tbuckley/cabot-search huggingface dataset:
Utilizing total neoadjuvant therapy (TNT) in rectal cancer: NRG-GI002, a phase II clinical trial platform.
Authors: Thomas J. George, Greg Yothers, Theodore S. Hong, Marcia McGory Russell, Y. Nancy You, William Parker, Samuel A. Jacobs, Katherine L. Pogue-Geile, Christina Sing-Ying Wu, Norman Wolmark
Journal: Journal of Clinical Oncology (2017)

TPS814 Background: Improvements in outcomes for locally advanced rectal cancer (LARC) have plateaued due to an inability to consistently deliver adjuvant therapy and thus far ineffective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms in LARC. The experimental arms are not intended for direct comparison, but to test a variety of sensitizers or hypotheses in a consistent and relatively homogenous high-risk patient (pt) population with correlative biomarkers. Success of any given experimental arm will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC as defined by any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, all pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. Based on promising phase I results, the first experimental arm will assess the activity of veliparib added to standard chemoRT (capecitabine + RT). Primary endpoint is to demonstrate an improvement in Neoadjuvant Rectal Cancer (NAR) score for the experimental arm vs control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional arms added through rolling protocol amendments. Support: U10 CA-180868, -180822, UG-189867; AbbVie. Clinical trial information: NCT02921256.
Association of the simultaneous expression of ephrin B3 receptor and E-cadherin in Barrett's adenocarcinoma with favorable clinical staging.
Authors: Matthias Schauer, Nikolas Stoecklein, Stephan Baldus, Marcus Feith, Arnulf Hoelscher, Feride Kroepil, Wilfried Budach, Christiane Matuschek, Edwin Boelke, Wolfram Trudo Knoefel
Journal: Journal of Clinical Oncology (2012)

e14527 Background: In intestinal epithelium tyrosine kinase receptor Ephrin B3 maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1. While loss of Ephrin B3 is linked to colorectal cancer initiation, overexpression of Ephrin B3 in cancer cell lines inhibits growth and induces functional changes with decreased mesenchymal and increased epithelial markers. In order to study this tumor suppressor activity of Ephrin B3 in esophageal adenocarcinoma we analysed the simultaneous expression of Ephrin B3 and E-cadherin in healthy esophagus and Barrett’s carcinoma. Methods: Simultaneous expression was investigated in samples of 141 patients with Barrett’s carcinoma and of 20 healthy esophagi. For analysis immunhistology and quantitative PCR was used. Results of healthy squamous epithelium, Barrett’s metaplasia and staging specific esophageal adenocarcinoma were correlated. Results: A significantly reduced E-cadherin mRNA activity in adenocarcinoma compared to dysplasia could be detected. Immunhistological activity of E-cadherin and Ephrin B3 was reduced in adenocarcinoma compared to dysplasia or healthy esophageal mucosa. The intracellular E-cadherin distribution changed significantly from the cytoplasm to the membrane, when Ephrin receptor was simultaneously expressed. Simultaneous expression of E-cadherin and Ephrin B3 showed a significant inverse correlation to tumorstage. Conclusions: We present first evidence of the tumor suppressor activity of Ephrin B3 receptor in esophageal adenocarcinoma possibly due to the impact on redistribution of cellular E-cadherin to the membrane. Our results suggest that this effect might play a role in the dysplasia-adenocarcinoma-sequence, the infiltrative growth pattern and the development of lymph node metastases.
Preliminary results of a phase II randomized study (ROMULUS) of polatuzumab vedotin (PoV) or pinatuzumab vedotin (PiV) plus rituximab (RTX) in patients (Pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).
Authors: Franck Morschhauser, Ian Flinn, Ranjana H. Advani, Laurie Helen Sehn, Kathryn S. Kolibaba, Oliver W. Press, Gilles A. Salles, Catherine S. Magid Diefenbach, Herve Tilly, Sarit E. Assouline, Andrew Tzong-Yow Chen, Martin H. Dreyling, Anton Hagenbeek, Pier Luigi Zinzani, Bruce D. Cheson, Sreenivasu Yalamanchili, Dan Lu, Akiko Chai, Yu-Waye Chu, Jeff Porter Sharman
Journal: Journal of Clinical Oncology (2014)

