tbuckley/cabot-search huggingface dataset:
CNS metastasis and colorectal cancer: A retrospective cohort study.
Authors: Emerson Yu Sheng Chen, Shimon Ben Boursi, Michelle Alonso-Basanta, Steven Brem, Bruce J. Giantonio
Journal: Journal of Clinical Oncology (2016)

e15055 Background: Long-term survival in metastatic colorectal cancer has improved with current treatment strategies. Central nervous system (CNS) metastases are rare and poorly characterized, and may represent a late event resulting from improved survival. This study aims to characterize the clinical presentation and outcome of colon and rectal cancer patients with CNS metastasis. Methods: A retrospective review of medical records of colon and rectal cancer patients treated at the University of Pennsylvania from June 2006 to May 2015. Patients were identified by any ICD9 code for colon or rectal cancer and for CNS metastasis. Tumor pathology, location of metastatic sites, clinical presentation, time to CNS metastasis, number and location of CNS lesions, CNS directed therapy, and clinical outcome were tabulated. Categorical variables were compared using the Chi square test, and continuous variables, with Student’s t test. Results: Of 1998 colon cancer patients, 15 (0.75%) had CNS metastasis. Of 707 rectal cancer patients, 17 (2.4%) had CNS metastasis. The mean duration from primary tumor diagnosis to CNS metastasis was 38.6 months (±32.2SD) in colon cancer and 52.3 months (±34.4SD) in rectal cancer (p = .26). Patients with colon cancer had a trend to present with < 3 CNS lesions (80% vs. 64.7% in rectal cancer, p = .9). None of the colon cancer patients presented with CNS metastasis as the only metastatic site compared to 5.9% in rectal cancer. The most common presentation of CNS metastasis in colon cancer patients was focal motor deficit (46.7% vs. 17.6% in rectal cancer), which reflected a higher frequency of frontal lobe metastasis (20.0% vs. 11.8% in rectal cancer). Colon cancer patients were less likely to receive surgical resection or radiosurgery compared to rectal cancer patients (66.7% vs. 88.2%, p = .14). Overall survival following CNS metastasis may be shorter in patients with colon cancer compared to rectal cancer (7.3 months vs.12.1 months, p = .2). Conclusions: The development of CNS metastasis appears to be a late event in those who experience prolonged survival. Patients with CNS metastasis from colon cancer receive less targeted treatment and have worse survival compared to similar patients with rectal cancer, despite having more focal disease.
Understanding docetaxel and cabazitaxel modes of action in prostate cancer.
Authors: Thomas Nelius, Courtney Jarvis, Stephanie Filleur
Journal: Journal of Clinical Oncology (2017)

e23149 Background: Despite the approval of several new agents, taxanes remains the main treatment with survival benefits for castration-refractory metastatic prostate cancer/mCRPC. Still their mechanisms of action and therapeutic efficacy remain incompletely characterized. In the present study, we proposed to compare docetaxel/Doc and cabazitaxel/Cab, delivered as monotherapy or in combination with the anti-angiogenic and anti-tumoral Pigment Epithelium-Derived Factor/PEDF, on CRPC cells in vitro and in vivo. Methods: CRPCcells were assessed for cell growth, cell cycle, and apoptosis under taxane/control treatment by cytotoxicity, PI incorporation and TUNEL assays. CL1 cells that express PEDF/control were used in vivo. Tumor cells were injected s.c. into CB17-SCID mice. After two weeks, mice were randomized into groups: 1) Placebo; 2) Doc 5mg/kg i.p. d4; and 3) Cab 5-1-0.5-0.1mg/kg i.p. d4, d1-7, d2, daily. To assess the anti-tumor effect of the combination, tumor cell migration and phagocytosis were measured by Boyden chamber and confocal microscopy analyses of CL1-RAW264.7 macrophages co-cultures. Results: Cab was more cytotoxic than Doc in all the cell lines tested.This effect was concomitant to increased cell death, but was not due to autophagy or necrosis. Inversely, we showed that apoptosis was superior in Cab-treated cells than in Doc treatment. In vivo, while 0.5 and 0.1 mg/kg Cab did not improve PEDF efficacy on tumor growth, 1mg/kg was very toxic. In contrast, PEDF combined with 5mg/kg Cab lead to stabilization of the disease and was also found to be drastically more efficient than PEDF/Doc in delaying the disease. In vitro, PEDF/Cab inhibited tumor cell migration at a significant superior level compared to PEDF/Doc. Finally, tumor cells phagocytosis was induced in PEDF/Cab suggesting that the combination may target macrophages within the tumor microenvironment. Conclusions: Our data demonstrated the greater anti-tumor efficacy of Cab compared to Doc. They also insist on the fact that PEDF/Cab could be used as a novel combined therapy for CRPC, and emphasize on the importance in evaluating the cytotoxicity of the novel combination tested and investigating the role of the tumor microenvironment in the anti-tumor effect.
