tbuckley/cabot-search huggingface dataset:
A strategy to reduce acute toxicity from chemoradiation therapy for limited-stage small cell lung cancer.
Authors: Michael Nino Corradetti, Eric Xanthopoulos, Surbhi Grover, Annemarie Therese Fernandes, Miranda Kim, Charles B. Simone, John Paul Christodouleas, Lilie L. Lin, Ramesh Rengan
Journal: Journal of Clinical Oncology (2012)

e17534 Background: The standard of care for limited stage SCLC as outlined in the Intergroup 0096 trial involves twice daily radiation therapy, delivered to two out of four fields at a time, which results in high rates of clinically significant acute toxicity. This study examines acute esophagitis and treatment breaks in patients treated with radiation therapy as outlined by Intergroup 0096 vs those treated with a slight modification to this technique. Methods: We identified SCLC patients who received 45 Gy in 1.5 Gy bid fractions from an institutional database. Associations were assessed via Chi-squared test. A break was defined as an interruption of 3+ days. Results: 74 SCLC patients were treated with 3D-conformal radiation therapy from 2004 to 2010. 16 patients did not satisfy criteria described in the Methods and were excluded. 28 patients were treated per Intergroup 0096 with AP/PA fields bid for 1 week followed by AP/PA treatment in the AM and 2 oblique fields in the PM for 2 weeks. 28 patients were treated with the same approach except all four fields were treated with each fraction. Patient characteristics were well distributed as outlined below (Table). 54% of patients had CTCAE grade 3 esophagitis with the Intergroup 0096 approach vs 23% in patients treated with a 4-field approach (p = 0.01). 29% vs 7% patients had a treatment break (p = 0.03). 32% of grade 3 esophagitis patients had breaks vs 8% with esophagitis grades 0 – 2 (p = 0.02). There was no difference in survival or distant/local failure. Conclusions: Grade 3 esophagitis and treatment breaks were reduced in patients receiving continuous 4-field treatment. Future investigation is required to determine whether the observed reduction in breaks could translate to a local control or survival benefit if applied to a larger patient sample. [Table: see text]
David Oliver: Confidentiality on the wards—regulations and reality
Authors: David Oliver
Journal: BMJ (2017)

In January the General Medical Council published its updated guidance on confidentiality and handling patient information.1 It’s a comprehensive manual highlighting doctors’ duties, backed by ethical frameworks, relevant law, good practice, and regulatory standards for most scenarios.23

For jobbing clinicians, the most relevant section is “Disclosure to support the care of an individual patient”—for patients who can consent and, crucially for modern hospital populations, for those who lack this capacity. The new guidance clearly states that we must act within the law and seek …
The VH3-21 Gene Status Correlates with Elevated β2-Microglobulin Serum Levels and Shorter Overall Survival of Patients with Chronic Lymphocytic Leukemia.
Authors: Ewa Lech-Maranda, Tadeusz Robak, Anna Szmigielska-Kaplon, Hanna Makuch-Lasica, Iwona Solarska, Krzysztof Jamroziak, Ewa Balcerczak, Marek Mirowski, Miroslaw P. Majewski, Krzysztof Warzocha
Journal: Blood (2005)
Multiple Myeloma Patients with Lenalidomide-Associated Skin Rash Have a Favorable Prognosis
Authors: Ayumi Kojima, Yuka Tanaka, Yuta Kimura, Daisuke Tsuchimoto, Rina Etani, Tetsufumi Kanematsu, Kenji Miyazawa, Akiya Mori, Atsuhiko Naruse, Hirokazu Nagai
Journal: Blood (2016)
Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease.
Authors: Susan Mary O'Brien, Richard R. Furman, Steven E. Coutre, Ian Flinn, Jan Andreas Burger, Kristie A. Blum, Jeff Porter Sharman, Jeffrey Alan Jones, William G. Wierda, Weiqiang Zhao, Nyla A. Heerema, Amy J. Johnson, Anh Tran, Cathy Zhou, Elizabeth Bilotti, Danelle Frances James, John C. Byrd
Journal: Journal of Clinical Oncology (2014)