8519 Background: PoV and PiV, antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in Phase I. The current study aims to compare PoV and PiV + RTX in R/R DLBCL and R/R follicular lymphoma (FL). Methods: Pts were randomized to receive PoV or PiV + RTX (ADC 2.4 mg/kg + RTX 375 mg/m2) every 21 days. Tumor assessments were performed every 3 months. Results: As of 8 November 2013, 58 received PoV + RTX (38 DLBCL; 20 FL), 63 PiV + RTX (42 DLBCL; 21 FL). Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced between treatment arms; 46% were RTX refractory. Median treatment (tx) cycles in DLBCL: 5 for both ADC (1-15); FL: 8.5 PoV (3-15) and 6 PiV (1-13). Overall safety profiles of both regimens were similar. Tx-emergent adverse events (AE) >25%: fatigue (52%), diarrhea (42%), nausea (37%), peripheral neuropathy (PN) (32%), constipation (26%). Grade ≥ 3 AE >3%: neutropenia (21%), diarrhea (6%), dyspnea (4%), febrile neutropenia (4%), hyperglycemia (4%) and PN (4%). Serious AE reported in 36%. Thirty-eight discontinued tx for AE after median 5 doses (range 1-14), including 16 for PN. Tx delays and ADC dose reductions reported in 27% and 22%. Two of 7 deaths (sepsis, urosepsis) unrelated to NHL were attributed to PiV. Complete (CR) and partial (PR) responses, n (%) [% 95% CI] (see Table). Conclusions: PoV and PiV + RTX were generally well-tolerated with similar toxicity. Neutropenia, PN and diarrhea were principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + RTX suggests greater clinical activity in R/R FL. Combination studies of R + PoV with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Clinical trial information: NCT01691898. PoV (CD79b) + RTX PiV (CD22) + RTX R/R DLBCL ORR CR PR N = 37 19 (51%) [34, 68] 5 (14%) [5, 29] 14 (38%) [23, 55] N = 37 20 (54%) [37, 71] 7 (19%) [8, 35] 13 (35%) [20, 53] R/R FL ORR CR PR N = 20 12 (60%) [36, 81] 6 (30%) [12, 54] 6 (30%) [12, 54] N = 21 14 (67%) [43, 85] 1 (5%) [0.1, 24] 13 (62%) [38, 82] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation.
Post-therapy fibrosis as a surrogate of original tumor bulk in locally advanced rectal cancer (LARA): An exploratory study of radiographic mis-staging and inflation of therapeutic benefit.
Authors: MinYuen Teo, Elaine M.A. Walsh, Jane Sze Yin Sui, Margaret Sheehan, Cormac Small, Joseph Martin, Myles Joyce, Mark Regan, Oliver J McAnena, Eddie Myers, Maccon M. Keane, Gregory D. Leonard
Journal: Journal of Clinical Oncology (2014)

e14551 Background: Delivery of neoadjuvant chemoradiotherapy (NACRT) in LARA is predicated on MRI staging. Small series of direct-to-surgery patients (pts) suggested high rates of over/under-staging of pts. Tumour bed fibrosis reflects the extent of NACRT response and could be used as a surrogate of pre-therapy tumour stage. Comparing to fibrosis-based staging, we sought to examine 1.) rates of staging discrepancy and 2.) true magnitude of response to NACRT. Methods: Consecutive pts with diagnosis of LARA who received NACRT were identified from institutional database between January 2011 and November 2013. Demographics and clinical stages were extracted from health records. Histopathology reports were reviewed to obtain post-NACRT staging and to estimate pre-therapy staging based on extent of fibrosis according to AJCC 7th edition. Results: 60 pts were identified with a median age of 66 years (range: 27 – 85), of which 42 (70%) were males. Distribution of clinical, fibrosis-based, and post-therapy T- and N- stages are tabulated below. Pathologic complete response was observed in 15% of patients. By fibrosis-based staging, 22% may be deemed over-treated based on clinical trial eligibility. Compared to fibrosis-based staging, clinical T-stage over-/under-staged in 28% and 17% of cases, respectively, while clinical N-stage over-/under-staged in 38% and 13% of cases, respectively. With respect to treatment response, T-stage was down-staged in 47% and up-staged in 13% of cases based on clinical staging but down-staged in 35% as per fibrosis-based staging. N-stage was down-staged in 52% and up-staged in 12% of cases based on clinical staging but only down-staged in 23% of cases. Conclusions: MRI-based staging of LARA may be discordant with true disease stage in up to 1/3 of cases, and the rates of disease downstaging achieved might have been over-estimated. More sensitive pre-treatment staging modalities would be required. Clinical staging Fibrosis-based staging n % n % p T2 6 10 17 28 0.03 T3 46 77 33 55 T4 8 13 10 17 N0 16 27 31 52 0.02 N1 34 57 23 38 N2 10 17 6 10 ypT0 9 15 ypT1 2 3 ypT2 15 25 ypT3 28 47 ypT4 6 10 ypN0 42 70 ypN1 13 22 ypN2 5 8
Reinduction of oxaliplatin-based chemotherapy after exposure to oxaliplatin in adjuvant setting for colorectal cancer.
Authors: Seung-Hoon Beom, Joong Bae Ahn, Sang Joon Shin, Minkyu Jung
Journal: Journal of Clinical Oncology (2017)

