stephanie Aguilar, Kevin Kalinsky, Katherine D. Crew, Ying Kuen Cheung
Journal: Journal of Clinical Oncology (2016)

e18123 Background: In cancer clinical trials, the safety of new drugs are conventionally assessed using outcomes obtained from clinicians. Recently, there has been a growing interest to incorporate the patient’s perspective, which has led to the development of the patient reported version of the National Cancer Institute Common Terminology Criteria for Adverse Events (PRO-CTCAE). However, it can be challenging to quantify the overall symptom burden using a checklist such as the PRO-CTCAE. Thus, it is of interest to evaluate feasible measures of overall symptom burden and to compare physicians’, nurses’ and patients’ report of burden. Methods: Sixty patients starting therapy for breast cancer were enrolled prospectively from 2013 to 2015 at Columbia University Medical Center. Symptom burden scores (SBS) were obtained directly from these patients using a scale from 0 to 10 based on how they feel their disease affects their daily life, with 0 being no effect and 10 being the effects are so severe they would rather be dead. Independently, considering the interactions with the patients and the captured CTCAE, the treating physician and nurse also provided their corresponding SBS. Percent agreements, Wilcoxon signed-rank and T tests were used to compare SBS from physicians, nurses and patients. Results: Out of the 60 patients, 1 was male, 57% were white and 39% were Hispanic. The average age was 55 years and 1 had metastatic disease. In 82% of the patients, physicians’ and nurses’ SBS were within one unit, although nurses’ SBS were slightly higher than physicians’ with a mean difference of 0.31 (p = 0.08). In contrast, physicians’ and nurses’ ratings were one unit within the patients’, in 39% and 42% of the patients respectively. Also, in 18% and 4% of the patients, physicians’ and nurses’ reported little or no symptom burden (SBS ≤ 1), while patients reported moderate to disabling burden (SBS ≥ 5). Both physicians and nurses reported lower scores compared to patients (both p < 0.001), with a median difference of 2. Conclusions: It is feasible to elicit an overall symptom burden score from clinicians and patients. While clinicians generally agree in their assessment of overall symptom burden, patients report higher levels of burden compared to clinicians.
Phase 1 study of onalespib, HSP90 inhibitor, and AT7519M, CDK9 inhibitor, in patients with advanced solid tumors.
Authors: Khanh Tu Do, Alice P. Chen, Robert S. Meehan, Geraldine Helen O'Sullivan Coyne, Jeffrey G. Supko, Jane B Trepel, Jeffrey W. Clark, John L. Hays, John F. Lyons, Harold N. Keer, Julia Hewes, Cameron Sze, Marissa Marzano, Ketki Bhushan, Alona Muzikansky, S. Percy Ivy, James H. Doroshow, Geoffrey Shapiro
Journal: Journal of Clinical Oncology (2017)

TPS2617 Background: The 90kDa heat shock chaperone protein (HSP90) exerts housekeeping functions within cells. HSP90 participates in the folding, stabilization, activation, and proteolytic turnover of mutant or over-expressed “client proteins” that contribute to the growth and survival of cancer cells. HSP90 inhibition leads to degradation of these aberrant proteins through the ubiquitin-proteasome pathway, allowing for simultaneous targeting of multiple pathways. Inhibition of HSP90 alone stimulates a compensatory upregulation of HSP70, which is anti-apoptotic at the pre-mitochondrial, mitochondrial and post-mitochondrial levels. The transcriptional induction of HSP70 has been linked to the activity of CDK9. In vitro and in vivo studies show that disruption of HSP70 induction by CDK9 inhibition can augment HSP90 inhibitor responses. Combined inhibition of HSP90 and CDK9 may produce synergistic anti-tumor activity. Methods: We are conducting an a phase I trial of the combination of the HSP90 inhibitor onalespib, and the CDK9 inhibitor AT7519, utilizing a 3+3 trial design, with dose-limiting toxicities defined during cycle 1. Estimated enrollment: 37 patients. Onalespib and AT7519M are both administered on days 1, 4, 8, and 11 of a 21-day cycle following a 1-week lead-in of onalespib alone to facilitate PK/PD endpoints. Patients must have histologically confirmed solid tumors that have progressed on standard of care therapy or for which no standard treatment exists, with an ECOG 0-1. Exclusion criteria include a prolonged QTc interval (Fridericia formula), pre-existing retinal disease, or cardiac dysfunction with EF &lt; 50% at study entry. Current pharmacodynamic analyses include the analysis of HSP70 expression in plasma and peripheral blood mononuclear cells after treatment with onalespib, and after the combination, as proof-of-principle of target inhibition. At this time, DL1 has completed enrollment; accrual is ongoing with measurement of HSP90 client proteins and HSP70 levels in patient plasma and PBMC samples. This trial is open through the ETCTN. Clinical trial information: NCT02503709.
The clinical characteristic of V600R-mutant melanoma: A single institution experience.
Authors: Karen Malkhasyan, Sydney L. Rooney, Anthony N Snow, Brian L. Swick, Mohammed M. Milhem, Yousef Zakharia
Journal: Journal of Clinical Oncology (2018)

