tbuckley/cabot-search huggingface dataset:
Effects of bendamustine, bortezomib, and rituximab on 1-year survival rates in elderly patients newly diagnosed with mantle cell lymphoma.
Authors: Shuangshuang Fu, Michael Wang, Hui Zhao, Ruosha Li, David R. Lairson, Sharon Hermes Giordano, Xianglin L. Du
Journal: Journal of Clinical Oncology (2018)

e19537 Background: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin lymphoma with a median age at diagnosis of 69. Over the past two decades, several novel agents have been approved to treat MCL. The study evaluated the comparative effectiveness in terms of 1-year survival rates for bendamustine, bortezomib, rituximab, and chemotherapy in elderly patients newly diagnosed with MCL. Methods: All newly diagnosed MCL patients aged 66 or older were identified in SEER-Medicare databases from 1999-2013. Patients were categorized into four groups based on their first-line treatment regimens (chemotherapy alone, rituximab ± chemotherapy, bortezomib ± chemotherapy, and bendamustine ± chemotherapy). Multivariate proportional hazard regressions were performed to compare the all-cause mortality and MCL-specific mortality rates among four treatment groups. Results: A total of 1,338 eligible MCL patients were included (chemotherapy alone group= 192, rituximab group= 919, bortezomib group= 35, and bendamustine group= 192). In the multivariate regressions with 1-year follow-up, rituximab and bendamustine groups showed decreased all-cause mortality rates (Rituximab vs. chemotherapy: hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.35-0.71; Bendamustine vs. chemotherapy: HR 0.59, 95% CI 0.35-1.00) and MCL-specific mortality rates (Rituximab vs. chemotherapy: HR 0.50, 95% CI 0.35-0.72; Bendamustine vs. chemotherapy: HR 0.53, 95% CI 0.30-0.93) compared with chemotherapy alone group. Bortezomib group did not show decreased 1-year mortality rates compared with chemotherapy alone group. When comparing bendamustine with rituximab groups, there was no significant difference in either 1-year all-cause mortality or MCL-specific mortality rates. Conclusions: For elderly patients newly diagnosed with MCL, addition of rituximab and bendamustine as first-line treatment showed significantly improved 1-year survival rates compared with chemotherapy alone, but addition of bortezomib did not improve the 1-year survival rate.
Everolimus in combination with Octreotide LAR in first line setting for patients with neuroendocrine tumors (I.T.M.O. study): A 5-years update.
Authors: Emilio Bajetta, Laura Catena, Sara Pusceddu, Nicola Fazio, Italo Sarno, Giandomenico Di Menna, Lorenzo Dottorini, Anna Maria Marte, Carmela Turco
Journal: Journal of Clinical Oncology (2016)

4092 Background: We previously presented data of this phase II study showing that the combination of Everolimus and Octreotide LAR for advanced neuroendocrine tumors (NETs), in the first line setting, is an active and safe treatment. At a median follow-up period of 277 days, the median time to progression (TTP) and the overall survival (OS) have not been reached (ASCO 2013 Abs. 4136). Methods: We performed a phase II, multicenter trial using a Simon two-stage minmax design. Patients with advanced well differentiated, previously untreated neuroendocrine tumors of the gastroenteropancreatic (GEP) tract and of the lung, received Octreotide LAR 30 mg every 28 days in combination with Everolimus 10 mg per day, continuously. The primary endpoint was objective response rate (ORR). Currently we performed an analysis of “long responder” patients and of OS and TTP after 5 years. Results: A total of 50 patients (58% males) were enrolled; 17 (34%) of these patients have received treatment for more than 2 year. The median exposure to study drugs is 519.5 weeks (range 48-2024). Currently 3 patients are still taking advantage from the above mentioned treatment. The primary tumor site was: liver 2 pts, pancreas 11 pts, small intestine 8 pts, lung 7 pts and unknown in 8 pts About 70% of these patients had no carcinoid Syndrome and 50% received surgery at the primary tumor site. The ORR (RP+RC) was 18%: CR 1 pt, PR 8 (22%) pts, SD 27 (75%) pts. The median TTP is 33.6 months (95% CI 18,7 – 41,2). The median OS is 61,9 months (95% CI 49,8 – n.d.). Conclusions: Everolimus in combination with octreotide LAR has shown to be active in advanced NETs. The current analysis showed a further prolongation of TTP, and a long exposure to the study drug without major side effects in the long term. The treatment with two drugs has induced objective responses, but also long duration SD. Because of scarce therapeutic options, phase III studies for this combination are desirable to improve the therapeutic possibilities for this disease. Acknowledgements: Italian Trials in Medical Oncology (I.T.M.O.) group, Giacinto Facchetti Foundation and Novartis.
