tbuckley/cabot-search huggingface dataset:
A phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual-action antibody, in patients (pts) with refractory/recurrent epithelial tumors: Expansion cohorts.
Authors: Andres Cervantes-Ruiperez, Dejan Juric, Manuel Hidalgo, Wells A. Messersmith, George R. Blumenschein, José Baselga, Desamparados Roda Perez, Rodrigo Dienstmann, Antonio Calles, Antonio Jimeno, Sandra Sanabria, Catherine Littman, Lukas C. Amler, Andrea Pirzkall, Josep Tabernero
Journal: Journal of Clinical Oncology (2012)

2568 Background: Dysregulated human epidermal growth factor receptor tyrosine kinase (HER RTK) signaling is an important driver of tumor growth, metastasis, and survival. Extensive co-expression and heterodimerization suggest that simultaneous blockade of multiple HER RTKs may be more effective than blockade of a single RTK. MEHD is a novel dual-action human IgG1 antibody. Each antigen-binding fragment blocks ligand binding to HER3 or EGFR, and intended to inhibit signaling from all major ligand-dependent HER dimers. MEHD has single-agent activity in multiple tumor models including models resistant to anti-HER3 or anti-EGFR. Methods: This Phase I study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) activity of intravenous MEHD every 2 weeks (q2w). Tumor PD assessments were pre- and post-dose FDG-PET and IHC for pS6, pPRAS40 or pERK in tumor biopsies. Tumor CT assessments were performed q8w. No dose-limiting toxicity (DLT) was observed in six 3+3 cohorts from 1-30 mg/kg (n=30). We report results from 4 tumor-specific cohorts receiving 14 mg/kg MEHD (recommended Phase II dose). Results: As of 21 Nov 2011, 36 pts (CRC=12, NSCLC=9, SCCHN=10, pancreatic=5), median age 62.5 (35–87), all PS 0-1, median # prior regimens 3.5 (1-8), received a median of 4 doses (1-9) of MEHD; 18 pts remain on study. PK data are consistent with human anti-EGFR antibodies. No related Grade (G) ≥3 adverse events (AEs) have been observed. Common related G1/2 AEs included rash/dermatitis (53%), diarrhea (36%), fatigue (22%), paronychia (19%), dry skin, nausea, and decreased appetite (all 17%), asthenia and stomatitis/oral pain (all 14%). Related AEs ≤ 24 h after first infusion included G1/2 headache (42%), fever (33%), and chills (17%), and decreased in intensity and frequency with later infusions. Early PD data indicate target inhibition in 8/36 pts (SCCHN=2, NSCLC=2, CRC=4), and best response by RECIST includes 2 PR (both SCCHN), 6 pts with SD ≥ 8 weeks (NSCLC=2, CRC=4), 7/8 previously treated with EGFR inhibitors. Conclusions: MEHD at 14 mg/kg q2w has an encouraging safety profile and evidence of anti-tumor activity. Phase II studies are planned.
Thrombospondin-1 expressions in non-cancer tissue correlated with gastric carcinogenesis.
Authors: Hideya Kashihara, Mitsuo Shimada, Kozo Yoshikawa, Jun Higashijima, Masaaki Nishi, Chie Takasu
Journal: Journal of Clinical Oncology (2017)

88 Background: Thrombospondin-1 (TSP1) correlated with the carcinogenesis in the intestinal inflammation. TSP1 binding CD36 evoked inflammation via the activation of TGFβ and STAT3. The aim of this study is to clarify the role of TSP1 in gastric carcinogenesis. Methods: Thirty-nine patients with gastric cancer who underwent gastrectomy were enrolled. The expression of TSP1 mRNA in non-cancer tissue was determined in clinicopathological factors (including mucosal inflammation and atrophy based on Sydney system). The expressions of CD36, STAT3 and TGFβR2 mRNA in the TSP1 high and low expression group in non-cancer tissue were examined. Results: TSP1 expression was high in mucosal atrophy group and tended to be high in Helicobacter pylori (H.pylori) (+) and multiple cancer group. In TSP1 high group, CD36, STAT3 and TGFβR2 mRNA showed significantly high. The expressions of TSP1 signaling pathway in multiple cancer or atrophy (+) or H.pylori (+) showed high compared with that in single cancer and atrophy (-) and H.pylori (-). The expressions associated TSP1 signaling pathway in non-cancer tissue with multiple gastric cancer showed higher than that with single gastric cancer. Conclusions: Our results indicated TSP1 expressions in non-cancer tissue correlated with gastric carcinogenesis.
Cervical cancer outcomes with the elimination of access to care disparities.
Authors: Maliha Agloria, Faisal Cheema, Gary Von Burton, Glenn Morris Mills, Runhua Shi, Amol Takalkar, Tannaz Armaghany
Journal: Journal of Clinical Oncology (2013)