7014 Background: CLL/SLL is generally very responsive to chemoimmunotherapy. However, relapses occur and resistance develops. In particular, del(17p) is associated with poor outcomes using all currently available treatments. Effective targeted therapies are needed. Ibrutinib, a first-in-class covalent inhibitor of Bruton tyrosine kinase, showed single-agent activity and mild toxicity in treatment-naïve (TN) (Lancet Oncology 2013) and relapsed/refractory (R/R) CLL (NEJM 2013) in the phase 1b/2 study (PCYC-1102). We present independent assessment of efficacy data 3 years following initiation of therapy to confirm and further characterize the durability of response. Methods: Analyses are based upon all patients (pts) treated from first dose on PCYC-1102 until data cut-off on the long-term follow-up study PCYC-1103. Patients received 420 or 840 mg ibrutinib daily. Best overall response rate (ORR) was assessed using iwCLL criteria. Results: Of 132 CLL/SLL (31 TN, 101 R/R) pts evaluated, the median age was 68 years (range, 37–84), with 61% aged ≥ 65 years; 36 (27.3%) pts (2 TN, 34 R/R) had del(17p) and 36 (27.3%) had del(11q). R/R pts including 34 with Del(17p) had a median of 4 (range, 1–12) prior therapies. The updated ORR (by independent review) was 78.0% for all-treated pts (83.9% TN-, 76.2% R/R and 55.9% for those R/R with del(17p)). Additionally, 5 R/R pts, 2 with del(17p), had a best response of PR with lymphocytosis. Median DOR was not reached for all-treated pts, and was 25.0 months (range, 4.8–34.3) in pts with del(17p). Median time on study was 29.4 months (range, 0.7–38.1) for all-treated pts, and 27.3 months (range, 0.9–37.5) for R/R pts with del(17p). More pts receiving prior therapy experienced serious or ≥ Grade 3 adverse events that decreased after 1 year on treatment. No new safety signals were observed in long-term follow-up; 64% of pts remain on treatment with ibrutinib. Conclusions: Single-agent ibrutinib showed durable responses in pts with TN or R/R CLL/SLL including those with del(17p), as independently confirmed with 3 years of follow-up.
New tyrosine kinase inhibitors in the treatment of imatinib resistant GIST: An updated meta-analysis.
Authors: Fiorella Pendola, John Guirguis, Caroline Ripat, Danny Yakoub, James Edward Hoffman, Nemer Dabage
Journal: Journal of Clinical Oncology (2017)

110 Background: Primary or secondary resistance to Imatinib, convolutes the control of Gastrointestinal Stromal Tumors (GIST). We aimed to evaluate clinical outcomes of new tyrosine kinase inhibitors (TKIs) in the treatment of Imatinib resistant GIST. Methods: Online database search of PubMed, MEDLINE, EMBASE, SCOPUS, COCHRANE, and GOOGLE SCHOLAR was performed (2000– Present); key bibliographies were reviewed. Studies comparing patients with Imatinib resistant GIST who were treated with placebo versus new generation TKIs (Regorafenib, Sunitinib, Nilotinib). Primary outcomes were overall and progression free survival (OS, PFS), secondary outcomes include the most common side effects described in trials using new TKIs. Meta-analysis was conducted using Statistical Analysis System (SAS) software. Relative risks with the corresponding 95% confidence intervals (CI) by random effects models of pooled data were calculated. Study quality was assessed using JADAD scoring system. Results: Out of 16 studies, 4 studies met our selection criteria including 825 patients in total; 553 treated with new TKIs and 272 were given placebo (control group). Median age was 57.85 years. Meta-analysis of included data showed significantly improved PFS in the new TKIs group (HR = 0.336, 95% CI 0.208-0.542, p &lt; 0.001.) Similar trend but without statistically significant difference was seen in OS (HR = 0.836, 95% CI 0.682-1.026, p = 0.086). Incidence of hypertension was found to be significantly higher in the new TKIs group (RR = 2.903, 95% CI 1.800-4.681, p &lt; 0.001); the same effect was observed in development of hand foot syndrome (RR = 4.818, 95% CI 2.723-8.525, p &lt; 0.001) and diarrhea (RR = 5.341, 95% CI 3.074-9.281, p &lt; 0.001). Conclusions: New generation of TKIs significantly improved PFS compared with placebo in patients with Imatinib resistant GIST. However new TKIs have increased secondary side effects. Randomized controlled trials are needed to evaluate longer term outcomes of these treatments.
Neoadjuvant sorafenib, gemcitabine, and cisplatin (SGC) for muscle-invasive urothelial bladder cancer (MIUBC): Final results and translational findings of an open-label, single-arm, phase II study.
Authors: Andrea Necchi, Salvatore Lo Vullo, Daniele Raggi, Patrizia Giannatempo, Nicola Nicolai, Luigi Piva, Davide Biasoni, Mario Catanzaro, Tullio Torelli, Silvia Stagni, Giuseppina Calareso, Elena Togliardi, Maurizio Colecchia, Adele Busico, Federica Perrone, Marzia Pennati, Nadia Zaffaroni, Luigi Mariani, Roberto Salvioni
Journal: Journal of Clinical Oncology (2017)

