tbuckley/cabot-search huggingface dataset:
A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors.
Authors: Carlos Becerra, Jeffrey R. Infante, Lawrence E. Garbo, Michael S. Gordon, David A. Smith, Fadi S. Braiteh, David R. Gandara, Robert M. Jotte, Karen L. Reckamp, Filip Janku, Howard A. Burris, Kevin M. Bellew, Olivia S. Gardner, Li Liu, Donna S Cox, Vijay Gopal Reddy Peddareddigari, George R. Blumenschein
Journal: Journal of Clinical Oncology (2012)

3023 Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherapy was given at full recommended doses. Erl was escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts have been enrolled across all arms except trametinib+nab-pac. Preliminary exposure results of trametinib+doc, erl, or pem suggest no PK drug-drug interaction. The predominant DLT for trametinib+doc without growth factors (MTD = 0.5 mg+60 mg/m 2 ) was neutropenia. When administered with growth factors, trametinib+doc has been given up to 1.5 mg+75 mg/m 2 with no DLTs. The predominant DLTs for trametinib+erl (MTD = 1 mg+100 mg) were diarrhea and mucositis and for trametinib+pem (MTD = 1.5 mg+500 mg/m 2 ) were mucositis and febrile neutropenia. The MTD for trametinib+pem+carbo has not yet been determined. To date there are 5 PRs in the trametinib+doc group and 2 PRs in the trametinib+pem group. An NSCLC expansion cohort for trametinib+pem is enrolling. Conclusions: Trametinib+doc and trametinib+pem have shown acceptable tolerability and initial evidence of clinical activity.
Pain severity and impairment of activity between pegfilgrastim (P) and fixed-dose filgrastim (F) in women with early-stage breast cancer receiving chemotherapy.
Authors: Mova Leung, Joy Eustaquio, Jessica Kano, Tiffany Marr, Brian Patrick Higgins, Robert Edward Myers, Jenny Kim, Glenn Jones
Journal: Journal of Clinical Oncology (2012)

e19570 Background: In comparative trials of P and F, bone and joint pain are evident and with similar incidences. Also, muscle pain is clinically noted. Pain severity may differ between P and F, especially when a short fixed-dose regimen of F is used. Methods: This is a prospective observational and ethics-approved study. It compares the incidence &amp; severity of muscle and/or joint pain (MJP) in patients (pts) receiving P (6mg SC for 1 day) or fixed-dose F (300mcg SC for 7-8 days) initiated 24 hours after chemotherapy. Eligible were women with breast cancer receiving neo- or adjuvant chemotherapy, and P or F. Choice of P or F were at the oncologist’s discretion based on patient preference &amp; insurance coverage. Pts were ineligible if they could not complete the pain diary, or had received P or F in the past 6 months. Efficacy of P and F was evaluated by comparing febrile neutropenia (FN) and neutropenia (N) requiring delay of the second cycle of chemotherapy. Patient &amp; treatment characteristics were captured to assess for risk factors for developing MJP. A pain diary assessed MJP severity, its management and impact on everyday activities. It was completed starting the evening of chemotherapy for 14 consecutive days. Statistical analysis was performed with Stata 12, including multi-level longitudinal mixed models for MJP scores. Results: 140 pts were enrolled with mean age 52 yr and 58% receiving docetaxel-based chemotherapy. One-third received F and two-thirds received P. Both diary muscle and joint pain peaked in prevalence and severity on days 3 to 6. Over 50% of pts reported MJP at the peak. Pain that increased ≥3 points from baseline was reported by 48% of pts. Daily activities were affected in 48% of 1,960 reporting-days, with 26% reporting moderate or severe impairment. Despite similar incidences of pain, P was associated with lower mean muscle (p=0.0049) and joint (p=0.014) pain scores by regression analyses. FN and N were not different. Use of docetaxel was the sole baseline risk factor for developing MJP. Conclusions: Patients experience substantial MJP with impairment of daily activities but pts receiving pegfilgrastim experience less pain and less burden relating to pain.
Ensuring Vaccine Safety in Pregnant Women
Authors: Kathryn M. Edwards
Journal: New England Journal of Medicine (2017)