e17585 Background: Previous studies suggest lack of insurance and quality of care variations may drive disparities in cervical cancer (CC) survival, while equitable care may close these gaps. SEER based CC mortality between 2005-9 amongst white (W) and black (B) patients (pts) was 2.2 and 4.3/100,000 respectively. To define the role of equitable care on racial disparities we selected a population of pts with CC treated irrespective of the insurance status at the Feist-Weiller Cancer Center (FWCC). We hypothesized that disparities would be less pronounced at FWCC due to equitable care. Methods: A retrospective cohort study of 151 pts with FIGO Stage I-IV cervical cancer who had clinical staging, PET imaging and treatment at FWCC between 2005-9. Collected information included age, race, date of diagnosis, histology, stage, retroperitoneal lymph node (RPLN) status, treatment received, distance from the cancer center and payer status. The treatment parameters and outcomes were compared between ethnic and financial groups. Overall survival (OS) was assessed by using the Kaplan-Meier method and compared by log rank test. Results: Patients included 88 B, 66 W and 3 other pts with median age 46 years (23 – 84). Payer status included 45% uninsured, 35% medicaid, 15% medicare, and 5% other insurance. Histological type, stage, distance from treatment center and RPLN were equally distributed between groups. All pts completed standard treatment. There was no difference in PFS (p = 0.80) and OS (p = 0.23) between ethnic groups. In concordance with prior studies the following were associated with decreased OS; non-squamous histology, 15% pts (p=0.05), advanced stage (1b2-IV; p=0.04) and RPLN on imaging, 7% pts (p=0.008). Conclusions: Cervical cancer disparities are differentially distributed across the US hospital systems. There were no disparities identified at our institution relative to payer status with all pts receiving currently recommended treatment standards. Our findings indicate that delivery of equitable care can eliminate survival differences. Future research should assess the effect of emerging Accountable Care Organizations on the elimination of racial disparities in cancer treatment outcomes.
Cardiovascular late effects among endometrial cancer survivors in a cohort study.
Authors: Sean Patrick Soisson, Patricia A. Ganz, Kerry G. Rowe, Yuan Wan, Vikrant Deshmukh, Michael Newman, Alison M Fraser, Ken R Smith, Heidi Hanson, Joseph B Stanford, Theresa Louise Werner, Veronica Setiawan, Mia Hashibe
Journal: Journal of Clinical Oncology (2017)

131 Background: Endometrial cancer is the second most common cancer among female cancer survivors in the US, with an estimated 757,000 endometrial cancer survivors in 2016. Cardiovascular disease is the leading cause of death among endometrial cancer survivors. Cardiovascular disease risk may be increased among endometrial cancer survivors due to shared risk factors such as obesity or because of cancer treatment. Because of the high overall survival rate and the large number of endometrial cancer survivors, studies that examine late effects among endometrial cancer survivors are critical. Methods: Cohorts of 3,337 endometrial cancer survivors diagnosed between 1997 and 2012, and 19,420 age-matched cancer-free women were identified using the Utah Population Database. All ICD-9 diagnosis codes were collected from the state’s two largest healthcare systems and statewide ambulatory surgery and inpatient visits. Diagnoses were collapsed into cardiovascular system disorders according to the Healthcare Cost and Utilization Project’s Clinical Classification Software. Cox regression models were used to estimate hazard ratios (HR) at 1-5 years and 5-10 years after cancer diagnosis. Models were adjusted for race/ethnicity, baseline BMI, and baseline Charlson Comorbidity Index. Results: Approximately 89.4% of cancer cases were diagnosed with stage I or stage II disease. At 1-5 years after diagnosis, the highest risks among endometrial cancer survivors were observed for phlebitis and thrombophlebitis (HR: 3.36, 99% CI: 1.96-5.77), lymphatic diseases (HR: 1.89, 99% CI: 1.64-2.19), pulmonary heart disease (HR: 1.82, 99% CI: 1.36-2.43), hypotension (HR: 1.64, 99% CI: 1.18-2.29), and atrial fibrillation (HR: 1.61, 99% CI: 1.25-2.06). At 5-10 years, elevated risk persisted for these and 17 out of 66 additional outcomes among the endometrial cancer survivors. Conclusions: Endometrial cancer survivors in this population are at higher risk for various long term cardiovascular outcomes compared to cancer-free women. This study presents sufficient evidence to suggest that increased monitoring is necessary for women diagnosed with endometrial cancer in the first several years after diagnosis, and out to ten years as well.
Proton radiation for treatment of infratentorial brain tumors in infants and very young children.
Authors: Christine E. Hill-Kayser, Robert A. Lustig, Jane E. Minturn, Stefan Both, Angela J Waanders, Jean Bello Belasco, Carol Armstrong, Peter Phillips, Michael J. Fisher
Journal: Journal of Clinical Oncology (2014)