345 Background: Despite cisplatin-based chemotherapy (CT) is recommended in MIUBC, an unmet need is to identify new drugs or combinations to improve the outcomes. SGC combination was evaluated in an open-label, single-arm, phase 2 trial (NCT01222676). Methods: After TURB, pts with T2-T4a N0 MIUBC received 4 cycles of cisplatin 70 mg/m 2 d1, gemcitabine 1000 mg/m 2 d1 and 8, q3 wks. Sorafenib 400 mg q12h was administered daily from day 1 until radical cystectomy. In a Simon’s 2-stage design, the primary endpoint was pathologic complete responses (pT0). Residual carcinoma in situ was considered pT0. ITT analysis was applied. Statistical hypothesis assumed H0: ≤0.20 and H1: ≥0.40 (α and β of 5% and 10%). ERCC1 immunohistochemistry (IHC) and next-generation sequencing (NGS) of TURB tissue, and measurement of baseline circulating VEGF levels, were planned. Results: From 04/2011-06/2016, 45 pts were enrolled. 28 pts (62.2%) had macroscopical residual disease after TURB, 17 (37.8%) presented with clinical stage T3-4. pT0 was obtained in 19 pts (42.2%, 95%CI: 27.6-57.9); pT≤1 in 24 (53.3%, 95%CI: 37.9-68.3). After median follow-up of 35 months, median PFS was not reached (IQR: 29.4-NE), like median OS (IQR: 30.3-NE). Pathological response (pT0 vs pT≤1 vs other) predicted for both PFS (p=0.015) and OS (p=0.046). Hematologic (hem) G3-4 adverse events (AE): platelet 28.9%, neutrophils 15.6%, Hb (4.4%). Extra-hem AEs were seen in 9 pts (20%). 24 (53.3%) pts needed S temporary interruption (5 cases discontinuation). Tumor samples were available from 23 pts for ERCC1-IHC, 24 for NGS: ERCC1 IHC expression was associated with non response (pT≥2, p=0.033). ERBB2/ERBB3 mutations were found only in responders (pT≤1, 20%). PIK3CA/AKTmutations (missense, and newly-identified mutations) were more frequent in pT≥2 pts (35.7% vs 20%). Baseline VEGF levels did not predict for PFS/OS. NGS of the remaining pts of the trial is ongoing. Conclusions: SGC combination was active and effective in MIUBC. Translational analyses are providing information to develop combination of CT with new more potent and selective TKIs, possibly in more selected pts. Clinical trial information: NCT01222676.
A survival comparison study of Chinese patients with primary lung adenocarcinoma harboring ALK rearrangements with crizotinib treatment detected by FISH, IHC, and RT-PCR.
Authors: Meilin Liao, Shun Lu, Xiaomin Niu, Zhiwei Chen, Xiangyun Ye, Ziming Li, Yongfeng Yu, Zhen Zhou
Journal: Journal of Clinical Oncology (2015)