A phase I study to evaluate safety, tolerability, pharmacokinetics and activity of oraxol in patients (pts) with advanced malignancies.
Authors: Wen Wee Ma, Nilofer Saba Azad, Elaine Tat Lam, Jennifer Robinson Diamond, Grace K. Dy, Mateusz Opyrchal, Denise Gallagher, Caden Brennen, David Cutler, Douglas Kramer, Wing Kai Chan, Rudolf Kwan, Gerald J. Fetterly, Alex A. Adjei, Antonio Jimeno
Journal: Journal of Clinical Oncology (2018)

2526 Background: Oraxol is an oral formulation of paclitaxel (PTX) co-administered with the potent, selective, poorly absorbed, P-glycoprotein inhibitor HM30181A (HM) that enhances the absorption of PTX. PK modelling of prior data showed fixed dose administration was feasible. The objectives were to determine the MTD and PK of Oraxol administered as a fixed dose for up to 5 consecutive days. Methods: Eligible pts had advanced solid tumors, ECOG PS ≤ 1 and adequate organ function. The dose escalation utilized the standard 3+3 design (Part 1) and then expanded to enroll additional pts at the MTD (Part 2). The treatment consisted of sequential administration of HM oral 15 mg then PTX oral 270 mg daily while fasting. Dose escalation was achieved by increasing the number of dosing days per week (2 to 5 days per week x 3 weeks then 1-week rest, per 4-week cycle). Pts were monitored for dose limiting toxicity (DLT) during the first cycle for dose escalation/de-escalation decisions. Adverse events (AEs) were assessed per CTCAE v4.03 and response by RECIST v1.1. Results: A total of 34 pts received treatment and were AEs evaluable. Twenty-one of 24 pts in Part 1 were DLT evaluable and 1 DLT (febrile neutropenia) occurred at the 5-day dose level. Ten additional patients were treated at the 5-day dose level in Part 2. The most common (≥30%) treatment-related AEs (TRAEs) were nausea, diarrhea, anorexia and vomiting. Serious TRAEs included febrile neutropenia, pneumonia and dehydration. Pre-medication with steroids/anti-histamines was not required and hypersensitivity reactions were not observed. Partial responses occurred in 2 pts at the 5-day dose level (salivary gland, ovarian cancers). The median Tmax was 1 to 2 hrs. PTX exposure (Cmax and AUC) was comparable following 2-5 days of treatment; with a Day 1 Cmax ranging from 147 to 246 ng/mL and AUC0-8hr ranging from 369 to 800 ng*hr/mL. Plasma levels of HM/metabolite were minimal. Conclusions: The MTD was not reached and the highest planned dose level (HM 15 mg/PTX 270 mg x 5-day) was selected for expansion. Sequential oral administration of HM and PTX achieved clinically efficacious PTX level and showed evidence of anti-tumor activity. Clinical trial information: NCT01967043.
A phase I NANT study of lenalidomide with ch14.18 and isotretinoin (RA) in patients with refractory/recurrent neuroblastoma (RR-NB).