Improving mental status evaluation in older adults with cancer: The development of the MHI-13.
Authors: Mackenzi Pergolotti, Michelle M Langer, Allison Mary Deal, Hyman B. Muss
Journal: Journal of Clinical Oncology (2016)

10044 Background: The Mental Health Index ([MHI], Viet & Ware, 1983) is widely used as a measure of mental health, but it has never been evaluated in the geriatric oncology population. This study psychometrically evaluated the MHI-17 in a geriatric oncology population, with the goal of establishing validity and scoring rules. Methods: The Carolina Senior Registry (NCT01137825) was used to obtain GA data for 686 adults 65+ with cancer who completed the MHI-17. The 17-item patient-reported measure produces one total score summing across 4 domains: anxiety, depression, positive affect, and sense of belonging; higher scores indicate better mental health. Reliability of the MHI-17 was assessed using Cronbach’s alpha (α) and item-total correlations. Confirmatory factor analyses (CFA) were used to evaluate dimensionality and validity. Item-level analyses and scoring algorithms were based on item response theory (IRT). Results: The MHI-17 had high internal consistency (α = 0.90) and substantial item-total correlations ( > 0.30). However, initial CFA testing of the MHI-17 as a one-factor model was rejected (CFI = 0.92; TLI = 0.91). Retaining only the 13 best-fitting items from the MHI-17, we then hypothesized the MHI as only two domains: depression and anxiety. The final model with two subscales, anxiety (4 items, CFI = 0.99; TLI = 0.98) and depression (9 items, CFI = 0.96; TLI = 0.95) supported a shorter 13-item scale. IRT analyses of the 4 anxiety items indicated good fit (RMSEA = 0.08) and precise measurement of adults with poor mental health, from 3 SDs below to 1 SD above the mean for anxiety. IRT analyses of the 9 depression items indicated good overall fit (RMSEA = 0.05) and precise measurement of adults with poor mental health, from 4 SDs below to 1 SD above the mean of depression. IRT scores were developed to provide meaningful norms. Conclusions: The new MHI-13 is a shorter, more accurate way to assess mental health in older adults with cancer. The MHI-13 allows clinicians to separately identify anxiety or depression - a clinically important distinction as treatment differs among these two types of mental dysfunction. We suggest the MHI-13 replace the MHI-17 for the geriatric oncology population.
Comparative molecular analyses of esophageal cancer: Adenocarcinoma vs. squamous cell carcinomas and impact on outcome.