755 Background: Oxaliplatin-based chemotherapy is commonly used chemotherapy in the adjuvant setting for colorectal cancer patients. In clinical practice, those patients may be retreated with oxaliplatin after relapse. The efficacy and predictive factor of oxaliplatin re-treatment are little known. Methods: We carried out a retrospective study of 53 consecutive patients who underwent surgery and adjuvant FOLFOX chemotherapy and who were re-treated oxaliplatin-based chemotherapy after relapse at Yonsei Cancer Center from April 2009 through October 2015. The main end-point was progression-free survival (PFS). Results: Among enrolled patients, 33 (62.2%) received curative resection in initially non-metastatic setting and the other 20 (37.7%) did R0 resection including metastasectomy in stage 4 at the time of previous oxaliplatin treatment. Median time from last cycle of adjuvant FOLFOX to the first cycle of palliative oxaliplatin based chemotherapy was 31.5 months. Palliative oxaliplatin was given as second and third or later in 37 (69.8%) and 16 (30.2%) patients respectively. Median PFS and overall survival (OS) were 5.1 and 17.5 months. Response rate and disease control rate to palliative oxaliplatin based treatment were 17.0 % and 66.0%. Patients with both shorter interval from first oxaliplatin exposure to recurrence (&lt;12 months) and shorter interval from recurrence to oxaliplatin re-exposure (&lt;18 months) experienced shorter PFS significantly compared to those who did not (2.8 vs. 7.3m, p = 0.004). It was an independent predictive factor for PFS in addition to use of targeted agent in multivaviate analysis. Conclusions: In this study, re-treatment with oxaliplatin based chemotherapy after recurrence demonstrated modest clinical efficacy. Non-use of targeted agent and both shorter interval from first oxaliplatin exposure to recurrence and shorter interval from recurrence to oxaliplatin re-exposure are poor predictive factors for PFS.
Diclofenac and ibuprofen are associated with increased risk of cardiac arrest
Authors: Jacqui Wise
Journal: BMJ (2017)

Use of the non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and ibuprofen are associated with a significantly increased risk of cardiac arrest, a large Danish study has found. 

The authors of the study, which was reported in the European Heart Journal: Cardiovascular Pharmacotherapy, 1 said that the findings were a stark reminder that NSAIDs were not harmless and should only be used after consulting a healthcare professional.

The researchers used the Danish Cardiac Arrest Registry to identify everyone who had a cardiac arrest out of hospital between …
Head-to-head pharmacokinetic and pharmacodynamic comparison of subcutaneous versus intramuscular leuprorelin acetate formulations in male patients.
Authors: Judd W. Moul, John A. McLane, Stuart Atkinson, Raoul S. Concepcion
Journal: Journal of Clinical Oncology (2017)