10076 Background: Radiation therapy (RT) has historically been delayed for infants with brain tumors due to data suggesting unacceptable toxicity after photon RT. Proton therapy allows definite sparing of normal brain, and may allow improved outcomes. Methods: 21 consecutive subjects age 3y or less with infratentorial brain tumors requiring RT were enrolled on a prospective registry from 6/2010 – 10/2013. All underwent maximal safe tumor resection. Eight received pre-radiation chemotherapy (ChT) based on diagnosis and tumor-specific treatment plan, but radiation was not delayed due to age. Focal RT was planned after CT simulation and fusion of pre and post-operative MRI scans. The tumor bed, clinical target volume (1 cm expansion), and organs at risk were contoured with Eclipse planning software. Doses are reported in radiobiologic-equivalent-weighted absorbed dose (cGyRBE). Brainstem planning constraints included maximum dose 6,000 and 95% ≤ 5,400. Results: The patient population at the time of RT ranged from 11 – 47m, and 13 (62%) were male. Diagnoses included ependymoma (13), medulloblastoma (5), ATRT (2), and Ewing sarcoma (1); the non-ependymoma patients received ChT pre RT. Median RT dose was 5,400 (R 5,040-5,940), and median days for RT course was 44 (R 40-50). RT was delivered using passive scattered proton beams for 20 patients, and pencil beam scanning for 1. All patients received daily general anesthesia. No patient experienced greater than grade 1 (CTCAEv4) acute toxicity. Grade 1 toxicities included fatigue (2), nausea (5), anorexia (4), constipation (2), dermatitis (15). With maximum follow-up of 35 months (range 1.4-35, mean 15 months), 19 patients are alive, no evidence of disease, 1 patient is LTFU, and one is dead of disease. No patient has experienced serious (grade 3-4) long-term toxicity related to radiation. Conclusions: With 3 years of follow-up, proton RT for infratentorial brain tumors appears to be well-tolerated by very young children, resulting in minimal acute toxicity and no serious long-term toxicity, with excellent disease control. Increasing use of RT for very young children supports more sophisticated toxicity evaluation prospectively, which is currently being performed at our center.
Effects of aprepitant on the pharmacokinetics of controlled-release oral oxycodone in cancer patients.
Authors: Yutaka Fujiwara, Naomi Kiyota, Masanori Toyoda, Takanobu Shimada, Yoshinori Imamura, Toru Mukohara, Hironobu Minami
Journal: Journal of Clinical Oncology (2014)

2579 Background: Oxycodone is a µ-opioid receptor agonist widely used in the treatment of cancer pain. The predominant metabolic pathway of oxycodone is CYP3A4-mediated N-demethylation to noroxycodone, while a minor proportion undergoes 3-O-demethylation to oxymorphine by CYP2D6. The aim of this study was to investigate the effects of the mild CYP3A4 inhibitor aprepitant on the pharmacokinetics of orally administered controlled-release (CR) oxycodone. Methods: This study design was an open-label, single-sequence with two phases in cancer patients with pain who continued to be administered orally with multiple doses of CR oxycodone every 8 or 12 hours. Plasma concentration of oxycodone and its metabolites were measured up to 8 hours after administration as follows; on day 1, CR oxycodone was administered alone; on day 2, CR oxycodone was administered with aprepitant (125 mg, at the same time of oxycodone dosing in the morning). The steady-state trough concentrations (Css) were measured from day 1 to day 3. Results: Aprepitant increased the area under the plasma concentration-time curve (AUC0-8) of oxycodone by 25% (p<0.001) and of oxymorphine by 34% (p<0.001), as well as decreased the AUC0-8 of noroxycodone by 14% (p<0.001). Moreover, aprepitant increased Css of oxycodone by 57% (p=0.001) and of oxymorphine by 36% (p<0.001) and decreased Css of noroxycodone by 24% (p=0.02) at day 3 compared to day 1. Conclusions: Aprepitant increased the exposure levels of oxycodone by inhibiting its CYP3A4-mediated N-demethylation. Clinical trial information: UMIN000003580.
Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans
Authors: Federica Buonocore, Peter Kühnen, Jenifer P. Suntharalingham, Ignacio Del Valle, Martin Digweed, Harald Stachelscheid, Noushafarin Khajavi, Mohammed Didi, Angela F. Brady, Oliver Blankenstein, Annie M. Procter, Paul Dimitri, Jerry K.H. Wales, Paolo Ghirri, Dieter Knöbl, Brigitte Strahm, Miriam Erlacher, Marcin W. Wlodarski, Wei Chen, George K. Kokai, Glenn Anderson, Deborah Morrogh, Dale A. Moulding, Shane A. McKee, Charlotte M. Niemeyer, Annette Grüters, John C. Achermann
Journal: Journal of Clinical Investigation (2017)