e19135 Background: EML4-ALK is a new driver gene of non-small cell lung cancer (NSCLC) and is associated with response to inhibition with crizotinib. ALK break apart fluorescence in situ hybridization (FISH) assay, Ventana immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR) can all be used as the primary assay for detecting ALK fusion events in tumor samples of lung cancer patients with SFDA approval in China. The objective of this study was to analyze the association of ALK rearrangements with clinical outcomes in different ALK testing methods, including FISH, Ventana IHC, and RT-PCR. Methods: ALK status was assessed by FISH, IHC and RT-PCR in 75 patients with advanced ALK-positive lung adenocarcinoma who had received crizotinib treatment from 2011,May to 2014, Nov in China. Clinicopathologic data and survival outcomes were analyzed. Kaplan-Meier cumulative probability was used to assess different testing methods for survival. Results: Of all 75 ALK-potitive lung adonocarcinoma, there are 23 FISH-positive ALK patients (23/75, 30.7%), 35 IHC-positive ALK patients (35/75, 46.7%) and 17 RT-PCR-positive ALK patients (17/75, 22.7%). 75 patients received crizotinib treatment with IHC-positive and FISH-positive had better progression-free survival (PFS) (P= 0.049), compared with those with RT-PCR-positive, but not for overall survival (OS) (P= 0.074). The median PFS survival for all these 75 patients was 16m, 14m, 8m, separately based on the IHC, FISH, and RT-PCR test. 23 patients received first-line crizotinib treatment with IHC-positive and FISH-positive had better PFS (P= 0.030), compared with those with RT-PCR-positive, but not for OS (P= 0.061), either. The median PFS survival for these 23 patients with first-line crizotinib treatment was 12m, 18m, 4.8m, separately based on the IHC, FISH, and RT-PCR test. Conclusions: The conventional IHC assay is a valuable tool and efficient technique for diagnosing ALK rearrangements in clinical practice. While RT-PCR is need to be further evaluated in clinical practice to identify its role in guiding patients' targeted therapy using crizotinib.
Cost-effectiveness analysis of pharmacokinetic-guided (PK) 5-fluorouracil (5FU) when combined with leucovorin and oxaliplatin (FOLFOX) chemotherapy for metastatic colorectal cancer (mCRC).
Authors: Daniel A. Goldstein, Qiushi Chen, David H. Howard, Joseph Lipscomb, Turgay Ayer, Donald Harvey, Bassel F. El-Rayes, Christopher Flowers
Journal: Journal of Clinical Oncology (2014)

6527 Background: Dosing chemotherapy based on body surface area (BSA) results in marked variability in inter-individual drug exposure. An immunoassay for 5FU has been developed that assists in PK-guided dose adjustments. A randomized trial showed increased overall survival (OS) and decreased toxicity with PK 5FU/Leucovorin compared to BSA 5FU/Leucovorin in patients with mCRC. Similar results were achieved in a non-randomized trial comparing PK FOLFOX with BSA FOLFOX. The objective of this study is to compare the cost effectiveness of PK FOLFOX with BSA FOLFOX in patients with mCRC. Methods: We developed a Markov model to evaluate the cost-effectiveness of PK FOLFOX compared with BSA FOLFOX. Published progression-free survival (PFS) and OS curves were fitted with Weibull models. Progression risks and cause-specific mortality were extrapolated from the fitted survival models. Costs for administration and management of adverse events were estimated based on Medicare reimbursement rates for hospital and physician services, and drug costs based on the Medicare average sale prices, (all in 2013 US $). Primary outcomes were incremental cost per quality adjusted life-year (QALY) gained. We performed univariate and probabilistic sensitivity analyses (PSA) to address parameter uncertainties. Results: PK FOLFOX provided 2.03 QALYs at a cost of $50,205 compared to BSA FOLFOX with 1.46 QALYs at a cost of $37,173. The incremental cost per QALY was $22,694/QALY. In all one-way and 99.7% of PSA, the incremental cost-effectiveness ratio of PK remained below $50,000/QALY. Conclusions: At a $50,000/QALY threshold, PK FOLFOX is cost-effective for mCRC. The main cost driver was the PK test ($400) that was used for 4 cycles to establish the optimal dose. The main driver of benefit was improved PFS and OS. Given the cost-effectiveness profile and OS advantage with PK FOLFOX, it should be evaluated further in comparative effectiveness studies.
Evaluation of monocytic myeloid-derived suppressor cell (M-MDSC) frequency in patients with metastatic urothelial carcinoma (mUC).
Authors: Samuel Funt, Zhenyu Mu, Catharine Kline Cipolla, Brooke Elizabeth Kania, Junting Zheng, Mariel Elena Boyd, Alexandra Snyder Charen, Margaret K. Callahan, Karen A. Autio, Ashley Marie Regazzi, Meredith Maisie Moran, Irina Ostrovnaya, Gopa Iyer, Phillip Wong, Alexander M. Lesokhin, Jonathan E. Rosenberg, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2017)

