tbuckley/cabot-search huggingface dataset:
Abiraterone after docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients (p) in an off-protocol routine clinical setting.
Authors: Maria Ochoa de Olza, Albert Font, Nuria Sala, Miguel Beltran, Maria Pilar Barretina Ginesta, Olatz Etxaniz, Maria de los Llanos Gil, Xavier Garcia del Muro, Pamela Celiz, Jose R. Germa-Lluch
Journal: Journal of Clinical Oncology (2014)

e16087 Background: Abiraterone acetate (AA) is a potent and irreversible inhibitor of CYP-17 activity that significantly improved survival in mCRPC p in the post-docetaxel setting in the COU-AA-301 trial (De Bono et al, 2011, Fizazi et al, 2012). However, these results were attained in selected p under favorable protocol conditions that are rarely found in routine clinical practice, where p may be older and highly pretreated and may have several comorbidities. We have retrospectively evaluated the activity of AA post-docetaxel in mCRPC p treated in a single institution in an off-protocol routine clinical setting. Methods: From September 2011 to April 2013, 61 p with mCRPC were treated with AA and prednisone after progressing to docetaxel. Median age: 74 years (45% of p older than 75 years). 46 p had PS 0-1; 15 p had PS 2. Gleason score was 8-10 in 52% of p. 52 p (85%) had bone metastases; 3 (5%) had visceral metastases. Median PSA was 97 ng/ml (range 1-6947); 47% of p had a PSA doubling time (PSADT) <1.5 months (m). Number of prior chemotherapy regimens: 2 in 16 p (26%) and 3 in 6 p (10%). In 26% of p, the time between the last dose of docetaxel and start of AA was <3 m. Results: Median duration of AA treatment was 26 weeks. Adverse events were most often grade 1-2. PSA decline of >50% in 29 (47%) p. Progression-free survival was 9 m (95% CI:5.0-12.9) and median survival (MS) was 25 m (95%CI:15.3-34.6). MS was shorter in p with PS 2 than in p with PS 0-1 (6 m vs 29 m; P<0.0001) and in p in whom <3 m elapsed between docetaxel and AA treatment (8 m vs 29 m; P=0.01). No differences in MS were observed according to age (<75 vs >75 years), Gleason score (<7 vs 8-10), PSADT (<1.5 vs >1.5 m), or number of prior chemotherapy regimens (1 vs 2-3). Conclusions: Compared to p in the COU-AA-301 trial, our p were older than 75 years and had received more than one prior chemotherapy regimen. Nonetheless, AA was effective as post-docetaxel treatment in this off-protocol routine clinical setting (PSA response, 47%; MS, 25 m). Although this benefit was not observed in p with PS 2, parameters associated with more aggressive tumors, such as a high Gleason score and short PSADT, did not reduce the effectiveness of AA.
Patterns of hospice use in patients with hematologic malignancies.
Authors: Amy Sexauer, M. Jennifer Cheng, W. Anthony Riley, Louise Knight, Thomas J. Smith
Journal: Journal of Clinical Oncology (2013)

e20638 Background: Despite advances in treatment there are still 70,000 deaths among U.S. patients with hematologic malignancies (HM). Nationally, fewer than 2% of HM patients use hospice and there is scarce published experience about palliative care programs for HM patients. The limited hospice use has been because of perceived HM special needs including curative intent, a less predictable course and the potential use of expensive anti-neoplastics, antibiotics, and transfusions. Methods: Study design: A single center retrospective review. Study endpoint(s): 1. What proportion of HM patients at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) were referred to and utilized hospice? 2. What are the locations of hospice services? 3. What is the median hospice length of stay (LOS)? Results: The patient characteristics were summarized using descriptive statistics. Fifty-nine HM patients were referred to hospice over this 30-month period. Only 53 patients (age 64, 26 women) utilized hospice services, representing about 20% of the estimated 250 HM decedents during this time period. Of the 53 patients, 34 received home hospice and 17 were admitted to inpatient hospice. The median home hospice LOS was 9 days (SD 12) and inpatient hospice 6 days (SD 11). Nine patients with open access hospice received only a few blood transfusions, and only one patient received radiation therapy. Conclusions: HM patients usually are referred late or not at all for hospice services. Of the patients who use “open access” hospice, there is infrequent utilization of expanded services. Studies evaluating integration of palliative care with usual HM care, triggers for hospice referral, and new open access models are needed.
Translational implications of sirtuins in chronic lymphocytic leukemia (CLL).
Authors: Savita Bhalla, Leo I. Gordon
Journal: Journal of Clinical Oncology (2015)

