tbuckley/cabot-search huggingface dataset:
Haploidentical transplantation (HaploSCT) with post-transplant cyclophosphamide (PTCy) and melphalan-based conditioning: A retrospective analysis of the first 100 patients treated at MD Anderson Cancer Center.
Authors: Piyanuch Kongtim, Sai Ravi Pingali, Antonio Martin Jimenez, Gabriela Rondon, Julianne Chen, Betul Oran, Partow Kebriaei, Aimee Hammerstrom, Roberto Ferro, Lindsey Lombardi, Martin Korbling, Uday R. Popat, Simrit Parmar, Dean Anthony Lee, Laurence Cooper, Katy Rezvani, Elizabeth J. Shpall, Richard E. Champlin, Stefan O. Ciurea
Journal: Journal of Clinical Oncology (2014)

7017 Background: Outcomes of HaploSCT have recently improved with the use of post-transplantation cyclophosphamide (PTCy). Here we report results of the first 100 pts treated at our institution between 9/2009-7/2013. Methods: Diseases were: AML/MDS 54 (36 had high-risk cytogenetics), lymphoma/CLL 17 (12 not in remission at transplant), ALL 12 (11 beyond first remission), CML 12 (all progressed to accelerated/blast phase), other 5 pts. The median age was 45 years (range 19-67). The conditioning regimen included melphalan (100-140 mg/m2), fludarabine (160 mg/m2) +/- thiotepa (5-10 mg/kg). GVHD prophylaxis consisted of PTCy 50mg/kg on day +3 and +4, tacrolimus and mycophenolate. All but 4 pts received a bone marrow graft. 23 pts had previous allogeneic (11) or autologous (12) SCT and 42 pts were not in remission at transplant. Results: The median follow-up was 18 months (range 2-48). 94 pts had neutrophil engraftment (median 18 days). Three-year PFS of the entire cohort was 43.3% (44.6% for 1st SCT and 32.7% for 2nd SCT). The cumulative incidence (CI) of relapse and treatment-related mortality (TRM) at 3 years were 38.4% and 25.4% for 1st SCT; 61.8% and 10% for 2nd SCT, respectively. CI of aGVHD was 45% (grade 2-4 30%, grade 3-4 10%) and cGVHD was 15% (extensive cGVHD 8%). Transplant outcomes by disease type are summarized in Table1. In multivariate analysis, factors associated with worse outcomes were lack of remission at SCT (HR 1.73, 95%CI 1.02-3.03, p=0.04) and the development of aGVHD grade 3-4 (HR 2.6, 95%CI 1.08-6.26, p=0.033). Conclusions: HaploSCT with melphalan-based conditioning and PTCy is well tolerated with low TRM and outcomes comparable with matched transplantation. Prospective studies comparing HaploSCT with matched transplants are needed. Transplant outcomes by disease type. Outcomes (%) Myeloid malignancies in CR (N=40) Lymphoid malignancies (N=17) ALL (N=12) 3-year PFS 56.5 62.3 44.4 1-year TRM 11.8 25.9 33.3 1-year CI of relapse 30.1 24.4 33.3 aGVHD grade 2-4 25 35.3 50 aGVHD grade 3-4 0 11.8 41.7 cGVHD 12.5 11.8 44.4 cGVHD (extensive) 10 5.9 8.3
Efficacy and toxicity of second-line AIO plus irinotecan (IRI) after pretreatment with AIO plus oxaliplatin (L-OHP) in the sequential therapy of metastatic colorectal cancer (CRC).