In this issue of the Journal, investigators from Denmark present a comprehensive review of the adverse pregnancy outcomes encountered in women who received quadrivalent human papillomavirus (HPV) vaccine during pregnancy, as compared with those who did not.1 The investigators assembled data on all the pregnancies in Denmark that occurred within a 7-year period, and they used nationwide registries to identify the dates of pregnancy, pregnancy outcomes, and maternal characteristics, including receipt of HPV vaccine and dates of vaccine administration. Vaccinated women and unvaccinated women were propensity-score matched in a 1:4 ratio, and pregnancy outcomes were compared. Although a large number . . .
Patience is a virtue: Wait and see strategy for metastatic or recurrent renal cell carcinoma.
Authors: Inkeun Park, Jae-Lyun Lee, Jin-Hee Ahn, In Gab Jeong, Cheryn Song, Bum-Sik Hong, Jun Hyuk Hong, Choung-Soo Kim, Hanjong Ahn
Journal: Journal of Clinical Oncology (2013)

e15519 Background: Metastatic renal cell carcinoma (MRCC) often presents with very indolent course without any symptom, and treatment (Tx) for MRCC is mostly palliative rather than curative in a molecular target agents era. There exist several Tx options for MRCC, but all available agents have considerable toxicities, cause economic burden to patients (pts), and impair quality of life. For some cancers like indolent lymphoma, “wait and see” strategy (W&amp;S) is adopted for asymptomatic pts. We retrospectively evaluate clinical outcomes of W&amp;S for asymptomatic MRCC pts. Methods: we enrolled MRCC pts who was followed-up with deferred treatment for the purpose of W&amp;S in our institution between 2000 and 2012. Clinical characteristics, response to W&amp;S, predictive factor for time-to-progression (TTP), and response to succeeding first line Tx were analyzed. Results: Of 44 pts found, 30 pts had recurrent disease and 13 pts initially metastatic disease. Most pts had good Karnofsty PS (KPS), 100% for 26 pts and 90% for 13 pts. Lung (38 pts), lymph nodes (16 pts), kidney (6 pts) were most common site of metastasis. During W&amp;S, stable disease (SD) and progressive disease (PD) were the best overall response for 36 (82%) and 8 (18%) pts, respectively, and 37 pts had PD finally. With a median F/U period of 24.7 months, median TTP and OS were 12.5 months (95% CI, 6.7-18.4) and 91.1 months (95% CI, 41.3-141.0). After univariate and multivariate analysis for TTP, KPS&lt;100%, liver metastasis, time from diagnosis to W&amp;S&lt; 1year, and neutrophilia were found to be predictive factors for TTP during W&amp;S. After PD, 27 pts proceeded to systemic treatment (13 sunitinib, 10 pazopanib, 3 immunotherapy, and 1 temsirolimus). Objective response rate were 54% for sunitinib, and 50% for pazopanib. Conclusions: This study suggests that W&amp;S could be a viable treatment option for the first-line approach in asymptomatic MRCC pts, especially for those who have good performance status without neurtrphilia or liver metastases.
Determinants of first-line treatment selection in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Hui-Li Wong, Ying Wang, Yaling Yin, Hagen F. Kennecke, Winson Y. Cheung, Daniel John Renouf, Sharlene Gill
Journal: Journal of Clinical Oncology (2017)

468 Background: Chemotherapy options currently available for the first-line treatment of advanced PDAC include FOLFIRINOX (FX), gemcitabine with nab-paclitaxel (GP) and single agent gemcitabine (Gem). GP was introduced most recently and funded for clinical use in British Columbia (BC) in September 2014. In this retrospective analysis, we explore the impact of GP availability on first-line treatment selection and overall survival (OS) in advanced PDAC. Methods: The BC Cancer Agency provincial pharmacy database was used to identify patients (pts) who started FX, GP or Gem between January and August 2014 (pre-GP) or January and August 2015 (post-GP). Pts were eligible for inclusion if they received at least one cycle of first-line therapy for locally advanced or metastatic PDAC. Clinical data were extracted from electronic medical records. OS was defined as time from diagnosis of advanced PDAC to death and compared by treatment era, adjusting for age, ECOG, comorbidities, disease extent and baseline CA19-9. Results: 286 pts fulfilled eligibility criteria: 88 (31%) with locally advanced and 198 (69%) with metastatic disease. 131 and 155 pts were treated in the pre- and post-GP eras respectively. Prior to GP approval, 44% and 49% of pts received Gem and FX; this decreased to 21% and 33% after GP funding, with 46% of pts receiving GP in the latter period. Nine (7%) pts received GP in the pre-GP era, either through self-pay or addition of nab-paclitaxel after approval. There were no significant differences in pt characteristics across both eras. 46% of pts who received GP post approval had ECOG ≥ 2. The proportion of pts receiving second-line therapy was lower in the post-GP era (22% vs. 38%). Median OS in the post-GP era was 8.1 vs. 10.1 months in the pre-GP era; adjusted HR 1.28 (95% CI 0.96–1.71). Pts with ECOG ≥ 2 who received GP had a median OS of 6.5 months. Conclusions: After GP was funded, it became the preferred first-line regimen for advanced PDAC. Its more frequent use instead of FX did not appear to compromise overall survival even though a substantial proportion of pts were ECOG ≥ 2 and few pts received second-line therapy.
Tremelimumab in combination with exemestane as novel immunotherapy for patients with advanced breast cancer
Authors: R. H. Vonderheide, P. M. LoRusso, M. Khalil, E. Heath, D. Khaira, D. Soulieres, P. Dorazio, G. L. Mariani, T. Usari, S. M. Domchek
Journal: Journal of Clinical Oncology (2009)