e589 Background: Leuprolide acetate (LA) is the standard-of-care luteinizing hormone-releasing hormone (LHRH) agonist used to suppress serum testosterone (T) in the treatment of advanced prostate cancer. There are currently two LA formulations available: a controlled-release implant injected subcutaneously (SC) or a microsphere intra-muscular (IM) injection. The study compared the pharmacokinetics/pharmacodynamics of both formulations at the same one-month dose. Methods: Thirty-two healthy men were randomized to receive a single 7.5 mg injection of SC-LA (n = 16) or IM-LA (n = 16) in this phase 1, open-label, parallel-group study. Serum LA, T, and luteinizing hormone (LH) were assessed. Results: The initial surge of LA was higher for IM-LA than SC-LA (Cmax 27±4.9 vs. 19±8.0 ng/mL, respectively), with a shorter t max (1.0±0.4 vs. 2.1±0.8 hrs). Mean serum LA remained above the level of quantification (LOQ, 50 pg/mL) through Day 49 for SC-LA, whereas for IM-LA, mean serum LA dropped below the LOQ after Day 28. Median LH concentration remained low at Day 56 in the SC-LA group, whereas LH levels began to rise after Day 35 in the IM-LA group. Consequently, serum T began to increase by Day 42 in the IM-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ≤ 50 ng/dL vs. 0 in the IM-LA group. Both SC-LA and IM-LA were well tolerated, however SC-LA subjects experienced more mild injection site disorders compared to IM-LA. Conclusions: The initial surge of LA was higher for IM-LA than SC-LA (Cmax 27±4.9 vs. 19±8.0 ng/mL, respectively), with a shorter t max (1.0±0.4 vs. 2.1±0.8 hrs). Mean serum LA remained above the level of quantification (LOQ, 50 pg/mL) through Day 49 for SC-LA, whereas for IM-LA, mean serum LA dropped below the LOQ after Day 28. Median LH concentration remained low at Day 56 in the SC-LA group, whereas LH levels began to rise after Day 35 in the IM-LA group. Consequently, serum T began to increase by Day 42 in the IM-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ≤ 50 ng/dL vs. 0 in the IM-LA group. Both SC-LA and IM-LA were well tolerated, however SC-LA subjects experienced more mild injection site disorders compared to IM-LA.
PARTNER: A randomized phase II study of docetaxel/cisplatin (doc/cis) chemotherapy with or without panitumumab (pmab) as first-line treatment (tx) for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).
Authors: Lori J. Wirth, Shaker R. Dakhil, Gabriela Kornek, Rita Axelrod, Douglas Adkins, Shubham Pant, Paul E. O'Brien, Philip R. Debruyne, Kelly S. Oliner, Jun Dong, Bruce A. Bach
Journal: Journal of Clinical Oncology (2013)

6029 Background: PARTNER was a multicenter, randomized phase II estimation study evaluating 1stEline tx of R/M SCCHN with doc/cis ± pmab. Methods: Patients (pts) were randomized 1:1 to doc/cis with pmab (Arm 1) or doc/cis alone (Arm 2). Arm 1 received 9 mg/kg pmab on day 1 of each 21-day cycle, and all pts received 1stEline doc/cis both at 75 mg/m 2 on day 1 for up to 6 cycles. In Arm 1, pts could receive pmab monotherapy upon completion of 6 cycles of doc/cis until disease progression (PD). In Arm 2, pts could receive pmab as 2ndEline monotherapy upon PD. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. HPV status was determined using p16 INK IHC. No formal hypothesis was tested. Results: Baseline characteristics were balanced between arms. Of 103 pts, HPV status was evaluable in 66 (64%); 29% were HPV positive. Efficacy results are shown (Table). Worst grade 3/4 adverse events (AEs) were 73% in Arm 1 vs 56% in Arm 2. Conclusions: Median PFS was increased in both arms over historical doublet cytotoxic chemotherapy. PFS and ORR were higher in the pmab arm in the overall population, in the HPV positive (n=19) group, and in the HPV negative (n=47) group. There was an increase in grade 3/4 AEs with this regimen. The crossover design, with 57% of Arm 2 pts receiving pmab as 2ndEline monotherapy, confounds interpretation of OS. Clinical trial information: NCT00454779. [Table: see text]
Evaluation and response of mucin pools in primary rectal cancer tissue during chemoradiotherapy (CRT).
Authors: Hiroshi Miyakita, Sotaro Sadahiro, Gota Saito, Kazutake Okada, Akira Tanaka, Toshiyuki Suzuki
Journal: Journal of Clinical Oncology (2017)