356 Background: M-MDSCs promote tumor progression through complex mechanisms, including immunosuppression and the production of mediators of angiogenesis and invasion. M-MDSCs are associated with poor outcomes in a number of malignancies. We conducted an exploratory analysis enumerating M-MDSCs (Lin-CD14 + /HLA-DR low/- ) in the blood of pts with mUC and assessed for assay variability and correlation with clinical outcomes. Methods: Whole blood was collected at a single time point for each pt and stabilized in Cyto-Chex tubes. M-MDSC% was calculated by flow cytometric analysis of HLA-DR expression on CD14+ monocytes using an MSKCC developed computational algorithm-based approach (Kitano et al. 2014). Individual samples were run in quadruplicate at MSKCC. The mean MDSC% was used in subsequent analyses and the replicate standard deviation (SD) was considered a reflection of intra-assay variability. Clinical variables were collected and pts followed for OS, which was calculated from time of sample collection. Results: 21 pts with mUC who progressed after prior chemotherapy were included. At the time of collection, pts were on clinical trials with immune checkpoint blockade (n=13) or targeted therapy (n=1), receiving salvage chemotherapy (n=2), or awaiting treatment on clinical trials with immune checkpoint blockade (n=4) or targeted therapy (n=1). The median follow up from the time of collection in surviving patients (n=15) was 11.1 months (range: 10.5-11.5). Median OS was not reached. Mean (SD) M-MDSC% was 29.2 (4.92). The range of replicate SD was 0.13-1.05. M-MDSC% was not higher in pts with visceral mets (p=0.109). Pts with above median M-MDSC% had worse OS (p=0.01; 6 patients died during follow up, all with above median M-MDSC%). Conclusions: In a heterogeneous cohort of pts with mUC, the enumeration of M-MDSCs in stabilized whole blood was feasible and demonstrated marked inter-patient but not intra-assay variability. Pts with higher M-MDSC% values had worse OS. Additional characterization of M-MDSCs in larger cohorts and in pts receiving immunotherapy is ongoing and may have important prognostic and therapeutic implications in mUC.
Changes in PD-L1 expression in non-small cell lung cancer by immunohistochemical analysis.
Authors: Shota Omori, Hirotsugu Kenmotsu, Masato Abe, Reiko Watanabe, Takashi Sugino, Kazushige Wakuda, Akira Ono, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Yasuhisa Ohde, Masahiro Endo, Yasuto Akiyama, Takashi Nakajima, Toshiaki Takahashi
Journal: Journal of Clinical Oncology (2015)