3034 Background: Tremelimumab (CP-675, 206) is a fully human IgG2 anti-CTLA4 monoclonal antibody (mAb) with single-agent antitumor activity presumed to be related to immune stimulation following blockade of CTLA4. Here, we conducted a phase I, open-label, dose-escalation trial of the combination of tremelimumab and exemestane in patients (pts) with advanced hormone receptor (or unknown receptor status if prior response with hormone therapy) breast cancer. Methods: Twenty-five pts with ER+ and/or PR+ breast cancer and 1 pt with unknown receptor status who had relapsed after treatment for advanced disease were enrolled. Pts received escalating doses of tremelimumab (3 to 10 mg/kg) delivered either every 28 days (Q28D) or every 90 days (Q90D) in combination with continuous exemestane (25 mg/day). Primary endpoints were assessment of safety and determination of recommended phase II dose. Tumor response evaluation per RECIST was a secondary endpoint. Results: Overall, 65 cycles of tremelimumab were administered in combination with exemestane. Pts received 3 mg/kg tremelimumab Q28D (n=6), 6 mg/kg tremelimumab Q28D (n=1), 6 mg/kg tremelimumab Q90D (n=13), or 10 mg/kg Q90D (n=6). No pharmacokinetic interaction between tremelimumab and exemestane was observed. Dose-limiting toxicities included transient serum transaminase elevation in cycle 1 (grade 3 in 1 pt) and diarrhea in cycle 1 (grade 3 in 3 pts, 1 of whom was hospitalized with steroid-refractory diarrhea and given anti-tumor necrosis factor-α mAb, infliximab) and cycle 2 (grade 3 in 1 pt). One pt developed grade 2 autoimmune thyroiditis requiring chronic hormone replacement. Other toxicities included constipation (n=6), fatigue (n=8), and rash (n=9). The MTD was 6 mg/kg Q90D. For pts receiving ≥2 cycles of therapy, best response was stable disease in 8 pts lasting 3 to 14 months (median 8 months); no pts had objective responses. Conclusions: MTD of tremelimumab in combination with exemestane is estimated at 6 mg/kg Q90D, which is lower than the single-agent dose of 15 mg/kg Q90D used in phase II and III trials in pts with melanoma or colorectal cancer. This may suggest that there is a biological interaction between tremelimumab and exemestane. [Table: see text]
Systemic inflammation score (SIS) to predict the effect of the postoperative adjuvant chemotherapy for patients with stage III colorectal cancer.
Authors: Yoshiyuki Suzuki, Koji Okabayashi, Hirotoshi Hasegawa, Masashi Tsuruta, Takashi Ishida, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2017)

