tbuckley/cabot-search huggingface dataset:
Salvage vinorelbine (VNR) in the 2nd to 4th line setting in advanced non-small cell lung cancer (NSCLC): A retrospective review at the Fox Chase Cancer Center (FCCC)
Authors: J. G. Devlin, C. J. Langer
Journal: Journal of Clinical Oncology (2006)

17072 Background: Published literature has demonstrated minimal activity for VNR in the salvage treatment of NSCLC, with response rates of only 0.8% (Fossella, et al, JCO 2000; 18(12), 2354–2362). However, in our clinical experience, we have observed a number of patients (pts) with clinical benefit. Methods: Retrospective evaluation was performed of all pts with NSCLC who had received VNR at FCCC from 6/02–6/05 in the salvage setting. Pts were evaluable if full medical records (including radiographic imaging for disease assessment) were available, had received ≥2 cycles of VNR, and had advanced, recurrent or metastatic NSCLC. Primary endpoint was response rate (RR); secondary endpoints included safety, median overall survival (OS), and median time to progression (TTP). Results: 52 pts were included, 28 pts were ultimately evaluable (13 pts received &lt;2 cycles of VNR, 7 pts did not have NSCLC, and 4 pts received VNR with RT or other agents). Median age was 64 yrs, 64% were female; ECOG-PS 0–18%, 1–50%, 2–28.5%, 3–3.5%. 82% exhausted 2 lines of systemic therapy before VNR; 32% exhausted 3; 21.4% received prior EGFR-TKI; 18% received other prior protocol therapies. 96.3% of pts had stage IV, stage IIIB, or recurrent disease. 21.4% had bone mets; 25% had brain mets; and 42.8% had visceral metastases. 85.8% had significant comorbidities. Median number of VNR cycles was 4. RR:PR 10.7%, SD/MR 35.7%, and PD 50%. 25% required dose reductions, predominantly for gr 4 hematologic toxicities. Non-hematologic toxicities were generally mild, and included neuropathy, fatigue and GI distress; there were no Tx-related deaths. 32% were able to receive other systemic therapy after VNR. Median OS was 5 months, and median TTP was 3 months. Conclusions: Vinorelbine is active and relatively well-tolerated in the salvage treatment of NSCLC, including heavily pretreated pts. Response rates exceed that observed in the literature. [Table: see text]
Implications of chemotherapy-induced diarrhea on dosing intensity
Authors: R. J. G. Arnold, N. Gabrail, M. Raut, R. Kim, J. Sung, Y. Zhou
Journal: Journal of Clinical Oncology (2004)

6128 Background: Diarrhea is a significant dose-limiting toxicity associated with chemotherapy treatment among cancer patients. The objective of this study was to describe the socio-demographic and clinical characteristics of patients who experience chemotherapy induced diarrhea (CID) and to describe their diarrhea-related management patterns in a real-world setting. Methods: We retrospectively reviewed management patterns of 378 cancer patients, ≥18 years, who experienced diarrhea during their chemotherapy treatment between 2000 and 2003 from 25 community oncology centers throughout the US. Demographic characteristics, severity of diarrhea, and changes to chemotherapy treatment due to diarrhea were evaluated using descriptive analysis. Comparisons of planned chemotherapy therapy versus actual chemotherapy received by patients due to diarrhea were conducted using analysis of variance (ANOVA) and logistic regression models. Results: Patients experiencing CID were mostly white (80%) and middle-aged (mean 67 years). The most common chemotherapy regimens were 5-fluorouracil intravenous push (5-FUIVP) + leukovorin (LV) 27%, 5-FU + LV 10%, and irinotecan (CPT-11) 9%. There was a mean of 3.9 diarrheal episodes per patient. The majority of diarrheal episodes were Grade 1 (75%), with approximately a third of the episodes being severe (NCI grades 3 or 4). The mean grade of diarrhea was highest for carboplatin, 5-FUCI, taxotere and cyclophosphamide (mean NCI grades:1.83 ± 0.86, 1.75 ± 0.77, 1.73 ± 0.83, and 1.66 ± 0.86, respectively). Patients who experienced CID underwent significant changes in their chemotherapy treatment, including dose reductions (45%), delays in therapy (71%), reduction in dose intensity (64%), and discontinuation of therapy (3%). The mean grades of diarrhea for patients who experienced changes ranged from 1.47 for patients with dosing delays to 1.64 for patients with dosing reductions. Conclusions: The study results showed that a significant number of patients experiencing CID tended to have changes to their chemotherapy treatment, which may ultimately impact patient clinical outcomes. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceutical Corp. Novartis Pharmaceuticals Corp.
STA-4783, a novel HSP inducer, enhances paclitaxel activity—Preclinical to clinical modeling
Authors: R. Salgia, A. Berkenblit, B. Dezube, T. A. Dahl, K. Koya
Journal: Journal of Clinical Oncology (2004)