e22211 Background: Sirtuins (SIRT) are NAD+ dependent class III histone deacetylases (HDACs), and share extensive homology with yeast silent information regulator 2 (Sir2). In mammals seven sirt2homologues (SIRT1-7) have been identified, which target histone and various non-histone proteins. SIRT1 and other sirtuins were found to regulate cell survival via deacetylation of key cell cycle and apoptosis regulatory proteins, (p53, Ku70 and FOXO). Elevated HDAC enzyme activity is associated with cancer, including leukemia and solid tumors. HDAC isoenzymes, including class III HDACs, SIRT1 and SIRT2 are significantly increased in CLL. Herein, we describe the role of SIRT1 and SIRT2 in promoting cell survival in CLL cells. Methods: CLL cells were purified from peripheral blood obtainedfrom CLL patients (after informed consent) and normal lymphocytes obtained from normal donors through the NU Pathology Core. CLL cells, normal lymphocytes and B-prolymphocytic cell lines (JVM-3 and MEC-2) were lysed followed by Western blotting. SIRT1 and SIRT2 protein expression was quantified using Image-J analysis. Cells were incubated with varying concentrations of SIRT inhibitors, EX-527 and Sirtinol for 24-72 hr. Cell viability and apoptosis were measured by MTT assay and Annexin V/PI staining respectively. Results: SIRT1 and SIRT 2 proteins were overexpressed in CLL samples and cell lines, although SIRT2 levels were lower than SIRT1 in almost allthesamples tested. SIRT1 expression was higher in primary cells than in cell lines and normal lymphocytes. SIRT2 expression was lower in primary cells compared to cell lines. Ex-527 induced growth inhibition and apoptosis at 50-100µM concentrations, while Sirtinol induced growth inhibition at 20-30µM concentrations following 48 hr. incubation. Inhibition of SIRT1 activity led to hyperacetylation of key stress response proteins (p53 and PARP) and promoted apoptosis. Knockdown of SIRT1 by shRNA mimicked the results of the pharmacologic inhibition of SIRT1. Conclusions: We demonstrate that SIRT1 and SIRT2 are important for survival of CLL cells and that SIRT1 inhibitors may be useful therapeutic agents in CLL.
Treatment of node-negative infra-centimetric HER2+ invasive breast carcinomas: A joint AERIO/REMAGUS study
Authors: M. J. Rodrigues, J. Wassermann, L. Albiges-Sauvin, D. Stevens, E. Brain, S. Delaloge, M. Mathieu, E. Guillot, A. Vincent-Salomon, P. H. Cottu
Journal: Journal of Clinical Oncology (2009)

517 Background: Trials have shown benefit of adjuvant trastuzumab (TZM) for node-positive (N+) or supra-centrimetric HER-2+ breast carcinomas. There are limited data concerning infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). These tumors are being recognized as a high-risk group among all T1a/b tumors. Methods: Retrospective multicenter series from 2000 to 2008 of infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). Tumors with ≥80% of ductal carcinoma in situ, multifocal and metastatic tumors were excluded. Results: 96 cases have been evaluated, 75 were node negative (N- InfraHER-2). All patients had surgery. 57% (n = 43) had a sentinel lymph node procedure. 73% (n = 55) had a local irradiation and 36 a tumor bed boost. Nodal irradiation of internal mammar and infra/supraclavicular regions was done in 20% and 17% respectively. 44% (n = 33) had chemotherapy (CT), almost all (31) were associated to TZM. Anthracycline-based (A), taxane-based (T) and A/T combinations were chosen for 54%, 4% and 42% respectively. One patient developed myocardial infarction after A resulting in heart failure; 2 had a transient left ventricular ejection fraction decrease below 50% after TZM. Decision of adjuvant CT was associated (all p &lt; 0.05) with hormonal receptors (HR) negative status, Elston-Ellis grade (EE) 2/3 and high mitotic index (MI) while patients with HR+/low MI tumors were rarely treated (p &lt; 0.001). 32/39 HR+ patients received hormonotherapy (80%); 21 received aromatase inhibitors, 6 tamoxifen and 5 LHRH agonists. With a 25 months median follow-up, there was no invasive recurrence in TZM treated patients. 3 of the 44 patients treated without TZM nor CT (7%) had local or metastatic recurrence including one fatal; they had initially HR- EE 2/3 T1b tumors. Conclusions: In our practice, decision of TZM-based therapy for InfraHER-2 N- tumors is associated with high-risk profile. Indeed, N- InfraHER-2 tumors may have a significant risk of recurrence which could be avoided by adjuvant TZM. Patients with N- InfraHER-2 tumors should be included in HER-2-targeted adjuvant trials. [Table: see text]
Phase II study of combination therapy with S-1 and cetuximab in patients with <i>KRAS</i> wild-type unresectable colorectal cancer who had previously received irinotecan, oxaliplatin, and fluoropyrimidines (KSCC0901).
Authors: Kazuma Kobayashi, Yasunori Emi, Yoshihiro Kakeji, Takao Takahashi, Eiji Oki, Yoshito Akagi, Akihito Tsuji, Yasuhiro Kodera, Kazuhiro Yoshida, Hideo Baba, Mitsuo Shimada, Yutaka Ogata, Mototsugu Shimokawa, Shoji Tokunaga, Shoji Natsugoe, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2012)