Authors: Mohamed E. Salem, Joanne Xiu, Shaheer A. Khan, Hongkun Wang, Brandon George Smaglo, Wafik S. El-Deiry, Jimmy J. Hwang, Michael J. Pishvaian, Emil Lou, Anthony Frank Shields, Philip Agop Philip, Zoran Gatalica, Sandeep K. Reddy, John Marshall
Journal: Journal of Clinical Oncology (2016)

4035 Background: Patients (pts) with esophageal cancer (EsophCa) have a poor prognosis and limited treatment options. The effect of histological subtype on tumor molecular profile remains unknown. Here we aim to compare the molecular aberrations in esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). Methods: EsophCa tumors submitted to Caris Life Sciences for IHC (protein expression), ISH (gene amplification), and NGS sequencing between 2009 and 2015 were studied and correlated with pt outcomes. Chi-square tests determined differences between histological subtypes. Kaplan-Meier methodology estimated survival. Results: A total of 966 tumors (883 EACs and 113 ESCCs) were examined. Most frequently mutated genes were TP53 (71%), BRCA2 (10%), HNF1A (9%), APC (8%), SMAD4 (6.3%), PIK3CA (4.4%), ATM (5.3%), cMET (3%), ERBB2 (2.2%), PTEN (2%), and NOTCH1 (1%). When we compared EACs with ESCCs, KRAS (6.5%), NRAS (1.4%), GNAS (1%), and BRAF (0.7%) mutations were seen only in EACs, whereas, NFE2L2 mutations (R34P and E79G), and HER-2/neu overexpression (12%) and amplification (20%), were seen only in ESCCs (p < 0.001). EACs had higher overexpression of P-glycoprotein (PGP) (51% vs. 8%, p < 0.01) compared with ESCCs. ESCCs showed higher PD-L1 expression (19% vs. 6%, p < 0.01), but there was no difference in the frequency of PD-1 expression on tumor-infiltrating lymphocytes. ESCCs also had higher overexpression of ERCC1 (55% vs. 36%, p = 0.01), MGMT (62% vs. 49%, p = 0.01), EGFR (93% vs. 75%, p = 0.003), TLE3 (70% vs. 34%, p < 0.001), RRM1 (52% vs. 36%, p = 0.006), PTEN (67% vs. 50%, p = 0.001), and TOPO1 (76% vs. 61%, p = 0.002) compared with EACs. In a small subset of pts, survival data were available, and low PGP expression was associated with prolonged survival (HR = 8.7, p = 0.004).Conclusions: Molecular profile differences between EACs and ESCCs indicate different carcinogenic pathways, and biology, that may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities. Correlation of low PGP with prolonged survival implicates PGP as a prognostic biomarker, and highlights the importance of targeting multi-drug resistance.
Chromatin instability as a marker of poor prognosis for a range of malignancies.
Authors: David J. Kerr, Havard Danielsen
Journal: Journal of Clinical Oncology (2016)

11586 Background: Chromatin organisation influences gene expression, regional mutation rates and is thought to contribute to carcinogenesis. Assessment of the texture of tumour cell nuclei has been utilised to detect aberrant organisation of the DNA and correlate this with prognosis, but hitherto, the methodology has not been sufficiently well validated to permit its clinical application. Methods: We developed an automatic method to identify chromatin instability which is independent of cancer type and robust to imaging discrepancies. The prognostic ability of the novel marker was evaluated by analysing 3.2 million images of DNA-stained tumour cell nuclei from 2088 patients with five different cancer types. Results: Patients with chromatin unstable tumours were consistently associated with increased risk of recurrence and mortality. Chromatin unstable tumours were present in 52% of the patients with poor prognosis and 22% of the patients with good prognosis; the overall correct classification rate was 71%. In 5-year overall survival, the hazard ratio was 2.8 (95% confidence interval [CI], 2.3 to 3.3) in univariate analysis and 1.6 (95% CI, 1.3 to 1.9; P < 0.001) after adjustment for established prognostic marker. The objective chromatin instability marker, termed Nucleotyping, accurately labelled patients with poor postoperative outcome following resection of uterine sarcoma, prostate, colorectal, ovarian and endometrial cancers, suggesting that it could permit selection of patients at higher risk of recurrence who would have a greater absolute benefit from adjuvant therapy. Conclusions: Chromatin instability, measured by the novel technique of Nucleotyping, seems to be a fundamental aberration in human cancers that provides clinically relevant prognostic information.
Predicting chemotherapy toxicity and death in older adults with colon cancer: Results of MOST (Massilia Oncologic Senior Tests) study.