Authors: Axel Wein, Frank Boxberger, Juergen Siebler, Kerstin Wolff, Nicola Ostermeier, Dagmar Busse, Gudrun Maennlein, Werner Hohenberger, Markus F. Neurath, Ralf Hofheinz
Journal: Journal of Clinical Oncology (2013)

3561 Background: The FOLFIRI followed by FOLFOX6 (or vice versa) schedule has been considered as the gold standard of sequential treatment in CRC (Tournigand C. JCO 2004). In contrast to those bi-weekly schedules, the wide-spread weekly chemotherapy administration (e.g. AIO regimen), has not been investigated as yet for second-line treatment. The AIO + IRI schedule has provided promising results in the first-line treatment of CRC (Köhne C.-H. JCO 2005). Therefore, we now investigated the efficacy and toxicity of this schedule in second-line treatment in a phase II study. Methods: From 5/02 to 6/10, 60 palliative patients (pts.) with histologically proven CRC were enrolled in an oligocentric phase II study based on the following regimen: weekly IRI (80 mg/m 2 i.v.) as 1h-infusion (inf.): d1, 8, 15, 22, 29, 36, qd 57 followed by 5-FU (2000 mg/m 2 i.v.) combined with sodium folinic acid (500 mg/m 2 , d1, 8, 15, 22, 29, 36, qd 57) as a 24h-inf. via port-a-cath. This study focused on the efficacy and toxicity of second-line treatment with AIO + IRI. Results: Last date of evaluation: November 30, 2012; evaluable for efficacy: n = 58 pts., evaluable for toxicity: n = 59 pts.; men/women: 28/72%; median age: 65y; primary tumor location: rectum/colon: 45/55%.; toxicity data: higher grade toxicity (grade 3-4): leukocytopenia: 5.1%; thrombocytopenia: 1.7%; vomiting: 3.4%; diarrhea: 13.5%; hand-foot-syndrome: 1.7%; alopecia (grade 2) 3.4%; efficacy data: PFS: 4.2 m; median OS 14.2 m, RR: 10%; AIO + IRI following AIO + L-OHP achieved a median OS of 25.0 months. Conclusions: In the field of second-linetreatment of CRC the AIO plus IRI regimen offers both a favorable toxicity profile and promising results in terms of efficacy compared with the FOLFIRI regimen.
First-in-human phase I study of the novel structure proteasome inhibitor NPI-0052
Authors: P. A. Hamlin, C. Aghajanian, A. Younes, D. S. Hong, M. A. Palladino, A. M. Longenecker, G. K. Lloyd, A. L. Hannah, M. A. Spear, R. Kurzrock
Journal: Journal of Clinical Oncology (2009)

3516 Background: NPI-0052 is a second-generation proteasome inhibitor that has a novel structure with preclinical studies suggesting unique proteasome inhibition (PI), signal transduction, efficacy and toxicology profiles, and activities in a broad range of models including bortezomib (BZ) resistant models. Methods: Patients were treated with NPI-0052 IV weekly x 3 in 4-week cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). PI was assayed in whole blood (PWB) and in PBMCs. Up to 10 patients each (lymphoma and solid tumors) are treated at the RP2D. Results: 39 patients have been treated between 0.0125 mg/m 2 to 0.8 mg/m 2 for up to 12 cycles. The RP2D was 0.8 mg/m 2 and has been well tolerated in this study, with the most notable drug-related adverse events being N/V, fatigue, diarrhea, dizziness, headache, decreases in hemoglobin, and insomnia. Thrombocytopenia or neuropathy did not appear to be induced by NPI-0052. Escalation was halted at 0.8 mg/m 2 , as DLT of transient “hallucinations” (visual imprints when eyes closed) and dizziness/unsteady gait were reported in another study at 0.9 mg/m 2 . PK data indicate T1/2 ∼4–10 minutes, with clearance at 3–15 L/min and Vz of 35–85L. PI (chymotrypsin-like activity) in PWB and PBMC were dose dependent (mean D1 and D15 PI in PWB at 0.8 mg/m 2 was 75 and 100%) (efficacious doses of BZ have been reported to result in a range of ∼40–70% PI). PI in PBMC returned to ∼baseline within one week of each dose, while inhibition remained in PWB. Stable disease was observed in patients with cervical carcinoma (11 months; maximum response was 24%; PI increased with dose escalation), colorectal, hepatocellular, adenoid cystic, melanoma, granulosis cell and ovarian. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects, with equal to greater PI seen than reported with therapeutic doses of BZ. At the RP2D toxicity is mild-to-moderate, without the toxicity profile associated with BZ. Together with preclinical data this suggests NPI-0052 may have utility in treating patients who are not candidates for BZ as well as in indications and combinations that have not supported BZ use. Additional trials have been initiated including combinations with other targeted agents. [Table: see text]
Patterns in place of cancer death in the state of Qatar: A population-based study.