e22118 Background:Expression of Programmed Death Ligand-1 (PD-L1) is considered a predictive biomarker of anti-PD-1/PD-L1 therapies. In melanoma with BRAF mutations, it was reported that PD-L1 expression increased with BRAF inhibition. Our study is to evaluate changes in PD-L1 expression for non-small cell lung cancer (NSCLC) with treatments in clinical courses. Methods: The medical records of NSCLC patients with two or more samples in their clinical courses were retrospectively reviewed at our institution between November 2002 and December 2014. In this study, immunohistochemical (IHC) analysis was done using anti-PD-L1 monoclonal antibody (E1L3N). IHC score was defined as the proportion of tumor cells with stained cell membrane, scale: 0, 0 %; 1, 1-4 %; 2, 5-9 %; 3, 10-29 %; 4, 30-49 %; 5, 50-100 %. Further, we defined three IHC score groups as follows; 0-1, group A; 2-4, group B; 5, group C. We considered migration of IHC score group as a significant change in PD-L1 expression. Results: Ninety-five patients were included in this study. Patient characteristics were as follows: median age (range) 67 (39-89) years; female 37 %; never-smoker 26 %; histology adenocarcinoma/squamous cell carcinoma/other 78/16/6 %; and stage I/II/III/IV 32/24/21/23 %. Expression of PD-L1 was positive ( ≥ scale 1) in 42 pretreatment samples (44 %), and was highly positive ( ≥ scale 2) in 26 (27 %). By histological type, 29 (39 %) of 74 patients with adenocarcinoma showed positive PD-L1 expression, and 10 (67 %) of 15 with squamous cell carcinoma. Only six (21 %) of 29 patients with EGFR mutations had PD-L1 expression and 19 (58 %) of 33 without EGFR mutations did. For 19 patients with EGFR mutations, who were treated with EGFR-TKI, significant increases in PD-L1 expression after treatment were observed in 4 (21 %) patients. Seven (13 %) of 56 patients treated with cytotoxic chemotherapy showed significant increases in PD-L1 expression, and only one (3 %) of 35 without chemotherapy or EGFR-TKI did. Conclusions: Pretreatment PD-L1 expression was frequently observed in tumor with squamous cell carcinoma or without EGFR mutations. This study results suggest treatment with EGFR-TKI may increase PD-L1 expression, and enhance the efficacy of anti-PD-1/PD-L1 therapies.
Association between circulating hepatocyte growth factor (HGF) and clinical response across five studies with the BRAF inhibitor dabrafenib or MEK inhibitor trametinib.
Authors: Ademi Santiago-Walker, Robert C. Gagnon, Jennifer Carver, C. Martin Curtis, Patricia Haney, Shonda Marie Little, Anne O'Hagan, Vicki L. Goodman, Jeffrey J. Legos, Kiran Patel, Anne-Marie Martin
Journal: Journal of Clinical Oncology (2014)

e20019 Background: To investigate the previously reported association between baseline HGF and clinical response in patients (pts) treated with RAF inhibitors, HGF levels were assessed in pt blood from the dabrafenib (D) and trametinib (T) single agent and combination (D+T) trials BRF113710, BRF112680, BRF113683, MEK114267, and BRF113220. Methods: Circulating levels of HGF were assessed in baseline pt plasma using Aushon BioSystems SearchLight ELISA. Within and between arm Cox and logistic regression models were utilized to assess the association between HGF levels and progression-free survival (PFS) and response rate (RR). The statistically optimal cut-point was determined (Simon 1995). The relationships between HGF levels and baseline covariates (SLD: sum of longest diameters; LDH: lactate dehydrogenase) were assessed using Spearman’s correlation, Wilcoxon’s test (ECOG), and covariate adjusted Cox models (when data permit). Analyses were conducted separately for each study. Results: Pts with ECOG 1 or 2 had higher levels of HGF than pts with ECOG 0. HGF was weakly positively correlated with LDH and SLD. HGF was not associated with RR. Higher levels of HGF were associated with shorter PFS in pts treated with D in 3 of 4 studies, but were not associated with PFS with T alone or in combination with D (Table). Optimal cut points were in the 60th-70th HGF percentile. HGF was not an independent predictor of PFS. Results for overall survival are being analyzed. Conclusions: High levels of HGF in circulation were predictive of shorter PFS in response to D monotherapy. The impact of HGF on PFS was not observed when pts received T or D+T, and HGF was not an independent predictor when adjusted for covariates. PFS PFS covariate adjusted Study N Hazard ratio (HR) P value (P) HR P D BRF113710 68 1.53 0.0068 1.35 0.1549 BRF112680 20 2.43 0.0110 NA BRF113683 179 1.42 0.0002 0.97 0.9066 BRF113220 21 1.31 0.5082 NA T MEK114267 186 1.09 0.3512 1.10 0.3862 Control arms BRF113683 (DTIC) 54 1.03 0.8897 0.97 0.9066 MEK114267 (CHEMO) 89 1.56 0.0006 1.37 0.0027 D+T BRF113220 (1 mg) 26 1.29 0.4867 NA (2mg) 24 0.73 0.4835 NA NA = Insufficient data for covariate models.