tbuckley/cabot-search huggingface dataset:
The role of pannexin 1 in chemotherapy-induced peripheral neuropathy (CIPN).
Authors: Adam Sterman, Regina Hanstein, David C. Spray
Journal: Journal of Clinical Oncology (2015)

6 Background: CIPN is a debilitating side effect and dose limiting toxicity of anticancer drug therapies. CIPN induces pathological changes in dorsal root ganglia (DRG), leading to increased cross-talk between sensory neurons and satellite glial cells (SGCs), specifically ATP mediated SGC-neuron signaling. We therefore investigated CIPN in mice with neuron- or glia-specific deletion of the ATP-releasing channel Pannexin 1 (Panx 1). Methods: To induce CIPN, mice were given two i.p. oxaliplatin (oxa) injections two days apart. Controls received saline (sal). We used C57Bl6 wildtype and transgenic mice with neuron- or glia-specific Panx1 deletion (NFHcre or GFAPcre:Panx1F/F) and littermate controls (Panx1F/F), 7-11 per group. Tactile sensitivity of the hindpaws was assessed prior to and every week after injections for 3 weeks using von Frey filaments. The number of paw withdrawals to 10 stimulations with each filament and pain thresholds (corresponding to filament that elicits 8/10 responses) were recorded. Overall mouse condition was assessed using Open Field Tests. Results: C57Bl6 mice developed transient tactile hypersensitivity after oxa injection, which was most prominent at day 9 and ceased at day 21. Oxa-injected mice had lower tactile thresholds (at 9 days: sal 5.5±0.3g vs. oxa 2.7±0.4g, p &lt; 0.001) and higher response rates to filaments compared to sal-injected controls (p &lt; 0.05), but revealed no changes in any other behavior. Mice with glia-specific Panx1 deletion did not display significant tactile hypersensitivity at any time after oxa (tactile threshold at 9 days: sal 5.5±0.3g vs. oxa 5.8±0.2g), whereas oxa induced tactile hypersensitivity did occur in mice with neuron-specific Panx1 deletion (at 9 days: sal 6±0g vs. oxa 1.3±0g, p &lt; 0.0001) and Panx1F/F littermates (at 9 days: sal 6.0±0g vs. oxa 1.3±0.1g, p &lt; 0.0001). Conclusions: We found that oxaliplatin induces transient CIPN, but no other behavioral changes in wildtype mice. Deletion of the ATP-releasing channel Panx1 in glia, but not in neurons, prevented CIPN development. This points to a new molecule (Panx1) and a new cell type (glia) as potential novel targets for pain therapy.
Association of hypophosphatemia-occurring sorafenib with prognosis and hepatic impairment in patients with advanced hepatocellular carcinoma.
Authors: M. Aizawa, S. Mitsunaga, H. Okuyama, K. Nakachi, I. Ohno, S. Shimizu, H. Takahashi, T. Okusaka, A. Ochiai, M. Ikeda
Journal: Journal of Clinical Oncology (2011)

188 Background: Hypophosphatemia is observed during sorafenib treatment. At the increased metabolic demand of the liver, hypophosphatemia is considered to be associated with a good clinical course. Hypophosphatemia associated with sorafenib treatment may also be a favorable event, but this has not yet been elucidated. The aim of this study was to evaluate the clinical significance of hypophosphatemia developing during sorafenib treatment for advanced hepatocellular carcinoma (HCC). Methods: The data of 41 advanced HCC patients (median age: 68 years, female/male: 4/37, HBs-Ag(+)/HCV-Ab(+):10/22) who received sorafenib treatment (800 mg, daily) for more than 30 days were reviewed. There were 27 and 14 patients with Child-Pugh class A and B. UICC stage II/III/IV was observed in 13/10 /18 patients. Clinical data, including those on the serum level of inorganic phosphate (IP), were collected before and after 30 days of sorafenib treatment. Overall survival time (OS) was calculated from the start of sorafenib treatment. The significance level was set at p&lt;0.05. Results: Mean serum IP level before sorafenib treatment was 3.2mg/dL (range 2.4-4.5). After 30 days treatment, IP level was decreased (mean 2.6mg/dL, range 1.3-3.9), compared to that at pre-treatment (p&lt;0.001). The patients in whom the serum IP was less than 2.4mg/dL at 30 days was assigned to the decreased IP group (N=14, mean IP 2.1mg/dL, range1.3-2.3). The decreased IP group showed a better prognosis (no event of death during the observation time) than the nondecreased IP group (MST 286 days, p=0.024). In the non-decreased IP group, the serum Alb (mean 3.6g/dL) and T.Bil (mean 0.8mg/dL) were worse after 30 days treatment (Alb 3.4g/dL p=0.007, T.Bil 1.1mg/dL p=0.037). However, deterioration of Alb (mean 3.7 vs. 3.6g/dL p=0.505) and T.Bil (mean 0.7 vs. 0.8mg/dL p=0.404) could be avoided in the decrease IP group. Conclusions: Hypophosphatemia occurring during sorafenib treatment for advanced HCC was associated with a favorable prognosis. The serum Alb and T.Bil levels were indicators of liver function and were preserved in patients with decreased serum levels of phosphate. No significant financial relationships to disclose.
Treatment patterns of patients with metastatic colorectal cancer in a large national U.S. claims-based data.
Authors: Yue Zhong, Rajesh Kamalakar, Carl V Asche, Sibyl Anderson, Brian S. Seal
Journal: Journal of Clinical Oncology (2014)