3558 Background: Anti-epidermal growth factor receptor (anti-EGFR) antibodies alone or in combination with irinotecan (Iri) can be considered standard third-line therapy for KRAS wild-type (wKRAS) unresectable colorectal cancer (UNCRC). However, some UNCRC patients (pts) cannot tolerate Iri-containing therapy. S-1, an oral fluorouracil (FU) derivative, enhances the anti-tumor effect by inhibiting dihydropyrimidine dehydrogenase activity and reducing digestive toxicity. Combination therapy with cetuximab (C-mab) may restore 5-FU resistance in 5-FU–resistant CCs. Therefore, we examined the efficacy of S-1+C-mab therapy in wKRAS UNCRC pts, who had previously received Iri, oxaliplatin (OX), and FUs. Methods: The study design was multicenter, single-arm, open-label phase II study. The major inclusion criteria were written informed consent; histologically proven CRC and clinically proven UNCRC; presence of measurable lesions; previous therapy with Iri, OX, and 5-FU; documented progressive disease after 5-FU–based chemotherapy; wKRAS tumors; age ≥ 20 years; performance status (PS) 0–1; and adequate organ function. The treatment protocol was as follows: weekly durable intravenous (DIV) C-mab administration at 400 mg/m 2 (day 1) and 250 mg/m 2 /week (except day 1) and oral administration of 80 mg/m 2 /day S-1 on days 1–28 of each 42-day cycle. The primary endpoint was progression-free survival (PFS). A sample size of 39 was planned for a threshold PFS of 3.5 months and expected value of 6.0 months, with one-sided alpha of 0.05 and beta of approximately 0.2. Results: One patient was ineligible; 38 pts (PS 0/1, 32/6; 1/2/&gt;3 prior chemotherapy regimens, 4/23/11) were enrolled from 10/2009 to 12/2010. The median PFS (central review) was 5.5 months (90% CI: 4.4 – 5.7); median overall survival (OS), 13.1 months; and the best ORR, 36.8%. The most common grade 3–4 adverse events were neutrophils, hypokalemia, rash, and dry skin. Conclusions: This study showed that S-1+C-mab may be a promising and well-tolerated treatment choice of wKRAS UNCRC, who had previously heavily treated by Iri, OX and FUs.
The subtype classification and management of gastric neuroendocrine neoplasms.
Authors: Huangying Tan, Yuan Li, Jie Luo, Yanli Zhang, Lili Yu, Liqun Jia
Journal: Journal of Clinical Oncology (2014)