Authors: Araz Marachelian, Judith Villablanca, Angela Duvalyan, Scarlett Czarnecki, Susan G. Groshen, Denice Tsao-Wei, Richard Sposto, Jemily Malvar, Jianping Sun, Kelly C. Goldsmith, Yael P. Mosse, Meaghan Granger, Nita Seibel, Jeffrey Moscow, Katherine K. Matthay, Michael Sheard, Robert Seeger
Journal: Journal of Clinical Oncology (2018)

10522 Background: Ch14.18 (dinutuximab) increases event free and overall survival in patients with high-risk NB when given in a regimen with GM-CSF/IL-2. However, this therapy has significant toxicities, and 40% of patients relapse. LEN has immunomodulatory effects in pediatric solid-tumor patients and is well tolerated. The combination of LEN with ch14.18, was supported by preclinical data that demonstrate the activity in NB. We conducted a phase I trial to determine the tolerability of LEN with ch14.1 and RA in patients with RR-NB. Methods: LEN dose escalation followed a 3+3 design (25, 50, 75 and 100mg /m2/day). The administration schedule is: LEN days 1-21, ch14.18 (17.5mg/m2/day) days 8-11, and RA (160mg/m2/day) days 15-28 (Dose level 2-5). Results: 27 patients enrolled with a median age of 8 years (range: 3-20), of whom 23 were evaluable for dose escalation. The median number of courses was 4 (range 1–12). No MTD was identified. There were 7 patients with dose limiting toxicities (course): grade 3 diarrhea(C1), grade 3 diarrhea/delayed neutrophils(C1), delayed neutrophils(C2), grade 4 ALT(C8), anaphylaxis(C5), delayed platelets(C5), delayed neutrophils(C4), delayed neutrophils/grade 4 sinus bradycardia(C6). Overall regimen was tolerable with no grade 3 capillary leak, 7% grade 3 hypotension and 4% grade 3 fever. there was 1 complete response, 3 partial responses, 3 minor responses, 8 stable diseases and 6 progressive diseases in 21 patients evaluable for response. Immunomodulation was seen with statistically significant increases in frequency of circulating effector NK cells, an increase in the frequency of CD4+ (T-helper) effector memory T lymphocytes and increased antibody dependent cytotoxicity (ADCC) in patients. Plasma protein concentrations demonstrated statistically significant therapy-associated increases in granzyme B, IL-15, IFNg, CXCL9, CXCL10, CXCL11, sIL-2R, and GM-CSF as well as IL-6, IL-8, IL-10, MCP-1, and M-CSF. Conclusions: LEN 100 mg/m2 QD for 21 days per cycle is tolerable with ch14.18 and RA, and is associated with antitumor response and immunomodulatory effects. Further studies are warranted in studying this combination. Clinical trial information: NCT01711554.
Apatinib administration following transcatheter arterial chemoembolization for hepatocellular carcinoma with pulmonary metastasis: A single-institutional experience.
Authors: Guoliang Shao, Jiansong Ji, Wenhao Hu, Liwen Guo, Zhongwei Zhao, Jun Luo, Song Wen, Jiaping Zheng
Journal: Journal of Clinical Oncology (2018)

e16104 Background: Prognosis of advanced hepatocellular carcinoma (HCC) with pulmonary metastases is poor. Anti-angiogenesis therapy plus transcatheter arterial chemoembolization (TACE, the mainstay of local-regional treatment) seems to be a promising strategy. Apatinib, an oral tyrosine kinase inhibitor targeting VEGFR-2, has been proven to be effective in advanced HCC. This observational study aimed to evaluate apatinib for pulmonary metastases in HCC patients following TACE procedure. Methods: From May 2015 to Jun 2017, advanced HCC with lung metastasis, who underwent TACE for the primary liver tumor and then received apatinib (500 mg qd) treatment, were included. The tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and the safety profiles were recorded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE 4.0). Results: Total 38 cases were included. The baseline data are shown in Table 1. The median medication time was 11.4 months (range 0.4–31.6). Among 30 assessable patients, 1 had a complete response, 14 had a partial response, 10 had stable disease, and 5 had progressive disease. An objective response rate of 50.0% was achieved, and the disease control rate was 83.3%. At the cut-off date of Nov 21 2017, the median progression-free survival was 10.1 months (95%CI, 3.5–14.8 months). The median overall survival had not reached, and the 12-month survival rate was 69.1%. The most common adverse events (AEs) related to apatinib were anemia, fatigue, and bilirubin increase. No unexpected AEs occurred. Conclusions: On the basis of TACE treatment for primary lesions, subsequent apatinib lead to an obvious good response of pulmonary metastases. TACE combined with apatinib could be an alternative first-line treatment for HCC patients with pulmonary metastases. Table 1 Baseline Data. Characteristics N (%) Age, yrs N (Missing) 37 (1) Median (Range) 51 (30, 66) Gender N (missing) 38 (0) Male 29 (76.3%) ECOG PS N (missing) 29 (9) 0-1 26 (89.7%) 2 3 (10.3%) Child-Pugh N (missing) 32 (6) A 27 (84.4%) B 5 (15.6%) BCLC N (missing) 32 (6) C 32 (100.0%)