Authors: Hassan Mohsen, Azza Adel Hassan, Ayman Allam, Pascale Haddad
Journal: Journal of Clinical Oncology (2014)

e20502 Background: The consensus from international studies of patient preferences is that, given adequate support, most cancer patients prefer to die at home; however, hospitals remain the most common place of death (PoD). The purpose of this study was to investigate the changing patterns in PoD and the associated factors, which are critical for end-of-life care enhancement. Methods: This retrospective, population-based study analyzed all cancer deaths in Qatar registered by the National Death Registry between January 1, 2006 to December 31, 2012. Time trends of age-standardized proportion of deaths in individual PoDs were evaluated using chi-square trend analysis. Variables associated with PoD in APCU & Heme/Onc ward versus ICU & general medicine ward for Qatari and non-Qatari patients were determined using odds ratio (OR) derived from the log-binomial regression. Results: A total of 1,224 cancer deaths occurred between 2006 and 2012. Throughout the study period, the Heme/Onc ward was the most common PoD (32.4%; 95% CI 26.7-35.3%) followed by ICU (31.4%; 95%CI 28.7-34.3%), APCU (26.9%; 95%CI 24.3-29.6%) and general medicine ward (9.2%; 95%CI 7.6-11.1%). Trend analysis at the APCU showed a constant increase (+ 0.057 per year; 95% CI 0.031–0.083; p-value <0.001), while the Heme/Onc ward showed a constant downward trend (-0.055 per year; 95% CI: -0.079 – -0.031; p-value <0.001). There was no statistically significant change in the other PoDs; home deaths remained very low (0.4%; 95%Cl: 0.38-0.42) and unchanged throughout the study period. Qataris who died from liver cancer (OR 0.23), and aged 65 and older were less likely to die in APCU and Heme/Onc ward. Non-Qataris who died from pancreatic cancer (OR 3.12), were female (OR 2.05) were more likely to die in APCU and Heme/ Onc ward. Both Qataris and non-Qataris who died from hematologic malignancy (OR 0.18, 0.41, respectively) were more likely to die in ICU & general medicine ward. Conclusions: An alarmingly high percentage of cancer deaths in Qatar occur in hospital. As home was the preferred place of death for most cancer patients, effective home care and hospice programs are needed to enable patients to remain at home in accordance with their preference.
Treatment strategies in colorectal cancer patients with initially unresectable liver-only metastases: The randomized phase III CAIRO5 study of the Dutch Colorectal Cancer Group.