Authors: Frédérique Retornaz, Olivier Guillem, Dany Gholam, Jean-François Codoul, Cécile Brativesic, Francois Morvan, Yves Rinaldi, Nicolas Barriere, Sophie Nahon, Chantal Butaud, Olivier Guerin, Rabia Boulahssass, Michel Grino, Frederique Rousseau
Journal: Journal of Clinical Oncology (2018)

10041 Background: Older patients with colon cancer are more vulnerable to chemotherapy toxicity and early death. Establishing simple scores specific for colon cancer (cc) patients able to predict severe chemotoxicity or early death is needed to select the best appropriate treatment. Methods: This prospective multicenter study included cc patients aged ≥ 70 years receiving first-line adjuvant or metastatic chemotherapy. Five frailty markers (FM) : nutrition, physical activity, mobility, energy, grip strength), six domains of CGA (functional status, comorbidities, falls, nutrition, cognition, depression) and laboratory parameters were collected at admission. Logistic or Cox regression was used to examine at 500 days the association between FM, CGA, laboratory parameters and grade 3-4 toxicity or death, respectively. Results: 93 patients (mean age 78.8 years, range 70-90) received adjuvant (32, 34.4 %) or metastatic (61, 65.6 %) chemotherapy. During the first 500 days grade 3-4 toxicity occurred in 49 (53.3 %) and 23 (26.7 %) died. Multivariate logistic regression identified polychemotherapy, albuminemia < 32 g/L, abnormal grip strength and C-reactive protein > 11 mg/L (odds ratio: 6.85, 2.79, 2.40, 1.43, respectively) as independent predictors of toxicity. Cox regression identified metastasis, alkaline phosphatases > 100 IU/ml, age > 82 years, sex (female), and abnormal grip strength (hazard ratio: 7.99, 3.45, 3.31, 3.2, 1.18, respectively) as independent predictors of premature death. The predictive model for grade 3-4 toxicity combined (polychemotherapy x 3) + (albuminemia x 2) + (abnormal grip strength x 1.5) + C-reactive protein, cut-off > 3. The predictive model for premature death combined (metastasis x 5) + (age x 2.5) + alkaline phosphatases + sex + abnormal grip strength, cut-off > 6. Characteristics of both models are : Clinical trial information: NCT02148731.Conclusions: These two simple and efficient scores will help clinicians to better identify cc older patients with increased risk of toxicity and/or premature death. Risk AUC ROC curve (± SD) 95 % CI P Sensitivity (%) Specificity (%) Toxicity 0.747 ± 0.052 0.647-0.832 < 0.0001 71.4 72.1 Death 0.908 ± 0.032 0.826-0.960 < 0.0001 87.0 81.0
Laparoscopic versus open surgery in the treatment of apparently early stage epithelial ovarian cancer: Case-control and case-matched study of Korean Gynecologic Oncology Group.
Authors: Jeong-Yeol Park, Jae-Weon Kim, Duk-Soo Bae, Dong-Hoon Suh, Hyun-Jin Roh, Sang-Yoon Park, Yoo-Kyung Lee, Chan-Yong Park, Seok Ju Seong, Yu-Jin Koo, No Firstname Yslee@Knu.Ac.Kr, Jung Hun Lee, Joo-Hyun Nam
Journal: Journal of Clinical Oncology (2016)

5560 Background: The efficacy and safety of laparoscopic surgery in the treatment of apparently early stage epithelial ovarian cancer is controversial. The aim of this study was to evaluate the long-term survival outcomes, surgical morbidity, and mortality of laparoscopic surgery compared with open surgery in apparently early stage epithelial ovarian cancer. Methods: Case-control population comprised 1342 patients who underwent laparoscopic surgery (n = 319) or open surgery (n = 1023) for apparently early stage epithelial ovarian cancer from 12 tertiary hospitals in Korea. Propensity score matching was performed using preoperative factors related to the selection of surgery mode, and case-matched population comprised 296 patients in each surgery groups. Survival analysis was performed using the Kaplan-Meier method and Cox’s proportional hazards model and surgical morbidity and mortality was compared. Results: In case-control population, the frequency of complete staging operation was 84.6% and 83.3% for laparoscopic and open surgery groups, respectively (P = 0.568). The 5-year recurrence free survival (82% versus 83%, P = 0.782) and disease-specific survival (91% versus 92%, P = 0.350) did not differ between laparoscopic and open surgery groups. The frequency of major postoperative morbidity was 2.8% and 7.7% for laparoscopic and open surgery groups, respectively (P = 0.002). Two patients in open surgery group required reoperation due to complication. No one in each surgery groups had postoperative mortality. In case-matched population, the 5-year recurrence free survival (80% versus 86%, P = 0.158) and disease-specific survival (90% versus 94%, P = 0.071) did not differ between laparoscopic and open surgery groups. Conclusions: Laparoscopic surgery had comparable survival outcomes and was more favorable in surgical morbidity compared to open surgery in apparently early stage epithelial ovarian cancer.