575 Background: Postoperative adjuvant chemotherapy (CTx) is a standardized treatment for patients with Stage III colorectal cancer (CRC). Since previous studies reported that the benefit of adjuvant CTx is estimated up to only 15% in Stage III patients, it is necessary to establish an appropriate patient selection for adjuvant CTx. Recently, systemic inflammation is reported to play a critical role in the progression of cancer and several studies demonstrate the impact of inflammation-based score, such as mGPS and SIS. There however is a lack of evidence for the influence of inflammation on patient requiring adjuvant CTx. The aim of this study is to evaluate the impact of SIS on patient selection of adjuvant CTx for Stage III CRC. Methods: Between 2004 and 2012 a total of 295 patients with Stage III CRC who underwent curative resection were included. The SIS was developed based on serum albumin and lymphocyte-to-monocyte ratio (LMR) levels (SIS = 0; albumin &gt; 4.0 g/dl and LMR &gt; 4.44, SIS = 1; albumin &lt; 4.0 g/dl or LMR &lt; 4.44, SIS = 2; albumin &lt; 4.0 g/dl and LMR &lt; 4.44). Primary endpoint was defined as disease free survival (DFS). DFS rates were compared using Kaplan-Meier curves and Prognostic factors were assessed by Cox proportional hazard model. Results: The median follow-up period was 5.99 years. 75.9% of patients received adjuvant CTx. The distribution of SIS was SIS = 0; 32.6 %, SIS = 1; 43.3 %, and SIS = 2; 24.1 %. In multivariate analysis for overall patients, SIS was not a significant prognostic factor. Subgroup analysis according to each SIS score demonstrated that adjuvant CTx significantly prevented postoperative recurrence just only in patients with SIS = 0 (5-year DFS rate; adjuvant CTx (+) 85.5 % vs. CTx (-) 33.7 %, p &lt; 0.001 ). In Cox proportional hazard model, protective effect of adjuvant CTx decreased in proportion to the increase of SIS (HR of adjuvant CTx (95 % CI): SIS = 0; 0.187 (0.089-0.393), SIS = 1; 0.601 (0.311–1.162), SIS = 2; 0.747 (0.319–1.752)). Conclusions: The SIS can provide an appropriate patient selection for patients with stage III CRC who can benefit from adjuvant CTx. The results from this study might enhance precision medicine for adjuvant CTx for Stage III CRC.
Meningism as a poor risk factor in breast cancer patients with relapse in central nervous system (CNS).
Authors: Luis Jesus Schwarz, Carlos S. Vallejos, Silvia P. Neciosup, Joseph Pinto, Tatiana Vidaurre, Greenlandia Ferreyros, Henry Leonidas Gomez
Journal: Journal of Clinical Oncology (2012)

e11518 Background: CNS relapse in breast cancer patients is invariably defined as a poor prognosis feature with varied and bizarre clinical presentation. We describe the commonest signs and symptoms in CNS relapse and their relation with prognosis Methods: We evaluate retrospectively 2597 women with breast cancer treated at the Instituto Nacional de Enfermedades Neoplásicas (Lima-Perú) between 2000-2005. Phenotypes were determined by IHC and categorized in [HR+, HER2-], triple-negative (TN) [HR-, HER2-] and Her-2 [HR+/-, HER2 +]. Post-CNS recurrence survival was calculated by Kaplan Meier method. We use Chi-square, or exact Fisher test when appropriate, to evaluate correlations between categorical variables. Results: 157 pts (6.04%) had CNS relapse from which 19 had only leptomeningeal carcinomatosis (LMC), 124 only brain metastases and 14 both. In regard to phenotype, 43pts were [HR+, HER2-] (5 LMC), 68 were TN (13 LMC) and 51 were [HR+/-, HER2 +] (15 LMC). 152 pts had stages I-III (96.8% of all SNC relapses). There was no association between phenotypes and age at CNS relapse, ECOG PS, extracraneal metastases, control of primary tumor, number or volume of brain metastases. Significant association was found between phenotype and time from diagnosis to CNS relapse (≤8 months: 16.3% in TN, 7.3% in Her-2 and 0% for [HR+, HER2-], [P=0.017] ) and histological grade (grade III: 74.4% in TN, 55.% in Her-2 and 30% for [HR+, HER2-], [P=0.006]). Symptoms/signs frequently described in LMC patients were cephalea (72%), meningism (24%), nausea (24%), vomiting (20%), ataxia (20%), facial palsy (16%), somnolence (16%), paraparesia (12%), hiporeflexia (12%), apraxia (12%), arreflexia (12%), poor sphincter control (12%), hemiparesia (8%), seizures (8%), bradipsiquia (8%), neuropathic pain (4%). Fifty percent of TN pts with LMC had meningism. Post recurrence survival was shorter in TN patients (3.61mo vs 4.89mo to [HR+, HER2-] vs 5.95mo to [HR+/-, HER2 +; P=0.044] and in patients with meningism (1.38mo vs 5.26mo; P=0.02). Cox regression identify meningism as a risk factor for survival in patients relapsed with LMC (HR: 4.33; P=0.066). Conclusions: Meningism seems to be the only sign related to poor prognosis in patients relapsed with LMC.
Impact of delaying adjuvant chemotherapy in colon cancer: A Brazilian experience.
Authors: Luciana Carla Martins de Aquino, Bruno dos Santos Vilhena Pereira, Ivanir Martins Oliveira, Jose Claudio Casali-da-Rocha, Thalita Matta-Castro, Isabele Avila Small, Roberto de Almeida Gil, Rubem Moreira, Cristiano Guedes Duque
Journal: Journal of Clinical Oncology (2012)