Authors: Joost Huiskens, Thomas M van Gulik, Krijn P van Lienden, Marc R.W. Engelbrecht, Gerrit A. Meijer, Nicole C.T. van Grieken, Jonne Schriek, Astrid Keijser, Linda Mol, I. Quintus Molenaar, Cornelis Verhoef, Koert P. de Jong, Cornelis H.C. Dejong, Geert Kazemier, Theo Ruers, Johannes H.W. de Wilt, Harm van Tinteren, Cornelis J. A. Punt
Journal: Journal of Clinical Oncology (2015)

TPS3622 Background: Colorectal cancer patients with unresectable liver-only metastases may be cured after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined, and the lack of consensus on criteria for (un)resectability complicates the interpretation of published results. Methods: CAIRO5 is a multicenter, randomized, phase III clinical study. Colorectal cancer patients with initially unresectable liver-only metastases are eligible, and will not be selected for potential resectability to avoid selection bias. The unresectability status is prospectively assessed by a central panel consisting of at least one radiologist and three liver surgeons, and defined as no radical resection possible in one session with resection only. Tumors of included patients will be tested for RAS and BRAF (for stratification purpose) mutation status. Patients with RAS wild type tumors are treated with doublet chemotherapy (FOLFOX/FOLFIRI, choice of investigator) and randomized between the addition of either bevacizumab or panitumumab, patients with RAS mutant tumors are randomized between doublet chemotherapy (FOLFOX/FOLFIRI) or triple chemotherapy (FOLFOXIRI), both with bevacizumab. Resectability status will be re-evaluated every two months. The primary study endpoint is median progression-free survival. Secondary endpoints include the R0/1 resection rate, and median overall survival. Conclusion CAIRO5 is a prospective multicenter trial that investigates the optimal systemic therapy for patients with initially unresectable, liver-only colorectal cancer metastases. Discussion The unique aspects of CAIRO5 concern the prospective phase III randomized comparison of neoadjuvant treatment regimens in this population with the use of uniform and transparent criteria for unresectability by an expert panel. This CAIRO5 panel may contribute to a consensus on criteria for unresectability and to awareness of secondary resections in these patients. Clinical trial information: NCT02162563.
Health-related quality of life (HRQoL) and symptom burden in patients (Pts) with myelofibrosis (MF) in the COMFORT-II study.
Authors: Jean-Jacques Kiladjian, Heinz Gisslinger, Francesco Passamonti, Dietger Niederwieser, Estella Mendelson, L. Andres Sirulnik, Kati Copley-Merriman, Xiaolei Zhou, Richard S. Levy, Laurent Knoops, Francisco Cervantes, Tiziano Barbui, Giovanni Barosi, Alessandro M. Vannucchi, Claire N Harrison
Journal: Journal of Clinical Oncology (2012)

6626^ Background: Ruxolitinib has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms and QoL in 2 phase 3 studies (COMFORT-I and -II) in pts with primary MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). The prevalence of individual symptoms among these pts has not been defined. We evaluated the baseline HRQoL and symptoms among pts enrolled in COMFORT-II. Methods: COMFORT-II is a randomized, open-label, multicenter, phase 3 study comparing ruxolitinib with best available therapy. HRQoL and symptoms were assessed at baseline using the European Organisation for the Research and Treatment of Cancer QoL Questionnaire–Core 30 (EORTC QLQ‑C30) and Functional Assessment of Cancer Therapy–Lymphoma (FACT‑Lym); this analysis summarizes these scores for all pts, regardless of assigned treatment. Results: In COMFORT-II (N = 219), 52% of pts were aged &gt; 65 years and 57% were male. By IPSS criteria (Cervantes et al. 2009), 40% had intermediate-2 and 60% had high-risk MF. Mean (95% CI) EORTC global health status/QoL (53.7 [50.6-56.7]; median, 50.0) and FACT-General total scores (73.0 [70.8-75.2]) were comparable to those for pts of similar age with other cancers (Oliva et al. 2011: median global health status score of 50 for acute myeloid leukemia [AML]). The most frequent symptoms (reported as “quite a bit” or “very much”) were fatigue (54%), dyspnea (30%), insomnia (30%), pain (29%), night sweats (23%), and itching (21%), and there were differences in baseline symptoms across MF subtypes (Table). Conclusions: This analysis shows that pts with MF experience severe disease-related symptoms and have diminished HRQoL similar to pts with AML, but because pts with MF have a longer life expectancy (an average of 2.3 to 4 years for high and intermediate-2 risk pts, respectively), they may suffer with a reduced QoL for many years. [Table: see text]
Sorafenib treatment of Asian patients with advanced renal cell carcinoma (RCC) in daily practice: Subset analysis of the large non-interventional PREDICT study.