Nausea and Vomiting in Pregnancy
Authors: Sagara Wijayasinghe, Alexandre Bentvelzen, Cécile Guenot, Jeton Murtezi
Journal: New England Journal of Medicine (2010)

Nausea and vomiting in early pregnancy is a common condition at risk to be minimized by women or care providers. If not treated in the early stages, it can evolve to a severe condition with a morbidity risk for the mother and/or the fetus, and expose to public health consequences. Severe forms of nausea and vomiting and hyperemesis gravidarum are a clinical diagnosis with nonspecific manifestations in addition to biologic and metabolic consequences for mother and/or child. Safe and effective treatments can prevent severe consequences if used in an early stage of symptoms.Les nausées et vomissements au premier trimestre de grossesse sont des manifestations fréquentes et donc à risque d’être banalisés par les femmes comme par les soignants. Mal contrôlés initialement, ils sont à risque d’évoluer vers une forme sévère, avec une morbidité maternelle et/ou fœtale non négligeable, et impliquer des conséquences en matière de santé publique. Les formes sévères de nausées et vomissements de grossesse (hyper-émèse gravidique) sont des diagnostics cliniques avec des manifestations aspécifiques et des complications biologiques, voire métaboliques, sur la mère comme sur le fœtus. Plusieurs lignes de traitement existent, qui ont montré leur efficacité et leur innocuité. Instaurés précocement, ils préviennent l’évolution vers des formes graves.
A randomized phase III study comparing S-1 plus docetaxel with S-1 alone as a postoperative adjuvant chemotherapy for curatively resected stage III gastric cancer (JACCRO GC-07 trial).
Authors: Yasuhiro Kodera, Kazuhiro Yoshida, Mitsugu Kochi, Wataru Ichikawa, Yoshihiro Kakeji, Takeshi Sano, Narutoshi Nagao, Masazumi Takahashi, Akinori Takagane, Masanori Nakamura, Masahide Kaji, Hiroshi Okitsu, Takashi Nomura, Takanori Matsui, Takaki Yoshikawa, Jin Matsuyama, Makoto Yamada, Yuichi Ito, Masahiro Takeuchi, Masashi Fujii
Journal: Journal of Clinical Oncology (2018)

4007 Background: Although postoperative adjuvant chemotherapy with S-1 is among the standard treatments for curatively resected pStage II/III gastric cancer (GC) in Asia, the outcome of pStage III GC remains unsatisfactory. Postoperative S-1/docetaxel had been among candidates for the new standard treatment. Methods: JACCRO GC-7, a randomized controlled trial to explore postoperative S-1/docetaxel, was participated by 138 Japanese institutions. After R0 resection by D2 gastrectomy, patients with pStage III GC were randomly assigned to either the S-1/docetaxel group (oral S-1 at 80-120mg/body on days 1-14 with 7 days of rest was followed by 6 cycles of S-1 at the same dosage and schedule combined with docetaxel 40mg/m2 on day 1 of each cycle, and then 4 further cycles of S-1 at 80-120mg/body on days 1-28 every 42 days) or the control group (8 cycles of S-1 at 80-120mg/body on days 1-28 every 42 days). Block randomization was performed by a central interactive computerized system stratified by the institution, stage (IIIA, IIIB, or IIIC) and histological type (differentiated or undifferentiated). The sample size of 1,100 was necessary to detect a 7% increase in the 3-year RFS, the primary endpoint, in the S-1/docetaxel group (HR 0.78, 2-sided alpha = 0.05, beta = 0.2). The secondary endpoints were OS, TTF and safety. Results: At the planned second interim analysis, the 3y RFS of the S-1/docetaxel arm (65.9%) was significantly superior to that of the S-1 arm at 49,6% (HR 0.632, 99% CI: 0.400~0.998, p = 0.0007), and the independent data and safety monitoring committee recommended termination of the trial. S-1/docetaxel suppressed all types of recurrences including hematogenous, lymphatic and peritoneal. Although ≥grade 3 adverse events including leucopenia, anorexia, stomatitis and anemia were more frequent, postoperative S-1/docetaxel was safe and manageable. Conclusions: Postoperative adjuvant S-1/docetaxel after D2 gastrectomy is recommended as the new standard of care for patients with pStage III GC. Clinical trial information: UMIN 000010337.