268 Background: FDA approved therapeutic choices for patients with metastatic colorectal cancer (mCRC) have evolved, including cytotoxic agents such as 5-fluorouracil (5-FU)/ leucovorin or levoleucovorin (LV), capecitabine, oxaliplatin, and irinotecan, biological agents such as bevacizumab, cetuximab, panitumumab, and aflibercept, as well as regorafenib, an oral multi-kinase inhibitor. The present study examined treatment patterns among patients with mCRC. Methods: We identified patients aged 18 or older with at least one primary CRC diagnosis between 01/01/2008 and 03/31/2012 in the MarketScan databases. mCRC patients were identified if claims indicated the presence of distant metastases (ICD-9-CM codes: 196.x, 197.0 to 197.4, 197.6 to 197.8, 198.x, and 199.0). All systemic treatment claims were extracted during 60 days after initiation of treatment. Patients were followed for more than 6 months, until end of enrollment or study end date (03/01/2013) to capture type and number of treatment lines (TLs). We also assessed regimen compliance to the current National Comprehensive Cancer Network (NCCN) treatment standards. Results: Of the total 2,934 mCRC patients retained, 2,046 (69.7%) received at least one TL: 801 (39.1%) patients with one TL, 679 (33.2%) with two TLs, and 566 (27.7%) with three or more TLs. For patients receiving first-line treatment, the most common regimens prescribed were FOLFOX (19.1%), FOLFOX+ bevacizumab (18.6%), and 5-FU/LV (17.8%). For patients receiving second-line treatment (60.9%), FOLFOX (14.1%), FOLFOX+ bevacizumab (11.0%), and FOLFIRI+bevacizumab (11.0%) were most frequently prescribed. Treatment regimens varied in patients receiving three or more TLs. FOLFIRI + bevacizumab was most frequently prescribed in the third TL (16.8%). Proportion of patients receiving NCCN-recommended regimens was 81.7% for first TL, 54.4% for second TL, and 25.3% for third TL. Conclusions: About one third of mCRC patients didn’t receive any treatment. Among mCRC patients with treatment, two thirds received at least two TLs. FOLFOX (+/-biologics) was the most frequently prescribed first and second TL. Only a quarter of patients received NCCN-recommended regimens in the third TL.
Staging documentation accuracy and adherence to workup and treatment guidelines: The M. D. Anderson Regional Care Center experience.
Authors: Amitabha Sarma, Sunil M. Patel, Laurie Sturdevant, Mee-chung Puscilla Ip, Carol L. Hundley, Leslie Kian, William Simeone, Michael Fisch
Journal: Journal of Clinical Oncology (2012)