e21581 Background: Currently several different targeted therapy regimens are approved as first-line treatment in V600E/K-mutant advanced and metastatic melanoma. Third most common BRAF mutation, c.1798_1799delGTinsAG; p.V600R, remains usually undetected by FDA-approved companion tests for BRAF inhibitors. Patients with V600R-mutant melanoma were not included in BRAF/MEK inhibitors clinical trials, leaving gap of information about the clinical characteristics of tumors with this mutation. We report a single-institution experience in diagnosis and treatment of patients with V600R-mutant melanoma. Methods: We retrospectively reviewed clinical BRAF mutation testing results and melanoma patients records at the University of Iowa Hospitals and Clinics from 2011 through 2016. DNA from formalin-fixed paraffin embedded tumor specimens were sequenced using an NGS panel or dye terminator sequencing covering exon 15 of the BRAF gene. The protocol was approved by the University of Iowa IRB. Results: Nine patients (5.3% of 168 cases with BRAF mutation) were found to have the V600R mutation. The mean age of the patients was 68 years. Eight out of nine patients were men. For all patients with confirmed primary cutaneous melanoma tumor micro-ulceration was characteristic (5 patients). Three patients in our cohort received BRAF inhibitors. We observed partial response of 5 months to vemurafenib in one patient and partial response of 9 months to the dabrafenib/trametinib combination in another patient. The third patient with metastatic disease demonstrated rapid progression on the dabrafenib/trametinib combination. Conclusions: The V600R-mutant melanoma accounts for a significant number of cases even in single institution practices. We believe that testing for BRAF-mutation should always include rare variants of this mutation. The high rate of ulceration, male predominance and advanced age at diagnosis are features of melanoma with V600R mutation, that are similar to those reported for V600K mutation. We observed objective response to BRAK/MEK inhibitors in majority of cases with V600R mutation.
The efficacy of tyrosine kinase inhibitors with steroid in ph+ acute lymphoblastic leukemia.
Authors: Gunhan Gurman, Mustafa Merter, Erden Atilla, Ugur Sahin, Pervin Topcuoglu, Onder Arslan, Muhit Ozcan, Osman Ilhan
Journal: Journal of Clinical Oncology (2016)

e18531 Background: Better response rates have been reported with the addition of tyrosine kinase inhibitors (TKI) in Ph+ ALL with poor prognosis into the treatment regimens. We evaluated the efficacy of TKIs combined with steroids as an alternative induction treatmentin Ph+ ALL patients.Methods: We present de novo (n=6) and secondary ALL transformed from chronic myeloid leukemia (n=5).Nine were newly diagnosed and 2 were refractory patients (7 M:4 F).Four patients received imatinib (I) 800 mg daily and 40 mg/m2 MP for 45 days, four patient received dasatinib (D) 200 mg daily and 60 mg/m2 MP for 32 days.Two patients had a history of resistance therefore they were treated with bosutinib (B) 500 mg daily plus MP 60 mg/m2 for 32 days.One patient had an allergic reaction to imatinib and dasatinib and was switched to nilotinib (N) 800 mg daily.Results: Ten patients achieved complete hematologic remission (CHR) at median 22th day and one patient achieved CHR at day 45.Complete molecular remission (CMR) was not obtained in our patients after the induction therapy.After a median follow-up of 14 months (range 3-24),nine patients are alive currently and six of them are in CMR.By completion of induction therapy three geriatric patients received TKI/d plus chemotherapy and 4 patients had only TKI/d as maintenance. Four patients underwent Allo-HSCT; median time from diagnosis to Allo-HSCT was 4.5 months (4-11). (Table1) Conclusions: Despite the poor prognostic effect of Ph chromosome in ALL patients, TKI plus steroid regimens may improve outcome and may allow to patients to proceed to Allo-HSCT with low toxicity profile.As shown among the elderly Ph+ALL patients, this regimen might also be appropriate for younger Ph+ ALL patients. Also it can be used as a salvage therapy in refractory patients who have poor performance status and feasible for outpatient follow-up. Patient characteristics. Patient 1 2 3 4 5 6 7 8 9 10 11 Age 69 65 38 70 29 21 61 34 75 50 45 BCR-ABL fusion protein (kD) 190 190 210 210 210 190 190 190 210 210 210 TKI I I I B D D D D B I N BCR-ABL ratio (RT-PCR) at presentation 3,8 - 30,76 40,9 2,7 - - 0,729 - - 25,39 BCR-ABL ratio (RT-PCR) at day 22 0,0006 0,1411 0,2964 25 0,2794 0,09 0,099 0,0025 0,017 0,018 0,005 Ex/Allo-HSCT +/- +/- -/+ -/- -/+ -/+ -/- -/+ -/- -/- -/-