Neuromuscular ultrasound for assessment of peripheral neuropathy in breast cancer patients receiving taxane therapy.
Authors: Thomas Lycan, Alexandra Thomas, Fang-Chi Hsu, Michael Stephen Cartwright, Francis O Walker, Christine Ahn, Omar P Sangueza, Yusuke Shiozawa, Sun Hee Park, Christopher Michael Peters, Susan Anitra Melin, Tiffany P. Avery, Steven Sorscher, Glenn Jay Lesser, Roy E. Strowd
Journal: Journal of Clinical Oncology (2018)

e22083 Background: Chemotherapy-induced peripheral neuropathy (CIPN) occurs in 40% of breast cancer patients receiving taxanes and may lead to early treatment discontinuation. Taxane microtubular hyper-stabilization causes nerve inflammation that may be mediated by mast cell activation. Neuromuscular ultrasound (NMUS) is a non-invasive modality to assess cross sectional area (CSA) of peripheral nerves. To date, one study of NMUS (n = 15) for oxaliplatin CIPN found increased CSA with no published studies for taxane CIPN. Methods: This cross-sectional pilot study of breast cancer patients with CIPN evaluated nerve fiber CSA by NMUS as compared to historical values in healthy adults. Findings were correlated with self-reported symptom scale (EORTC-QLQ CIPN20); nerve conduction studies; and two skin biopsies for intraepidermal nerve fiber (IENF) and mast cell densities. This interim analysis reports on feasibility and descriptive results. Results: In 8 months, 11 female participants completed analysis out of 28 approached. They reported moderate to severe CIPN symptoms (QLQ-CIPN20 sensory subscale: mean 52, range 31-78 out of 100) with median 113 days (range 0-1,299) after completion of paclitaxel (5), docetaxel (4), or nab-paclitaxel (2). Sural sensory nerve CSA was 0.8 mm2 smaller than historical controls (p = 0.08), which may be consistent with a sensory-predominant axonopathy; mixed nerve CSA was similar (each p > 0.27) [Table]. IENF was reduced at ≥1 site in all patients (mean thigh 14/mm, ankle 8/mm, p < 0.05). Longer time since taxanes was associated with greater IENF loss (r = -0.56, p = 0.07). Exploratory analysis suggests increased mast cell infiltration at 6-12 months post-taxane as opposed to during or > 12mo after treatment (63, 31, 29 cells/mm2, respectively). Conclusions: These data support a sensory predominant axonopathy in patients with taxane-induced CIPN and warrant longitudinal assessment of NMUS to non-invasively track and monitor CIPN. Clinical trial information: NCT03139435.Table: CSA measurements by NMUS (n = 11). Site Sample, mm2 mean (st dev) Historical control, mm2 mean (st dev) Sural nerve (Sensory) 4.5 (1.4) 5.3 (1.8) Median nerve at wrist (Mixed) 12.7 (5.8) 10.1 (2.7) Tibial nerve (Mixed) 14.3 (3.9) 14 (4.3)
Institutional retrospective analysis of definitive chemo-radiotherapeutic treatment (QRT) in locally advanced cervical cancer.