e14027 Background: The optimal timing to initiation adjuvant chemotherapy in colon cancer is unknown. Studies suggest that the delay to start chemotherapy may compromise the therapeutic outcome. The purpose of this study was to assess the reasons for delaying adjuvant treatment and the implications in clinical outcome of patients treated in a public institution from Brazil. Methods: Retrospective analysis of medical records of patients enrolled in National Institute of Cancer in Brazil, from 2000 to 2006, with colon adenocarcinoma, stage II and III. Patients were dichotomized into early and late treatment groups. Results: Of 327 patients studied, 172 underwent adjuvant chemotherapy, the majority of these (62%) were stage III. Time to onset ranged between 10 and 142 days (mean 61). Eighty patients (45%) started treatment with more than 60 days after surgery, the reasons for delay were: postoperative complications 8.7%, related to the system (delay in the histopathological, referral, or surgery at other institutions) 72.5%, related to patients 5% and for medical reasons 7.5%. In 6.2% of cases the reason for the delay was not identified. There was no difference in progression-free survival or overall survival between those who received adjuvant chemotherapy within 60 days post surgery compared with those who received it after more than 60 days. Conclusions: Despite the high rate of delaying for start adjuvant treatment in the study population, no difference was observed in clinical outcomes. The referral system and test results should be reviewed, since the main causes of delay were related to the system.
Nucleophosmin expression in ovarian cancer.
Authors: Dineo Khabele, Andrew J Wilson, Annie Y Liu, Joseph Roland, Sarah Fletcher, James Slaughter, Marta A. Crispens, Michael Gold, Howard Jones, Samuel James, Oluwole Fadare
Journal: Journal of Clinical Oncology (2012)

e15582 Background: The nucleolar protein, nucleophosmin (NPM1) is implicated multiple cellular processes, including proliferation, duplication of centrosomes, ARF-HDM2-p53 signaling. NPM1 is associated with sites of double strand DNA breaks, with persistence of its expression indicative of impaired DNA repair. Data from the TCGA data have emphasized that genomic instability through impaired DNA repair processes is a characteristic feature of many ovarian cancers. Our aim was to determine the expression of NPM1 in ovarian cancers and to determine the relationship between NPM1 expression and clinical outcomes including overall survival (OS), progression-free survival (PFS) and chemotherapy response. Methods: Tissue microarrays were created from 209 patients treated for ovarian cancer at a single institution from 1994-2004. Expression levels of NPM1 were examined by immunohistochemical staining. Slides were scored using the an automated image capture and analysis system. Positive nuclear staining was used to stratify tumors into high (&gt;50%) and low (&lt;50%) groups, and the results were related to overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analysis. The relationship between ki67, a proliferation marker and pH2AX, a mark of double strand DNA breaks was measured with Spearman rank correlation coefficient analyses. Results: The majority of tumors, 140/209 (69%) were of serous histology, advanced stage 146/209 (70%) and high grade 158/209 (76%). There was &gt;50% NPM1 expression in 83/209 (40%) and &lt;50% in 126/209 (60%) of the cases. Expression of NPM1 was higher in high grade tumors, and its expression alone was a significant predictor of PFS (p=0.022) but not OS (p=0.053). When adjusting for other predictors, NPM1 expression was predictive of PFS (p=0.047), but not OS (p=0.054). No relationship between NPM1 expression and response to platinum chemotherapy was observed. However, NPM1 expression correlated with Ki67 (r=0.43, p&lt;0.0001) and pH2AX (r=0.22, p=0.0014). Conclusions: NPM1 expression is a mark of poor prognosis in ovarian cancer. Whether these observations reflect increased proliferation and/or genomic instability in ovarian cancer cells will be the focus of future investigation.