3124 Background: STA-4783 is a newly synthesized bis-thiobenzoylhydrazide (MW 400) that promotes tumor-specific induction of heat shock protein 70 (HSP70) (AACR, Koya et al, 2004). Methods: We have performed in vitro, mouse in vivo and a Phase I trial of STA-4783. A Phase II trial is ongoing for non-small cell lung cancer (NSCLC). Results: Xenograft modeling with solid tumor cells—such as breast cancer, lung cancer, and lymphoma showed dramatic anti-tumor activity with paclitaxel. This was absent in vitro, implying an immune mechanism. In toxicity studies, rats and dogs tolerated STA-4783 at the dose of 125 mg/kg and 30 mg/kg, respectively; and STA-4783 is mainly renally excreted. In a Phase I trial (AACR-NCI-EORTC, Berkenblit et al, 2003), STA-4783/paclitaxel (doses 135 mg/m2 paclitaxel + 44 mg/m2 STA-4783 up to 175 mg/m2 paclitaxel + 263 mg/m2 STA-4783) given every 3 weeks was well tolerated and STA-4783 did not alter the PK or toxicity of paclitaxel. Fourteen patients were evaluable, 2 had partial response (Kaposi's sarcoma), and 4 stable disease at 3 cycles. We have now begun a Phase I/II trial in NSCLC. The study groups consist of 6 patient cohort with 263 mg/m2 STA-4783, 175 mg/m2 paclitaxel, AUC =6 carboplatin; 6 patient cohort same as previous but increase paclitaxel to 200 mg/m2; 84 patients in a 1:1 randomization of paclitaxel (200 mg/m2) and carboplatin (auc = 6) versus paclitaxel (200 mg/m2), carboplatin (auc = 6) and STA-4783 (266 mg/m2). The primary endpoint is TTP, with secondary endpoints of RR, survival, and QOL. Pharmacodynamic parameters to be determined are NK cell activity as well as the role of circulating tumor cells. Conclusions: STA-4783 has a novel mechanism of action with induction of HSP70 and immune modulation, and the efficacy of this drug in combination with paclitaxel and carboplatin will be tested in a trial of patients with NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Synta Pharmaceuticals Corp. Synta Pharmaceutical
Role of NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2 in Clear Cell Renal Cell Carcinoma
Authors: Denise R. Minton, Leiping Fu, Nigel P. Mongan, Maria M. Shevchuk, David M. Nanus, Lorraine J. Gudas
Journal: Clinical Cancer Research (2016)

We delineated the functions of the hypoxia-inducible factor-1α (HIF1α) target NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) in clear cell renal cell carcinoma (ccRCC) and characterized NDUFA4L2 as a novel molecular target for ccRCC treatment.We evaluated normal kidney and ccRCC patient microarray and RNAseq data from Oncomine and The Cancer Genome Atlas for NDUFA4L2 mRNA levels and the clinical implications of high NDUFA4L2 expression. In addition, we examined normal kidney and ccRCC patient tissue samples, human ccRCC cell lines, and murine models of ccRCC for NDUFA4L2 mRNA and protein expression. Utilizing short hairpin RNA, we performed NDUFA4L2 knockdown experiments and analyzed the proliferation, clonogenicity, metabolite levels, cell structure, and autophagy in ccRCC cell lines in culture.We found that NDUFA4L2 mRNA and protein are highly expressed in ccRCC samples but undetectable in normal kidney tissue samples, and that NDUFA4L2 mRNA expression correlates with tumor stage and lower overall survival. In addition, we demonstrated that NDUFA4L2 is an HIF1α target in ccRCC and that NDUFA4L2 knockdown has a profound antiproliferative effect, alters metabolic pathways, and causes major stress in cultured RCC cells.Collectively, our data show that NDUFA4L2 is a novel molecular target for ccRCC treatment. Clin Cancer Res; 22(11); 2791-801. ©2016 AACR.
A phase I dose-escalation study of the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the novel cyclin-dependent kinase inhibitor SCH 727965 administered every 3 weeks in subjects with advanced malignancies
Authors: G. I. Shapiro, R. Bannerji, K. Small, S. Black, P. Statkevich, M. Abutarif, J. Moseley, S. Yao, C. H. Takimoto, M. M. Mita
Journal: Journal of Clinical Oncology (2008)