e15164 Background: The diagnosis and management of gastric neuroendocrine neoplasms (g-NENs) is not familiar to most physicians even cancer doctors due to its low incidence, and misdiagnosis and mistreatment (overtreatment or undertreatment) have occurred occasionally.Here we reported our center experiences on subtype classification and management of 39 cases with g-NENs, with the aim of promoting standardized diagnosis and treatment of g-NENs in China. Methods: Patients from our NET clinic from June 2012 to December 2013, in addition to EGD and biopsy, the serum gastrin and gastric pH measurement were performed in all g-NEN cases, image studies such as CT/MRI/SRS were done in some cases. Subtype classification criteria: after EGD and pathological diagnosis, g-NENs with elevated serum gastrin and elevated gastric pH belong to type 1, those with elevated serum gastrin and ZES belong to type 2, for those with normal gastrin values and normal gastric acid secretion, well differentiated NET G1, G2 or G3 are classified into type 3, poorly differentiated NECs are classified into type 4. Treatment and follow-up: in accordance with NCCN Guideline Neuroendocrine Tumors: gastric carcinoid tumors and poorly differentiated (high grade) sections. Results: Out of thirty-nine g-NEN cases, 21 males, 18 females, average age 52. Elevated gastrin levels were found in twenty-three cases (21 type 1, 2 type 2), normal gastrin levels in sixteen cases( 12 type 3, 4 type 4). In the twenty-one cases with type 1, from 2 months to 96 months g-NET history, all NET G1 and tumor <1-2cm, multiple lesions in 12 cases, 21 endoscopic resection, 9 recurrence diseases, none metastasis. Two type 2 cases were treated with PPI and SSA. Out of twelve cases with type 3, 5 treated with endoscopic resection, 2 surgical resection, 5 SSA or chemotherapy. Four type 4 cases which had mets at diagnosis received EP chemotherapy. Conclusions: Among g-NENs type 1 is the most common type which has good prognosis by endoscopic treatment, but its high recurrence rate remains a troublesome problem. Prognosis of type 3 is different according to tumor size and metastasis. Serum gastrin and gastric pH measurement are important for classifying subtype which should be done before treatment in all cases with g-NENs.
A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated chronic lymphocytic leukemia (CLL).
Authors: Herbert Aaron Eradat, Steven E. Coutre, Jacqueline Claudia Barrientos, Kanti Roop Rai, Charles Michael Farber, Peter Hillmen, Jeff Porter Sharman, Paolo Ghia, Bertrand Coiffier, Jan Andrzej Walewski, Zwi N. Berneman, Susan Mary O'Brien, Jennifer R. Brown, Sissy Peterman, Roger D. Dansey, Thomas Michael Jahn, Paula Cramer, Michael J. Hallek
Journal: Journal of Clinical Oncology (2013)

TPS7133 Background: PI3K-delta is critical for the activation, proliferation and survival of B cells and plays a role in homing and retention of B cells in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and alters trafficking of malignant B cells in lymphoid tissues (Lannutti, 2011). Phase 1 trials demonstrated that idelalisib is highly active in heavily pretreated pts with CLL as a single agent or in combination with rituximab (R), bendamustine (B), or BR: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Coutre et al, 2012; Sharman et al, 2011). Methods: Study will enroll 390 pts with previously treated CLL who have measurable lymphadenopathy, have received prior therapy containing a purine analog or B and an anti-CD20 monoclonal antibody, are not refractory to B, have experienced CLL progression within 36 months from the completion of the last prior therapy, and are currently sufficiently fit to receive cytotoxic therapy. Pts are randomized in a 1:1 ratio to Arm A or B. On Arm A, subjects receive idelalisib continuously at 150 mg BID + R at 375 mg/m 2 (1 st dose) and then 500 mg/m 2 every 4 weeks for 6 cycles + B at 70 mg/m 2 on Days 1 and 2 of each 4-week cycle for 6 cycles. On Arm B, subjects receive placebo instead of idelalisib. Stratification factors address IGHV mutational status, del(17p)/p53 mutation status, and refractory vs relapsed disease. The primary endpoint is PFS and key secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set. The study was initiated in June 2012 and a data monitoring committee has begun regular review of data. Clinical trial information: NCT01569295.
A phase I dose escalation study of the tolerability of the oral VEGFR and EGFR inhibitor vandetanib (V) in combination with the oral MEK inhibitor selumetinib (S) in solid tumors.
Authors: Wasiru Olugbenga Saka, Simon Pacey, Fiona Helen Blackhall, Javier Garcia-Corbacho, Alberto Fusi, Ioannis Karydis, Mirela Hategan, Glenda Laviste, Sarah E. R. Halford, Caroline Foxton, Robert McLeod, Susan Wan, Denis Charles Talbot
Journal: Journal of Clinical Oncology (2015)