244 Background: MD Anderson Cancer (MDACC) disease-specific faculty experts have developed institutional guidelines for diagnostic workup and treatment of common tumor types. The institution has four Regional Care Centers in suburban Houston staffed by a total of 10general medical oncologists. The primary intent of this project was to measure the accuracy of staging documentation and adherence to guidelines. The secondary intent was to improve documentation and guideline adherence by regularly reporting results directly to the involved physicians. Methods: Between July 2009 and April 2012, charts for all new medical oncology visits for patients with breast, non-small cell lung, or colon cancer for whom no previous medical oncology plan had been implemented were reviewed by a team of quality nurses on a weekly basis. Source documents were analyzed for (a) adherence to MDACC diagnostic workup guidelines (n=782); (b) accuracy of both TNM and AJCC staging documentation (n=782); and (c) adherence to MDACC treatment guidelines (n=731). On a monthly basis, a graph with rates over time of guideline adherence and accuracy of staging documentation was provided to each general oncologist. Results: The adherence rate to MDACC diagnostic workup guidelines was 79%. The agreement rate for accurate documentation of both TNM and AJCC stage was 72%. The adherence rate to MDACC treatment guidelines was 94%. Providing monthly reports of individual results to each physician did not lead to an increase in the rates of adherence of accurate staging documentation. Analysis comparing all Regional Care Center medical oncologists (not provided to the involved physicians) showed significant variation in rates for all three categories. Conclusions: Providing MDACC Regional Care Center general medical oncologists with simple graphs over time reflecting guideline adherence and accuracy of documentation did not lead to any improvement on those measures. More creative interventions to improve performance in these realms will need to be explored.
Correlation between change of FA score and postoperative recurrence in esophageal cancer patients who received neoadjuvant treatment.
Authors: Satoru Matsuda, Hiroya Takeuchi, Kazumasa Fukuda, Rieko Nakamura, Tsunehiro Takahashi, Norihito Wada, Hirofumi Kawakubo, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2016)

41 Background: We previously reported that fibrinogen and albumin score (FA score), which was consisted of plasma fibrinogen level (FNG) and serum albumin level (Alb), was shown to predict postoperative survival in esophageal cancer patients who underwent transthoracic esophagectomy. In this study, in patients who received neoadjuvant chemotherapy (NAC), change of FA score during NAC was reviewed and the correlation with recurrence free survival (RFS) was investigated. Methods: We retrospectively reviewed 125 patients who received neoadjuvant chemotherapy and underwent transthoracic esophagectomy in our institution between 2001 and 2012. FNG and Alb before (preTx) and after (preope) NAC were confirmed in 92 patients. Based on our previous reports, patients with elevated fibrinogen ( &gt; 350 mg/dL) and decreased albumin ( &lt; 3.8 g/dl) levels were allocated a FA score of 2, those with only one of these abnormalities were allocated a FA score of 1, and those with neither of these abnormalities were allocated a FA score of 0. Regarding change of FA score, based on the preTx and preope FA score, we classified into decrease group and increase (no change or increase) group. Patient characteristics, clinicopathological factors, preTx FA score, and preope FA score were reviewed, and correlation with RFS was investigated. Results: The number of preTx and preope FA score 0/1/2 was 39/41/12, 36/37/19. Regarding change of FA score, FA score decreased in 70 patients (76%), increased in 22 (24%). There was no significant difference in patient background and clinicopathological factors between groups. In survival univariate analysis, change of FA score (Increase group, HR 2.023, p = 0.025) were significantly correlated with RFS. In multivariate analysis, using preTx clinical stage as a covariate, FA score was shown to be an independent predict factor (Increase group, HR 2.076, p = 0.023) for RFS significantly. Conclusions: Change of FA score between before and after NAC was shown to be a predictive factor of RFS in esophageal cancer patients who received NAC. Both fibrinogen and albumin are popular indicators routinely measured in daily clinical practice, FA score may be highly validate and feasible.
Clinicopathological features of ruptured GIST in the ReGISTry study of high risk GIST patients after complete resection in Japan.
Authors: Toshirou Nishida, Masato Kondo, Masato Ozaka, Haruhiko Cho, Yoshito Komatsu, Toshihiko Doi, Hideo Baba, Yuko Kitagawa, Yukinori Kurokawa, Tetsuo Kanda, Toshiro Sugiyama, Akira Sawaki, Yoshihiro Kakeji, Toshihiro Hirai, Shinji Hato, Kuniaki Shirao, Chikashi Ishioka, Seiichi Hirota, Tatsuo Kagimura, Masakazu Takagi
Journal: Journal of Clinical Oncology (2016)