3532 Background: SCH 727965 is a novel pyrazolo[1,5-a]pyrimidine which potently and selectively inhibits the cyclin- dependent kinases CDK1, CDK2, CDK5 and CDK9 with IC50's of < 5nM. Inhibition of CDK2/CDK1 in tumor cells leads to cell cycle arrest and apoptosis. SCH 727965 induces apoptosis in >100 tumor cell lines (including NCI 60) and results in tumor growth inhibition or regression in multiple xenograft models. SCH 727965 was advanced into clinical trials because of its CDK inhibition specificity, broad anti-tumor activity, and safety. Methods: SCH 727965 was administered by 2-hour IV infusion on day 1 of a 21-day cycle utilizing an accelerated titration design for dose escalation. PD assessments include an ex vivo PHA lymphocyte stimulation assay and functional imaging using FDG-PET/CT scans. PK and PD data were obtained during cycle 1 of treatment. Results: 23 subjects treated at doses from 1.85 to 58mg/m2. The most common treatment-emergent adverse events are nausea/vomiting, diarrhea, neutropenia, and fatigue. Neutropenia, complicated by fever or infection, represented the dose limiting toxicity in 2 of 3 subjects at 58mg/m2. The most common grade 3 or 4 treatment related adverse event is neutropenia. SCH 727965 is rapidly eliminated with a terminal half-life of 1.5 to 3 hours. Exposure is dose-proportional. Inhibition of lymphocyte proliferation (measured by BrdU uptake) correlates with drug concentration and indicates a PD effect. Decreased cycle 1 day 8 PET signal, measured by SUV, is observed in some subjects, although no objective responses by RECIST criteria are observed to date. Conclusions: SCH 727965 is safe and well tolerated at dose levels below the maximum administered dose of 58mg/m2. The study is ongoing. Subjects are exposed to plasma concentrations above those required for in vivo efficacy in xenograft tumor models. Lymphocyte proliferation assay data verify drug exposures at current doses are associated with PD activity. Preliminary changes on PET/CT suggest drug related modulation of tumor metabolic activity. SCH 727965 will be evaluated further in phase 2 studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough Schering-Plough
Caffeine oral contraceptives and over-the-counter drugs [letter]
Authors: Fazio A
Journal: JAMA Internal Medicine (1989)

It should be noted that in addition to cimetidine oral contraceptives also augment the pharmacologic effect of caffeine by decreasing its metabolism.  Even after modest doses of caffeine such as 2-4 cups of coffee the half-life is prolonged and caffeine accumulates and is eliminated more slowly in women taking oral contraceptives.  Clinicians should be aware of the widespread occurrence of caffeine in over-the- counter medications including analgesics cold and allergy medications menstrual diuretics and stimulants.  Doses range from around 32 mg in many over-the-counter products to 250 mg in 1 caffeine stimulant.  These products are often overlooked by patients and clinicians.
Cisplatin, carboplatin, and cyclophosphamide combination chemotherapy in advanced-stage ovarian carcinoma: an Eastern Cooperative Oncology Group pilot study.
Authors: J Grem, P O'Dwyer, P Elson, N Simon, D Trump, M Frontiera, G Falkson, S Vogl
Journal: Journal of Clinical Oncology (1991)