2583 Background: The clinical utility of agents that target EGFR and VEGFR signaling in Non-Small Cell Lung Cancer (NSCLC) is limited by resistance due to emergent alternative growth stimulatory pathways, particularly that of MEK. Thus, there is a strong rationale for developing a strategy to combine EGFR, VEGFR and MEK inhibitors. Methods: Patients (Pts) aged > 18y, life expectancy > 12w and cytologically proven solid tumors for which no conventional therapy exists were eligible to participate. Six dose levels have been explored. PK samples were obtained on D4, 15 and 29. Pts remained on treatment until progressive disease or unacceptable toxicity. Results: 41 pts of median age 62y (36 – 80y); M-20, F-21; lung-23, CRC-9, Mesothelioma-3, pancreas-2, Other-4 were enrolled. 40 pts were eligible for safety assessment. Median treatment time was 10 w (range 2-44 w). GI and skin toxicities were the most prevalent related AEs (GI: 124 AEs in 88% pts; Skin: 74 AEs in 95% pts). Sixteen related eye disorders were seen in 12 pts to include retinal detachments-6 (G1-2) and retinopathies-2 (G2 and 3). Evidence of dose dependent skin and eye toxicity was observed. Six DLTs were identified; Cohort (Coh) 1 - G3 hypertension, Coh 3 & 5a - G2-3 eye events (3 AEs), Coh 4 - G3 bradycardia and Coh 5b - G3 raised ALP. The PK data for V alone and in combination with S were similar to those previously reported for either drug alone. Conclusions: V and S have overlapping toxicities, yet the combination has been manageable, with the AE profile consistent with the known monotherapy profiles. A higher incidence of reversible eye events was observed in combination than with single agent S. PK has shown no drug interaction. S dose of 100mg once daily or 50mg twice daily is the MTD in combination with V. V combination MTD to be confirmed. Stable disease was confirmed in four NSCLC patients who received 6-10 cycles. An expansion cohort in NSCLC with known EGFR, VEGFR and MEK activation status will open with anti-tumor efficacy endpoint. Clinical trial information: NCT01586624. Cohort V Lead in (po) Days 1-4 V Steady state (po) Days 5-14 S (po), from Day 15, in combination with steady state V 1 300mg od 100mg od 25 mg bd 2 50 mg bd 3 75 mg bd 4 100mg od 5a 125mg od 5b 200mg od 50 mg bd
Comparison between local and extended field radiotherapy, including regional nodes radiotherapy, in combination with concurrent chemotherapy for T1bN0M0 esophageal cancer.
Authors: Yukihiro Nakatani, Ken Kato, Hirokazu Shoji, Satoru Iwasa, Yoshitaka Honma, Atsuo Takashima, Tetsuya Hamaguchi, Yoshinori Ito, Jun Itami, Yutaka Saito, Narikazu Boku, Rei Umezawa
Journal: Journal of Clinical Oncology (2017)

142 Background: Extended field (EF) radiotherapy including regional nodes, has been adopted for the treatment of esophageal squamous cell carcinoma (ESCC), but it sometimes causes severe radiation-related adverse events. The purpose of this study is to compare local-field (LF) to EF radiotherapy administered as chemoradiotherapy (CRT) in early esophageal cancer. Methods: Selection criteria included histologically proven T1bN0M0 ESCC, performance status (PS) 0-1, adequate organ function and no other active malignancy. Data on patients who received CRT concurrently with 5-FU and cisplatin between Jan. 2000 and Dec. 2012 in our hospital were evaluated. All patients received radiotherapy at a dose of 60Gy without a planned break. The clinical target volume (CTV) of LF included gross tumor volume (GTV) plus 3-cm superior and inferior margins, and that of EF included GTV plus regional lymph nodes. Overall survivals (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test. The Cox regression model was used for multivariate analysis. Adverse events were graded according to the CTCAE v.4.0. Results: The characteristics of the EF group (n = 120) and LF group (n = 79) are: Median age, 68.0 years and 65.0 years; male/female, 106/14 and 67/12; PS 0/1, 93/27 and 63/18; median tumor length, 40.6mm and 35.4mm, respectively. The complete response rates were 90.0% and 98.7%, respectively. The median follow-up periods were 103 months and 69 months, respectively. The 5-year overall and cause-specific survival rates were 74.5% and 90.6%, 89.5% and 91.8%, respectively. According to a multivariate analysis, EF was a significant negative prognostic factor for OS (hazard ratio = 2.88, p = 0.002) but not for cause-specific survival. Cardiopulmonary toxicities of grade 3 or greater were observed more frequently in the EF group (p = 0.035), with statistical significance. Treatment-related death occurred at 6.7% and 1.3%, respectively, in the two groups. Conclusions: It is suggested that radiation with LF may be better than EF in combination with concurrent chemotherapy in early esophageal cancer (T1bN0M0).