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.
Impact of delay in adjuvant oxaliplatin-based chemotherapy for stage III colon cancer.
Authors: Renata D'Alpino Peixoto, Aalok Kumar, Caroline Speers, Daniel John Renouf, Hagen F. Kennecke, Howard John Lim, Winson Y. Cheung, Barbara L. Melosky, Sharlene Gill
Journal: Journal of Clinical Oncology (2014)

3561 Background: Less than 8 weeks (w) has been recommended as the optimal time to initiate adjuvant chemotherapy (AC) based upon two meta-analyses suggesting worse OS with delayed AC. However, neither included studies with oxaliplatin-based chemotherapy and the impact of its delay remains uncertain. Methods: Records of pts who initiated AC with either 5-FU or capecitabine plus oxaliplatin for stage III colon cancer between 2006 and 2011 at the BC Cancer Agency were reviewed. Cox proportional hazards models were used to analyze the impact of timing of AC on RFS. Pts were categorized into initiation of AC within 8 w (G1) and after 8 w (G2) Results: 635 pts (52% male) with a median age of 62 yrs (range 26–80) were included. Median lymph nodes examined and involved were 15 and 3, respectively. Median time from surgery to initiation of AC was 8.3 w (SD 18.58). At a median follow-up of 57.9 months, 176 pts (27.7%) have recurred and 118 (18.6%) have died. 5y-RFS was 70.9% (95% CI 65.2-76.5) for G1 and 72.1% (95%CI 67.2-77) for G2. On multivariate analysis, T stage, N stage, obstruction and perforation were identified as poor prognostic factors for RFS. Timing for AC did not have prognostic significance (HR 1.03, p = 0.83). Conclusions: In our population-based study, time to oxaliplatin-based AC following stage III colon resection did not impact on RFS. Contrary to most of the existing data which is primarily based on 5FU-based AC, delay of oxaliplatin-based therapy beyond 8 w is not associated with inferior outcomes. Prognostic factors for RFS – univariate and multivariate analysis. Variables Univariate HR p value Multivariate HR p value Age <65 ≥65 1.0 0.49 1.0 0.55 1.11 1.09 Male Female 1.0 0.19 1.0 0.22 1.21 1.20 Grade 1/2 3 1.0 0.04 1.0 0.72 1.44 1.06 LVI no yes 1.0 < 0.001 1.0 0.05 1.89 3.12 PNI no yes 1.0 0.005 1.0 0.84 1.69 1.04 T 1/2 T3 T4 1.0 < 0.001 1.0 0.003 2.69 2.16 5.42 3.27 N1 N2 1.0 < 0.001 1.0 <0.001 2.11 1.80 Examined LN ≤12 >12 1.0 0.85 1.0 0.05 0.97 0.72 Obstruction no yes 1.0 < 0.001 1.0 0.007 2.18 1.73 Perforation no yes 1.0 < 0.001 1.0 0.002 3.40 2.45 Location right left 1.0 0.02 1.0 0.07 1.40 1.32 Time surgery-chemo ≤ 8 w > 8 w 1.0 0.60 1.0 0.83 1.08 1.03
Phase II study of lenalidomide in patients (pts.) with metastatic renal cell carcinoma (MRCC)
Authors: T. K. Choueiri, R. Dreicer, B. I. Rini, P. Elson, J. Garcia, T. Mekhail, R. M. Bukowski
Journal: Journal of Clinical Oncology (2006)