Comprehensive gene copy number alterations profiling predict efficacy of adjuvant chemotherapy in resected stage II-IIIA lung adenocarcinoma.
Authors: Qiaoyun Tan, Teng Xiong, Sheng Yang, Wumin Dai, Dongmei Lin, Yong Zhou, Hua Lin, Xiaohong Han, Yuankai Shi
Journal: Journal of Clinical Oncology (2018)

e24278 Background: Platinum-based adjuvant chemotherapy(PBAC) is recommended for stage II-IIIA resected lung adenocarcinoma(RLUAD) patients. However, the efficacy varies from individuals, which necessitates the discovery of new potentially prognostic biomarkers. As a major source of genomic variations driving tumor evolution, somatic copy number alterations(CNAs) screening may identify predictive biomarkers. Methods: The patterns of CNAs were analyzed by Oncoscan MIP array on formalin fixed paraffin embedded tumor specimens collected from 145 consecutive stage II-IIIA RLUAD patients, who received PBAC. Results: Among the 145 patients, 93(64.1%) relapsed within three years after surgery. The most frequent aberrations identified were 1q, 5p, 5q, 7p, 8q, 14p, 16p, 17q, 20q for copy number gains and 8p, 9p, 13p, 16q , 18q for losses. GISTIC analysis generated 45 amplification peaks and 41 deletion peaks, including some significantly mutated genes TERT, EGFR, MYC, CCND1, CDK4, MDM2, ERBB2, NKX2-1, CCNE1, CDKN2A, most of which were consistent with previous results in TCGA database. 145 patients could be well classified into 4 groups with significantly different clinical outcomes based on thresholded copy number at reoccurring alteration peaks from GISTIC analysis. 5-year survival rates and 3-year recurrence rates are shown(table). Compared with unrelapsed patients, focal amplification of ERBB2 and deletion of 4q34.3 were found to be specific in relapsed patients. This result was validated in an independent 159 cases from the cohort in Imielinski et al, indicating these two CNAs may contribute to RLUAD recurrence. Conclusions: This study suggests that CNAs may be a potential prognostic classifier in RLAUD patients, amplification of ERBB2 and deletion of 4q34.3 predicted early relapse after PBAC. These novel findings may provide implication for better clinical decision making. Group Focal amplification Gene 5-year survival rate(95% CI) P value 3-year recurrence rate(95% CI) P value A EGFR 0.47(0.35-0.63) 0.0269 0.33(0.22-0.48) 0.0273 B ERBB2 and TERC 0.57(0.44-0.75) 0.27(0.16-0.46) C MYC 0.64(0.49-0.84) 0.51(0.36-0.73) D MDM2 0.65(0.50-0.85) 0.36(0.22-0.59)
Immunotherapy utilizing the combined use of NK and ADCC mediating agents with PARP inhibition.