Cyclophosphamide (CTX) 600 mg/m2, carboplatin 280 mg/m2, and cisplatin 50 mg/m2 were administered on day 1 every 4 weeks to 41 previously untreated ovarian cancer patients with residual disease greater than 2.0 cm after primary laparotomy. Of 22 patients with measurable disease treated with up to eight cycles of therapy, the overall clinical response rate was 73% (exact 95% confidence interval [CI], 50% to 89%), with 50% complete response (CR). Six of 11 clinical CR (cCR) patients underwent surgical restaging; three pathologic CRs (pCRs) and three pathologic partial responses (pPRs) with residual disease less than 2.0 cm were documented. Fourteen patients had nonmeasurable but assessable disease; the clinical response rate was 57% (Cl, 29% to 82%) with two (14%) CRs. Second-look surgery was performed in one of the two cCR patients; a pPR was documented. Five patients with nonassessable disease were stable during chemotherapy; two underwent surgery and had pCRs. The median time to treatment failure (TTF) was 14.8 months, and median survival for the 41 patients is 26.7 months. Overall, 37% of the patients had progression-free intervals of at least 2 years, and 27% have survival times in excess of 3 years. Hematologic toxicity was substantial but manageable, with 58% and 66% experiencing a granulocyte nadir less than 500/microL and a platelet nadir less than 50,000/microL, respectively. One treatment-associated fatality occurred as a result of leukopenic sepsis and renal failure in the setting of progressive disease and ureteral obstruction. Mild to moderate nausea and vomiting occurred in most patients, but none experienced severe ototoxicity or peripheral neuropathy. Over all courses, 73% of the projected dose intensity of CTX and carboplatin and 86% of cisplatin were delivered. Since granulocytopenia and thrombocytopenia were dose-limiting, the addition of colony-stimulating factors that support both myeloid and megakaryocyte precursors may permit further dose intensification.
Improved 5-year overall survival (OS) in breast cancer (CA) patients from 1994 to 2008.
Authors: David Naji Aljadir, Francis J. Cummings
Journal: Journal of Clinical Oncology (2012)

e13126 Background: A Canadian Study (Chia, ASCO 2003, Abstract 22) comparing OS across 4 time cohorts in patients with metastatic Breast CA demonstrated OS benefit at 1 and 2 years that appears related to the release of aromatase inhibitors (AI)/docetaxel and trastuzumab/capecitabine but not paclitaxel or vinorelbine. Methods: 5 yr overall survival (OS5) in breast CA patients (all stages) was separated into 3 time cohorts corresponding to dates of release of chemotherapy or hormonal treatments (cohort 1:1994-1997 (paclitaxel/vinorelbine), cohort 2:1998-2002 (AI /trastuzumab) and cohort 3:2003 (bevacizumab)) to determine if there was an impact on OS5 in all stages and if there was a relation to survival based on stage of disease. Data was extracted from the National Cancer Database (NCDB) for the US and Northeastern US (MA, ME, CT, RI, VT, NH). Results: The OS5 in the US was 80.0% [CI 80.6-80.9], 84.7% [CI 84.4-84.6] and 85% [CI 84.8-85.2] for cohorts 1, 2 and 3, respectively. The OS5 in the Northeast US was 82.3% [CI 81.8-82.8], 85.7% [CI 85.4-86.1] and 87.3% [CI 86.6-88.0] for cohorts 1, 2 and 3, respectively. Stage II 5 yr survival in the US was 78.9% [CI 78.7-79.1], 82.8% [CI 82.6-83.0] and 84.8% [CI 84.4-85.2] and in the Northeast US was 79.1% [CI 78.2-80], 82.4% [CI 81.7-83.1] and 83.7% [CI 82.2-85.3] for cohorts 1,2, and 3, respectively. 5 yr survival for stage III in the US was 53.8% [CI 53.2-54.3], 57.8% [CI 57.3-58.3] and 64.5% [CI 63.7-65.4] and in the Northeast US was 53.2% [CI 50.9-55.6], 58.8% [CI 56.7-60.8], and 70.7% [CI 67.3-74.1] for cohorts 1,2 and 3, respectively. Stage IV patients showed no change in 5 yr survival over the 3 cohorts, but showed improvement in 2 yr survival at the National Level (44.6%, 46.1%, and 46.7%) and in the Northeast US (46.7%,47.5% and 49.4%) for cohorts 1,2 and 3,respectively. Conclusions: 5 yr survival in stage II and stage III breast CA between cohorts 1 and 3 has improved, whereas stage IV survival at 5 yrs showed no improvement in any cohort, even though there was an improvement in stage IV 2 yr survival in the US and within the Northeast US. The improvement in OS5 is more pronounced between cohorts 1 and 2 than between cohorts 2 and 3, which appears to correspond to the addition of AI and trastuzumab.
Abstract 13499: A 34-year-old Man With Debilitating Polyneuropathy, Pericardial Effusion and Monoclonal Gammopathy Presents With Right Heart Failure
Authors: Kenta Nakamura, Mary H Zhang, Jordan T Shin
Journal: Circulation (2014)