4539 Background: MRCC is a disease with susceptibility to immunomodulatory and anti-angiogenic approaches. Lenalidomide (LEN) is a structural and functional analogue of thalidomide with enhanced immunomodulatory properties and unique activity and toxicity profiles. A phase II study of LEN in MRCC was conducted to determine efficacy and safety. Methods: Eligibility included histologically confirmed MRCC, measurable disease, ≤ 1 prior systemic therapy, ECOG PS 0–1, adequate organ function, and no brain metastases. LEN was administered orally at 25 mg daily for the first 21 days of a 28-day cycle. The primary endpoint was objective response rate as determined by RECIST criteria. Patients received treatment until disease progression or unacceptable toxicity. A two-stage design was employed to test the null hypothesis that the true response rate is ≤ 5% versus the alternative hypothesis that the true response rate is ≥ 20% (alpha = 0.05, power = 90%). Results: 28 pts. were enrolled. Median age was 67 years (range, 42–76). All patients had prior nephrectomy and 57% (16/28) received prior therapy. 21 pts. (75%) had clear cell histology. Pts. received a median of 4 cycles of therapy (range, 1–12+) with 21 pts. (75%) completing at least 2 cycles. Three pts. (10.7%; 95% CI = 2.3–28.2 %) demonstrated a partial response (PR) and 8 pts (28.5%) had stable disease (SD). A total of 11 pts. (39%) experienced median tumor shrinkage of 5% (range, 1–72%). Median time to progression (TTP) for the entire cohort was 4 months (m) (range, 0.67–14+). Ten pts (36%) were progression-free for ≥ 6 m and five pts (18%) were progression-free for ≥ 12 m. Previously treated pts had a TTP of 3 m compared to 5 m for pts with no prior therapy (p = .19). 6 pts (21%) continue on-study with a median follow up of 12.6 m (range, 7.3–14.2 m). Toxicities (all grades) included fatigue (93%), skin toxicity (rash, dry skin and pruritus; 68%) and leukopenia/neutropenia (65%). Grade 3/4 toxicities included fatigue/constitutional symptoms (11%), skin toxicity (7%) and leukopenia/neutropenia (29%). Conclusions: LEN demonstrated an anti-tumor effect in MRCC as evidenced by partial responses and additional pts. with tumor shrinkage. LEN was well tolerated with manageable toxicity. Further studies are warranted. [Table: see text]
Correlation between thymidylate synthetase (TS) expression and progression-free survival (PFS) in patients receiving pemetrexed (pem) for advanced NSCLC: A prospective study.
Authors: Marianne Nicolson, Keith M Kerr, Riyaz N.H. Shah, Vanessa Potter, Sunil Upadhyay, Paul Taylor, Scott Myrand, Tuan Stevon Nuguyen, Mayukh Das, Dean Anthony Fennell
Journal: Journal of Clinical Oncology (2012)

7583 Background: Pem efficacy in non-squamous (NS) NSCLC is hypothesised to be associated with TS expression. Our primary objective was to assess the correlation between TS and PFS, prospectively. Methods: Context: A Phase II, single-arm, exploratory, multicenter, UK study with appropriate approvals and consents. Key eligibility criteria: ECOG PS 0-1, NS-NSCLC histology, stage IIIB/IV. Patients (n=70) received pem/cisplatin induction x 4. Non-progressive patients continued on maintenance pem until tumor progression or discontinuation. All patients were followed until death or study closure. TS by IHC (H-scores) and qPCR (delta CQ values normalized) were assessed on diagnostic FFPE samples. Kaplan-Meier estimates for median PFS (mPFS) and Cox regression to determine the statistical correlation between PFS and TS IHC nuclear score, (continuous variable) were performed. Maximal Chi-square analysis identified the optimal association cutpoints between PFS and low vs. high TS scores. Results: Patient demographics were unremarkable, 32/70 (45.7%) were female. 55 (78.6%) had adenocarcinoma; 15 were not otherwise specified. Maintenance pem was started in 43/70 (61.4%) patients. Evaluable patients had at least one dose of study treatment and a valid TS score (n=60). For the evaluable population, the mPFS from start of induction was 5.5 months (95% CI 3.9-6.9). A statistically significant correlation between PFS and TS IHC nuclear scores was observed [p&lt;0.0001, HR= 1.01 (95% CI 1.01, 1.02)], suggesting higher TS values are associated with shorter PFS. When the population was dichotomized at the identified optimal H-score cutpoint of 70, the mPFS in the low expression group (n=40) was 7.1 months (5.7-8.3) compared to 2.6 months (1.3-4.1) in the high expression group (n=20) [adjusted p=0.0015, HR=0.28 (95% CI 0.16-0.52)]. Similar trends with cytoplasmic TS IHC (p=0.09) and TS qPCR (p=0.05) levels were observed. Statistical correlations were seen among the TS levels. Data is preliminary. Conclusions: Study suggests statistically significant association between low TS IHC nuclear expression and improved PFS in this Phase 2 single-arm trial.