96 Background: Ruptured GIST, either preoperatively or intraoperatively, has ominous prognosis and is classified as high risk GIST in the modified Fletcher risk stratification. Although patients (pts) with these GISTs are recommended for 3-year imatinib adjuvant therapy, their clinicopathological features and compliance of guidelines are unknown. Methods: Between Dec. 2012 and Aug. 2015, 474 pts with high-risk GISTs locally diagnosed were prospectively registered. Among them, 453 pts with GISTs histologically confirmed by central review were analyzed. There were 243 males and 210 females with median age of 65 yrs. In the central review, H&amp;E, immunohistochemistry, and genotyping were tested. Results: Disease was located in the stomach (n = 279), small intestine (n = 137), large intestine (n = 25), or others (n = 12). Median tumor size was 7.7 cm and median mitosis (local pathology) was 10/50HPF. Tumor rupture was seen in 54 pts (12%) who had preoperative rupture (28 pts) or intraoperative rupture (25 pts). After surgery, adjuvant therapy was administered for 342 pts (75%) and withheld for 89 pts (20%). Tumor rupture was frequently observed in small intestinal GIST (23.6%) other than the duodenum and in epithelioid and/or mixed features (24%). Mitosis of ruptured GIST (median = 5.0/50 HPF) was significantly lower than that of non-ruptured (11/50 HPF). Age, gender, tumor size and genotype are not related with rupture. There was no difference in postoperative complications and adhibition of adjuvant therapy in pts who have ruptures vs pts who don’t. Preoperative rupture was associated with small intestinal GIST and R1 surgery. Mitosis was significantly lower in GIST with preoperative rupture (5/50 HPF) than that without rupture (11/50 HPF). GIST with intraoperative rupture (11.8 cm) was larger than that without rupture (7.5 cm) although there was no difference in mitosis, location and genotype. Frequency of intraoperative rupture was not different between laparoscopic surgery (4.8%) and open one (6.3%). Conclusions: Tumor rupture was not infrequent in high risk GIST and half of rupture was occurred during surgery, which may be related to large tumor size but not with laparoscopic surgery. Clinical trial information: UMIN000009531.
Tolerability study of adjuvant modified FOLFOX6 treatment in curatively resected stage II/III colon cancer (JFMC41-1001-C2: JOIN trial).
Authors: Katsunori Shinozaki, Masahito Kotaka, Tetsuo Touyama, Dai Manaka, Takanori Matsui, Kiyoshi Ishigure, Junichi Hasegawa, Yoshinori Munemoto, Akinori Takagane, Hiroshi Ishikawa, Hideyuki Ishida, Yutaka Ogata, Yasushi Tsuji, Koji Oba, Koichi Goto, Junichi Sakamoto, Shigetoyo Saji, Toshiaki Watanabe, Atsushi Ohtsu, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2014)

530 Background: Adjuvant FOLFOX is a widely accepted standard regimen for resected colon cancer. The incidence of grade ≥ 3 peripheral sensory neuropathy (PSN) was 12.4% and 5.7% in Western MOSAIC and Eastern MASCOT (outside Japan) trials, while that of grade ≥ 3 allergic reactions (AR) was 2.9% and 3.1%, respectively. JOIN Trial investigated the tolerability of modified FOLFOX6 (mFOLFOX6) in Japanese patients (UMIN ID: 000004443). Methods: Twelve cycles of mFOLFOX6 were given to patients fitting the following criteria, which were the same as those of MOSAIC: stage II/III resected colon cancer, PS of 0-1, 20 years or older, starting FOLFOX within 7 weeks of surgery, and adequate organ function. The primary endpoint was the incidence of PSN persisting for at least 8 days that interfered with daily activities and that of grade ≥ 3 AR. Target sample size was 800, assuming the expected incidence of grade ≥ 3 PSN and grade ≥ 3 AR would be 12.0% and 3.0%, and the two-sided 95% confidence interval (CI) would not include the corresponding threshold levels (16.5% for PSN and 6.5% for AR) with a 95% probability. Results: From Nov 2010 to Mar 2012, 882 patients were enrolled at 198 institutions. The safety data was analyzed in 828 patients whose data were finalized out of 848 patients received mFOLFOX6, and patient characteristics included: median age of 64 years (21-83); Male/ Female: 444/384; PS 0/1: 776/52; colon/rectosigmoid: 633/195; and stage IIA/IIB/IIC/IIIA/IIIB/IIIC: 96/33/23/61/437/178. The incidence of persistent PSN was 3.3% (95% CI: 2.2%-4.7%), while that of grade ≥ 3 AR was 1.7% (95% CI: 1.0%-2.8%), and the primary endpoint was met. Only grade ≥ 3 neutropenia showed a ≥ 10% incidence (28.7%). The incidence of grade ≥ 3 PSN was 5.8% and interstitial pneumonitis was observed in one case. There was no treatment-related death. The median number of cycles of chemotherapy was 12, and the completion treatment rate was 67.0%. The median total dosage of oxaliplatin (L-OHP) was 811.1 mg/m 2 . The median relative dose intensity of L-OHP, fluorouracil (FU) bolus and FU infusion were 90.0%, 76.9% and 81.7%, respectively. Conclusions: Adjuvant mFOLFOX6 is tolerable in Japanese patients with colon cancer. Clinical trial information: UMIN000004443.
Weight change in patients with treatment of breast cancer.
Authors: Lubna Chaudhary, Sijin Wen, Jie Xiao, Anne Swisher, Sobha Kurian, Jame Abraham
Journal: Journal of Clinical Oncology (2013)