Authors: Tomas Jose Soule, Pablo Mando, Juan Pablo Sade, Gonzalo Giornelli Gomez, Sergio Gabriel Rivero, Matias Chacon, Reinaldo D. Chacon, Mauro Orlando
Journal: Journal of Clinical Oncology (2017)

e17016 Background: Retrospective analysis of toxicity and treatment impact of gemcitabine and platinum plus radiotherapy in patients with locally advanced cervix cancer. Methods: Descriptive, retrospective and observational study of patients with locally advanced cervix cancer (EIla/IVa).The analysis included toxicity Grade III/V and it impact in treatment. Results: We analyze 56 pts, median age: 46.5, median follow up: 24 months. Patients and tumoral characteristics are described in the table below. Regarding platinum group, 2pts required dose reductions of chemotherapy, 2pts suspended a cycle due to toxicity and 4pts needed RT split. 100% pts completed chemo radiotherapy concurrent treatment. Regarding platinum+gemcitabine group: 11pts required CT dose reductions, 14pts suspended a cycle due to toxicity and 5 didn´t complete CT due to toxicity; 6 had a RT split and 18 completed RT. Grade 3-4 toxicity was more frequent in the platinum+gemcitabine group (38.9% vs 73.7%, p=0.01) In platinum group, 14 pts presented disease recurrence. In the platinum + gem group 3pts had a recurrence. Median disease free interval (DFI) was not reached in both groups, but in the univariate analysis statistical significance was achieve, favouring the combine treatment (Log rank test, p=0.03). 2 year global survival rate was 82.1% in platinum group and 91.7% in platinum+gemcitabine groups. Conclusions: This report shows that the scheme of concurrent combine chemotherapy offers higher toxicity, requiring treatment discontinuation in some patients. Nevertheless, in a univariate analysis the platinum+gemcitabine group showed better results, even in a population with more advance disease with greater risk of relapse, understanding that the retrospective evaluation may miss confounders. A correct institutional manage of toxicities may allow the use of intense treatment to obtain potential benefits. [Table: see text]
Gene expression signature development to decode breast cancer heterogeneity.
Authors: Heather Ann Brauer, Afshin Mashadi-Hossein, Wesley Buckingham, Patrick Danaher, Sean Ferree
Journal: Journal of Clinical Oncology (2018)

e24243 Background: The heterogeneity of breast cancer is driven by many factors, including processes driven by tumor, stroma, and immune cell populations. Using PAM50 and Tumor Inflammation Signature (TIS) as a base, we developed 15 gene expression signatures that describe the diverse biological processes underlying the tumor-stroma-immune interactions in breast cancer. The Breast Cancer 360 gene expression panel captures this biology in a single assay. Methods: Signature development followed a three-step process of signature curation, evaluation and refinement. First, we mapped a curated list of primary biological drivers of breast tumor heterogeneity to published or internally developed sets of gene expression signatures. Next, using data from The Cancer Genome Atlas (TCGA), each signature was evaluated to eliminate those which were not consistently reproduced in an independent dataset. Lastly, exploiting co-expression patterns, we eliminated genes with low informational value to enrich each geneset for the primary biological signal of interest. Results: The 15 signatures were trained and demonstrated expected agreement with each other and with independently measured biomarkers and clinical characteristics. For instance, within TCGA, we observed gene expression-based p53 score predicting p53 mutation with 79% accuracy (CI = 72%, 87%) and the HRD score was associated with DNA scar metrics (p < 0.001, R2= .3). Additionally, TIS was significantly associated with PAM50 subtypes (p < 0.001), with the basal-like and Her2-enriched subtypes having higher inflammation than the luminal subtypes. However, the information overlap was minimal (R2= .07) pointing to the complementary nature of these metrics. Conclusions: The Breast Cancer 360 panel and signatures provide a comprehensive view of breast cancer biology, allowing for a deeper understanding of processes underlying the complex heterogeneity of the disease. The intersection of these signatures with PAM50 and the Tumor Inflammation Signature improves statistical power and interpretation of results in a wide range of breast cancer studies. Our training procedure demonstrates strong expected concordance between each signature and the associated biology.