Authors: Dingwei Ye, Jun Guo, Jae-Lyun Lee, Ai-Ping Zhou, Yiran Huang, Zhiquan Hu, Cheng Fu, Jiyan Liu, Lin Qi, Hanzhong Li, Qing Zou, Sung Joon Hong, Kathrin Stauch, Annette Böckenhoff, Gyunji Kim, XiaoJing Zhang, Hanjong Ahn, Jianhui Ma
Journal: Journal of Clinical Oncology (2012)

4628 Background: Previous studies with sorafenib in Asian patients with advanced RCC were relatively small and used strict entry criteria. Here we investigated safety and efficacy in a large subset of Asian patients in the prospective, non-interventional PREDICT study of sorafenib in routine practice (NCT 00895674). Methods: Patients were eligible based on a diagnosis of advanced RCC and the decision by the investigator to prescribe sorafenib under compliance of the local product label. Tumor status, patients’ performance and physician assessment of efficacy and tolerability were collected up to 12 months. Results: Between Jan 2007 and June 2010, 1092 patients were enrolled in China (n=1033), South Korea (n=55), the Philippines (n=3) and Indonesia (n=1). In the efficacy population (n=909), baseline characteristics were: 71% male; 89% &lt;70 years old; 89% clear cell histology; 78% prior nephrectomy; 56% prior systemic therapy; 16% high MSKCC risk; 35% ECOG PS ≥2; 5% brain metastases. Overall, 19% of patients had ≥1 concomitant disease at baseline; the most frequent concomitant diseases were hypertension (14%) and diabetes (6%). Initial sorafenib dose was 800 mg daily in 97% of patients, of whom 91% were also receiving 800 mg daily as last dose. Median duration of sorafenib treatment was 9.7 months (range 0.2–24.1), and in clinically relevant subgroups was as follows: treatment-naïve, 9.7 months; high MSKCC risk, 9.3 months; brain metastases, 8.4 months; age ≥70 years, 7.6 months; ECOG PS 2, 9.7 months; ECOG PS 3, 6.1 months. At last follow up, 63% of physicians reported good/very good efficacy and 59% good/very good tolerability. Sorafenib was well tolerated; &lt;2% of the safety population (n=1022) reported serious drug-related adverse events (SDRAEs) and only 3% discontinued due to DRAEs. In all, 35% of patients reported a DRAE, with the most frequent being hand-foot skin reaction (21%), diarrhea (7%), rash (7%), alopecia (5%), hypertension (3%). Conclusions: In this large subset of Asian patients with advanced RCC treated in daily practice settings, sorafenib was well tolerated and provided benefit, including in clinically relevant patient subgroups.
Utility of a novel quantitative EGFR-mutated protein analysis using AQUA system for EGFR-TKI treatment in non-small cell lung cancer.