A 34-year-old man with debilitating polyneuropathy and monoclonal gammopathy presents with progressive lower extremity edema, pericardial effusion and dyspnea. Pulmonary edema, elevated jugular venous pressure and peripheral edema suggested right heart failure, and dyspnea responded initially to diuresis. Echocardiography revealed occult pericardal effusion, right heart dysfunction and estimated right ventricular systolic pressure of 54 mmHg. The differential diagnosis included pulmonary hypertension secondary to chronic pulmonary or left heart processes, pericardial constriction, restrictive myopathy or a syndromic condition capturing his neurologic and hematologic findings. Chest CT and VQ-scan were negative for acute and chronic pulmonary thromboembolic disease, respectively. Cardiac magnetic resonance imaging was most consistent with amyloidosis. Pericardial enhancement was normal, arguing against constriction. Amyloidosis was thought to be unlikely given preserved left ventricular size and function, increase in both serum free κ and λ light chains, and was ultimately excluded by fat pad biopsy. The paraneoplastic disease Crow-Fukase or POEMS syndrome, classically described as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes explained the patient’s constellation of signs and symptoms. Pulmonary hypertension subsequent to cor pulmonale is common and reversible with treatment of the underlying gammopathy. Diagnosis of the POEMS syndrome was confirmed by the presence of sclerotic bone lesions and markedly elevated vascular endothelial growth factor (VEGF) level of 1028 pg/mL (ref. range 31-86 pg/mL). VEGF is highly induced in the POEMS syndrome and correlates closely with disease activity. VEGF-mediated microangiopathy, neovascularization, and vasopermeability likely underlie multiple clinical sequelae of extravascular volume overload such as pericardial effusion and peripheral edema. The patient responded to sildenafil for pulmonary arterial hypertension and immunomodulatory therapy for the monoclonal gammopathy. At six months of treatment, the patient has recovered substantial strength, heart failure has not reoccurred and repeat VEGF level reduced to 383 pg/mL.
Radiosurgery alone for solitary and multiple brain metastasis
Authors: J. L. Fox, L. Kleinberg, S. Kharkar, R. E. Clatterbuck, P. Wang, M. Wharam
Journal: Journal of Clinical Oncology (2006)

1541 Background: Whole-brain radiation (WBRT) in the management of brain metastases treated with radiosurgery (RS) is controversial. Methods: Ninety-eight patients were treated for brain metastases with RS at Johns Hopkins between 4/03 and 7/05. Twenty-eight patients received RS alone after failing WBRT, 33 received RS alone for initial metastases and 37 received RS along with WBRT. Forty-five patients were women and 53 were men, with a median age of 56 (range, 18–92). Histology was: non-small cell lung cancer - 35, breast -14, melanoma -10, renal cell carcinoma - 9, and other - 30. Ninety-two (94%) pts had a KPS of ≥ 70 (median 80). The median number of metastases was 2 (range, 1–14). Results: Follow-up data from date of RS was available for 96 patients. Among those who received RS along with planned WBRT, median survival (MS) was 6.6 months with 1-yr overall survival (OS) 38%. Among patients treated initially with RS alone, MS was 9.7 months with 1-yr OS 42%. Among patients treated with RS for recurrent metastases after prior WBRT, MS was 6.8 months with 1-yr OS 24%. There were no significant differences in survival amongst these 3 treatment groups (p=0.73, log-rank test). For patients with 1–3 metastases (n=66), 1-yr OS was 38% versus 32% for those with ≥ 4 (n=32). Median survivals were 8.4 and 6.7 months, respectively (p=NS). Of patients treated with RS for recurrence, 7 of 25 (28%) with available follow-up data developed recurrent or new metastases whereas 11/27 (41%) treated with RS and planned WBRT and 15/27 (56%) who had RS alone as initial treatment had documented recurrent or new metastases. Conclusions: RS alone may be an effective treatment that preserves survival for those with single or multiple brain metastases at initial presentation or recurrence, but the tradeoff between the marginal increase in risk of brain recurrence versus toxicity and time commitment for WBRT needs further evaluation. The ongoing US Intergroup randomized trial, N0572/Z300, will address some of these questions. No significant financial relationships to disclose.
Variations in Peripherally Inserted Central Catheter Use and Outcomes in Michigan Hospitals
Authors: Vineet Chopra, Shawna Smith, Lakshmi Swaminathan, Tanya Boldenow, Scott Kaatz, Steven J. Bernstein, Scott A. Flanders
Journal: JAMA Internal Medicine (2016)

This multicenter study examines whether recently developed and evolving guidelines may reduce current substantial variation in indications, patterns of use, and outcomes of the use of peripherally inserted central catheters.