798 Background: Mucinous carcinoma (MC) has been defined as carcinoma with &gt; 50% of tumor volume showing mucin pool (MP). The incidence of MC had been reported to be 4 to 12% of colorectal cancer and to be less effective for chemotherapy and CRT. The incidence of MC was 3 to 8% in rectal cancer treated with surgery alone and 13 to 24% in patients treated with CRT. These findings suggest that MP may be induced by CRT in some patients. We therefore compared the degree of MP in MRI findings before CRT, after CRT and in resected specimens. Methods: The study group comprised 205 patients with rectal cancer who received CRT (40 to 45 Gy) from 2006 through 2014. MPs on MRI were evaluated using T2-weighted fast-spin echo images, and the MP area ratios on maximum cross-section of the primary tumor were calculated. An MP area ratio of 0% was designated as class 0, 1 to 9% as class I, 10 to 29% as class II, 30 to 50% as class III, and 50% or higher as class IV. Results: On MRI before CRT, the MP area ratio was class 0 in 181 patients (88%), class I in 11 (5%), and class II or higher in 13 (6%). On MRI after CRT, the MP area ratio was class 0 in 186 patients (91%), class I in 4 (2%), and class II or higher in 15 (7%). The prevalence of MP classes did not change appreciably. The MP class evaluated on MRI before and after CRT changed by 2 or more levels in only 2 patients, both of whom had marked tumor shrinkage. Among 175 patients with an MP area ratio of class 0 or I in the resected specimens, the MRI findings after CRT were consistent with the findings of the resected specimens. However, the MP area ratio was underestimated by 2 or more levels on MRI in 14 (47%) of 30 patients who had an MP area ratio of class II or higher. A pathological complete response (pCR) was obtained in 24 patients (12%), all of whom had an MP area ratio of class 0 or I on MRI before CRT. No patient with an MP area ratio of class II or higher before CRT had a pCR. Conclusions: The degree of MP evaluated on MRI did not change during CRT. In patients who had an MP area ratio of &gt; 10% in their resected specimens, the evaluation of MP on MRI was often underestimated. Patients with an MP area ratio of &gt; 10% before CRT had a poor response to CRT, with no pCR.
Primary tumor site as a useful predictor for cetuximab efficacy in KRAS wild-type (exon 2 non-mutant) metastatic colorectal cancer.
Authors: Kuo-Hsing Chen, Ho-Min Chen, Yu-lin Lin, Mei-Shu Lai, Ann-Lii Cheng, Kun-Huei Yeh
Journal: Journal of Clinical Oncology (2015)

e14592 Background: Cetuximab is one of the standard treatments for patients with wild-type KRAS metastatic colorectal cancer (CRC). Previous studies had shown left-sided and right-sided CRC (LCRC and RCRC) have different molecular and clinic-pathological features [Ann Oncol 2014; 25:1995-2001]. We conducted this study to explore the association of primary tumor site (left-sided versus right-sided) and cetuximab efficacy in KRAS wild-type CRC. Methods: This study enrolled a cohort of patients who had received cetuximab as salvage treatment for wild-type (exon 2 non-mutant) KRAS metastatic CRC by national reimbursement policies from the databases of Taiwan Cancer Registry (Year 2004-2010) and National Health Insurance (Year 2004-2011). Information regarding to age, gender, histology, grade, initial stage, chemotherapy prescriptions and primary tumor site were also retrieved. Survival data was obtained from the National Death Registry. Time to treatment discontinuation (TTD) and overall survival (OS) after cetuximab usage were compared between patients with left-sided (splenic flexture to rectum) versus right-sided (cecum to hepatic flexture) CRC (LCRC versus RCRC). Results: A total of 969 patients were included. Among them, 765 (78.9%) and 136 (14.0%) patients had LCRC and RCRC, respectively, excluding the transverse colon site and undetermined primary sites. Patients with RCRC tended to more female (45.6% vs. 36.9%, p = 0.0536) and have more grade 3 (G3) tumors (20.6% vs. 8.5%, p = 0.002) than those with LCRC. Compared with patients of RCRC, those of LCRC had significantly longer TTD (median, 4.59 vs. 2.75 months, p= 0.0005) and OS (median, 12.62 vs. 8.07 months, p< 0.0001) after cetuximab usage. Multivariate analysis revealed right-sided primary tumor is an independent predictor of overall mortality (adjusted hazard ratio [HR] = 1.49, [using LCRC group as a reference], p= < 0.0001) and treatment discontinuation after cetuximab treatment (adjusted HR = 1.39. p= 0.001). Conclusions: Our findings demonstrated left-sided primary tumor site (LCRC) is a useful predictor for better cetuximab efficacy in KRAS wild-type metastatic CRC.