Authors: Koichi Goto, Genichiro Ishii, Kaori Fujimoto-Ouchi, Masatoshi Shirane, Tatsuro Saito, Morie Nishiwaki, Hironobu Ohmatsu, Seiji Niho, Kiyotaka Yoh, Shigeki Umemura, Yuki Yamane, Toshihiro Shiozawa, Yoko Yamaguchi, Tetsuhiko Taira, Kanji Nagai, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2012)

e18064 Background: Lung cancer carrying EGFR mutation (muEGFR) expresses good response to EGFR tyrosine kinase inhibitors (TKIs). However, not all patients (pts) with mutation showed similar clinical benefits from EGFR-TKIs. Heterogeneity of tumor cells is considered to be one plausible reason. MuEGFR was usually genotyped in qualitative manner in present clinical practice. In addition, new technology of AQUA system enables us to measure protein levels objectively with considering expression heterogeneity in tissues. Here we investigated the correlation between AQUA score obtained from each specimen and the response and the response duration by EGFR-TKIs. Methods: Slice sections from genotyped 105 pts with muEGFR and 33 pts with wild-type EGFR were stained by E746-A750 deletion (6B6)- and L858R (43B2)-specific antibodies. Homo- or heterogeneous staining and muEGFR protein levels of these specimens were evaluated with AQUA system. Results: Concordance rate between genotypes and AQUA-based phenotypes (deletion and L858R), with cut-off values based on ROC curve, were 60% and 82%. Low sensitivity of 6B6 was due to lucking of reactivity for other deletion variants. Alternatively, specificities of both antibodies were 96% and 92%, indicating highly selectivity to muEGFR protein. The AQUA score of 27 pts treated with EGFR-TKIs were varied (8.7 – 907.4) but the falls plot analysis indicated that pts with high AQUA score showed better objective response. Specimens of partial response (PR) had significantly higher AQUA score than those of progression disease (136.5 vs 9.8, p=0.014). When divided pts into two groups based on median AQUA score, the pts with high AQUA score showed a tendency of longer treatment duration (21 mo vs 14 mo, p=0.162). These results indicate that AQUA-based analysis can classify pts carrying genotyped muEGFR into susceptible and less susceptible ones to EGFR-TKIs. Conclusions: We observed that pts with high AQUA score were more sensitive to EGFR-TKIs. It is important for predicting sensitivity to EGFR-TKIs to investigate not only genotyping but also muEGFR protein levels by using AQUA system.
Integrated analysis of RNAi screens in pediatric rhabdomyosarcoma.
Authors: Fernanda Irene Arnaldez, Sirisha Chakka, Carly J Smith, Choh L Yeung, Natasha Caplen, Lee J. Helman
Journal: Journal of Clinical Oncology (2013)

10040 Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Embryonal RMS (ERMS) are characterized by 11p15 LOH, while alveolar RMS (ARMS) harbor a translocation between PAX3 or PAX7 and FOXO1. Relapsed or metastatic RMS has a poor prognosis with a 5-year survival rate of 25%. We hypothesized that a reduction in proliferation of ARMS cell lines as result of the loss of function (LOF) of a specific protein via RNAi likely point to novel targets that exhibit “synthetic lethality” with the PAX3/7-FOXO1 translocation, and can be used to reveal unique ARMS vulnerabilities. Methods: We are using two complementary screening strategies to identify genes critical for RMS cell growth and survival. One RNAi screening strategy used an inducible LOF shRNA screen of 15,000 shRNA -5,000 genes- introduced into RH30 (ARMS) or RD (ERMS) cells. Data analysis after subtraction of targets related to common survival pathways revealed 40 genes with close association with RMS cell growth. Follow up analysis included further comparison of the effects of gene specific LOF in ARMS and ERMS cell lines and assessment in orthotopic xenografts. To increase the strength of our findings, we have also conducted parallel siRNA screens of the human kinome targeting 704 kinase genes (3 siRNAs per gene) in RH30 or RD cells. Results: Of the 40 genes identified by shRNA screening, 15 genes were identified as selectively needed for ARMS cell growth. Follow up analysis of one of these genes, TNK-2 (tyrosine kinase, non-receptor 2) in orthotopic xenografts, confirmed that LOF of TNK2 markedly decreases ARMS cell growth. The siRNA screen has identified a further putative 26 genes that selectively reduce ARMS cell growth. These screens have led us to focus on members of the ERK, PI3K and IGF1R pathways as potential targets for the treatment of ARMS. Conclusions: RNAi screening affords an unbiased method for the discovery and elucidation of gene function. Ongoing efforts are focused on the integration of results obtained to gain further insight into the signaling networks influencing alveolar rhabdomyosarcoma biology and thus identify a small group of druggable genes that could represent alveolar rhabdomyosarcoma specific vulnerabilities.