Authors: Kathleen Fenerty, Michelle R. Padget, Jeffrey Schlom, James W. Hodge
Journal: Journal of Clinical Oncology (2018)

5021 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. PARPi has antitumor activity in patients with known double-stranded DNA repair deficiencies (germline BRCA mutations). Olaparib is FDA approved for BRCA mutant ovarian and breast carcinoma. Emerging clinical data*NCT02484404. JCO, Karzai et al. suggests a benefit of combining olaparib with checkpoint inhibition in prostate cancer patients. Here, we interrogated the immunomodulatory potential of olaparib in-vitro, focusing on prostate carcinoma. We hypothesized that olaparib increases immune cell killing of tumor cells independent of BRCA status or checkpoint modulation. Methods: BRCA mutant and BRCA wildtype prostate carcinoma cell lines were pretreated with olaparib and then exposed to human healthy donor natural killer (NK) cells with or without the antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAb) avelumab (anti-PD-L1) or cetuximab (anti-EGFR). Tumor cell lysis was monitored. Anti-CD16 antibody was used to confirm NK-induced ADCC. Flow cytometry was performed on tumor cells treated with olaparib to evaluate phenotypic changes of NK ligands and death receptors. Results: NK-mediated killing was significantly increased in both BRCA WT and mutant prostate cell lines. NK killing was further increased using ADCC-mediating mAbs in both WT and mutant cell lines. The enhanced ADCC was blocked using anti-CD16 mAb. Notably, the expression levels of PD-L1 and EGFR did not change with olaparib treatment. On tumor cells, olaparib exposure upregulated NK ligands and death ligands. Additional tumor cell lines (lung, breast) were also assessed. Conclusions: We show here for the first time that a) olaparib increased tumor cell sensitivity to NK-mediated killing and ADCC in both BRCA wild-type and BRCA deficient prostate carcinoma cells, independent of PD-L1 or EGFR modulation; b) olaparib treatment enhanced NK killing in 6/6 cell lines; and c) mechanistically, treatment with olaparib upregulated NK ligands MICA/B, CD112, and death receptors Fas and Trail-R. These studies support the combined use of NK and ADCC mediating agents with PARPi in BRCA mutant and WT prostate carcinoma.
The effect of pre-transplant JAK 1/2 inhibitors on outcomes of myelofibrosis patients who receive allogeneic stem cell transplant.
Authors: Kathleen Miller, Gabriela Hobbs, Vincent T. Ho, Shuli Li, Yi-Bin Albert Chen
Journal: Journal of Clinical Oncology (2018)

7072 Background: The use of JAK 1/2 inhibitors (JAKi) for myelofibrosis (MF) treatment is becoming commonplace, but their impact on outcomes after hematopoietic stem cell transplant (SCT) is not well studied. We conducted a retrospective analysis of 132 patients who underwent SCT for primary or secondary MF at two partner institutions to assess the impact of receiving pre-SCT JAKi on several outcomes, including overall survival (OS), progression free survival (PFS), and GVHD-free and relapse-free survival (GRFS). Methods: 132 patients with MF who received allogeneic SCT between 2004 and 2017 at Massachusetts General Hospital or Dana Farber Cancer Institute were identified. The use of this data was approved by the local Institutional Review Board. We limited our final analysis to the 116 patients who were intermediate-1 (41) and intermediate 2 risk (75) by DIPSS prior to SCT, as there were very few patients in the high or low risk groups. Cox proportional hazard regressions were fit to estimate the association between the use of pre-SCT JAKi and OS, PFS, and GRFS after SCT, adjusting for baseline ECOG performance status, conditioning intensity and DIPSS status. Results: Of the 116 DIPPS-intermediate patients in the study, 41 received a JAKi prior to SCT and 75 patients did not. Patients who received pre-SCT JAKi had increased OS (75% vs 41%) and increased PFS (73% vs 44%) but not in GRFS (17% vs 14) in unadjusted analysis. In models adjusted for baseline ECOG performance status, conditioning regimen intensity, and DIPPS status, the use of JAKi prior to SCT was associated with a marginally-significant improvement in PFS [hazard ratio (HR) = 0.54, 95% CI 0.27 – 1.07, p = .075] and OS [HR = 0.53, 95% CI 0.26 – 1.07, p = .077], and was not associated with an improvement in GRFS [HR = 0.77, CI 0.49 – 1.23, p = .28]. Conclusions: Our data suggest that the use of JAKi prior to SCT may improve survival outcomes for patients with MF intermediate risk 1 or 2 who undergo SCT. However, further investigation with a larger sample size is needed to better understand the effect of pre-SCT JAKi use on patient outcomes after SCT. Future investigation should also focus on the use of post-SCT JAKi given their exhibited activity for GVHD.