127 Background: Studies have shown that breast cancer (BC) treatment can increase weight (wt). Wt gain during chemotherapy is usually significant and maybe associated with poor survival. Role of current treatment regimens and wt gain is not reviewed. Methods: We retrospectively analyzed the mean percentage (%) wt change during the 1st year following BC diagnosis in 246 patients (pts) between Sept 2007 and Oct 2010. Kruskal-Wallis test and post-hoc pairwise comparisons were used to assess the influence of various factors including age, histology, stage, ER/PR/HER-2/neu status, menopausal status and types of therapeutic modalities received on the % wt change. Kaplan-Meier method with log-rank test was used to evaluate recurrence free survival (RFS). Local or distant recurrence and disease progression were events for RFS analysis and disease-free pts were censored at last follow-up. Results: Mean wt gain was 0.39% (±0.40) at 1 year from diagnosis of BC. Premenopausal status was the only factor associated with significant wt gain (+1.67% vs. -0.10% for postmenopausal pts; p=0.02). Stage ≥ III was associated with significant wt loss (-1.64% for III/IV vs. +0.85% for 0/I/II; p=0.02) and a lower RFS at 3yrs and 5yrs (p&lt; 0.0001). Higher baseline wt (&gt;90th percentile) did not have any significant impact on RFS at 3 years (0.84 vs. 0.91; p=0.19). There was no significant change in wt relative to other factors as shown in Table. Conclusions: Our study using current treatment regimens did not show any significant change in % wt with chemotherapy during the 1st year of BC diagnosis. Premenopausal status was the only factor associated with significant wt gain while stage ≥ III was associated with significant wt loss and lower RFS. [Table: see text]
Prognostic analysis of intratumor microvessel density (MVD) and vascular endothelial growth factor (VEGF) in high-risk primary breast cancer (HRPBC) patients (PTS) receiving high-dose chemotherapy (HDC)
Authors: Y. Nieto, J. Woods, R. B. Jones, E. J. Shpall, S. I. Bearman, A. E. Baron, S. Nawaz
Journal: Journal of Clinical Oncology (2005)

597 Background: The prognostic value of tumor angiogenesis in N- and early N+ disease is well known. Its effect in advanced HRPBC is less clear. Methods: We analyzed MVD and VEGF by immunohistochemistry of paraffin-embedded tumor blocks from 210 pts enrolled in trials for 4–9+ (N=73), >=10+ nodes (N=89), or inflammatory carcinoma (IBC) (N=48), at long-term follow-up (F-U). All pts received adriamycin-based chemotherapy, uniform HDC (cyclophosphamide/cisplatin/BCNU), radiotherapy, and tamoxifen if hormone receptor (ER/PR)+. Anti-CD31 and anti-VEGF monoclonal antibodies (Santa Cruz, CA) were used. The MVD assay involved separate counting of CD31-stained microvessels by two pathologists in a hot neovascularization spot on the peripheral tumor margins on a 400x power field. VEGF was scored semiquantitatively, with any staining considered +. Results: Median microvessel count was 7 (0–27). VEGF expression was seen in 51% pts (1+: 29 pts, 2+: 44, 3+: 36). No correlation was seen between VEGF and MVD (p=0.3). MVD correlated directly with EGFR+ (p<0.0005) and larger tumors (p=0.01). VEGF+ prevalence was higher among pts with IBC (p<0.005), EGFR+ (p=0.01), or HER2+ (p<0.05) tumors. No correlations were seen between VEGF or MVD and ER/PR or nodal status. At median F-U of 7.5 (2–12) years, relapse-free (RFS) and overall survival (OS) rates of the entire group were 66% and 70%, respectively. A prognostic cut-off count of 14 microvessels was identified. High MVD (>14) was associated with worse RFS [74% (67–80%) vs. 44% (36–51%), p<0.005] and OS [76% (69%–82%) vs. 44% (36–51%), p<0.001] than low MVD (<=14). No differences in RFS (p=0.8) or OS (p=0.4) per VEGF were observed. Multivariate analyses of MVD with other known prognostic factors (HER2, nodal status, ER/PR and tumor size) showed an independent effect on RFS and OS. Conclusions: MVD has independent prognostic value in HRPBC pts receiving HDC. VEGF lacked prognostic value in this population with advanced disease, in contrast to prior observations in earlier tumors. No significant financial relationships to disclose.