tbuckley/cabot-search huggingface dataset:
Second neoplasms in survivors of endometrial cancer: Impact of radiation therapy
Authors: S. Kumar, C. S. Bryant, J. P. Shah, J. J. Ruterbusch, M. L. Cote, A. Vay, L. A. Solomon, R. Ali-Fehmi, R. T. Morris, J. M. Malone
Journal: Journal of Clinical Oncology (2008)

5539 Objective: To evaluate the association of radiation therapy and the development of second cancers in endometrial carcinoma survivors. Methods:Subjects with a diagnosis of endometrial cancer as their first malignancy were identified from the Surveillance, Epidemiology and End Results (SEER) database from 1973 to 2004 and were divided into patients who received radiation (R) and who did not (NR). Person years at risk (PYR), standardized incidence ratios (SIRs) and observed (O) to expected (E) ratio = (O/E) were determined using SEERStat. Percent increase in relative risk for R vs. NR group was calculated using Poisson regression model. Absolute Excess Risk (AER) was defined as (O) minus (E) per 10,000 PYRs. All confidence intervals (CI) are 95%. Results: Of 90,502 subjects, 31,643 (34.9%) received radiation (R), 52,182(57.6%) did not receive radiation (NR) and the status of 6,677 (7.3%) was unknown. 5,563 subjects in NR group and 4,203 in R group developed a second cancer, giving a relative risk (RR) of 1.25 (CI 1.20 to 1.29) for the development of a second cancer associated with radiation. For NR group, the SIR of all the second malignancies combined was 0.82 (95% CI 0.79 to 0.84; p<0.05) with a total of 504,353 PYR. For R group on the other hand, the corresponding SIR was 0.95 (95% CI 0.92 to 0.97; p<0.05) with a total of 310,538 PYR. The SIRs were higher for R group in all the latency periods which were studied (2 months to >10years), and the maximum difference was observed at prolonged latencies (>10 years); 0.72 (CI 0.69 to 0.75; p<0.05) for NR as compared to 0.90 (CI 0.85 to 0.94; p<0.05) for R. A total of 17.11 excess tumors were observed per 10,000 PYR with use of radiation (AER) in R group. In R group (vs NR group), the SIR was both, higher and statistically significant for cancer of lung, colon & rectum, urinary bladder & ureter, vulva, and vagina whereas the SIR was both, lower and statistically significant for cancer of esophagus, ovary and chronic lymphocytic leukemia. Conclusion: Although we recognize the limitations of SEER data, this is the largest study reporting on association of radiotherapy to subsequent second neoplasms in patients with endometrial cancer. The increased risk of second cancers due to radiation is most pronounced in the field of exposure and is affected by latency since exposure. No significant financial relationships to disclose.
Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non–Small Cell Lung Cancer: Double-Edged Sword of <i>DDR2</i>
Authors: Masato Terashima, Yosuke Togashi, Katsuaki Sato, Hiroshi Mizuuchi, Kazuko Sakai, Kenichi Suda, Yu Nakamura, Eri Banno, Hidetoshi Hayashi, Marco A. De Velasco, Yoshihiko Fujita, Shuta Tomida, Tetsuya Mitsudomi, Kazuto Nishio
Journal: Clinical Cancer Research (2016)

This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets.Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitroMutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growth-suppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor.Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen. Clin Cancer Res; 22(14); 3663-71. ©2016 AACR.
Severe life-threatening toxicities observed in study using leucovorin with 5-fluorouracil.
Authors: J L Grem, D D Shoemaker, N J Petrelli, H O Douglass
Journal: Journal of Clinical Oncology (1987)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1987.5.10.1704 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 3309201 Severe life-threatening toxicities observed in study using leucovorin with 5-fluorouracil. J L GremxJ L GremSearch for articles by this author , D D ShoemakerxD D ShoemakerSearch for articles by this author , N J PetrellixN J PetrelliSearch for articles by this author , H O Douglass JrxH O Douglass JrSearch for articles by this author https://doi.org/10.1200/JCO.1987.5.10.1704 PDF "Severe life-threatening toxicities observed in study using leucovorin with 5-fluorouracil.." Journal of Clinical Oncology, 5(10), p. 1704© 1987 by American Society of Clinical Oncology
A phase II study of NK012, a polymeric micelle formulation of SN-38, in colorectal cancer patients who had received prior oxaliplatin-based regimen.
Authors: Akihito Tsuji, Tetsuya Hamaguchi, Kensei Yamaguchi, Koji Takeda, Hiroyuki Uetake, Taito Esaki, Kenji Amagai, Naotoshi Sugimoto, Hideo Baba, Masami Kimura, Yasuhiro Matsumura, Yoshihiro Nambu
Journal: Journal of Clinical Oncology (2015)

3527 Background: NK012 is a micelle-forming macromolecular prodrug of SN-38, an active metabolite of irinotecan. In the completed phase I study, the recommended dose was decided to be 28 mg/m2, with a DLT of myelosuppression. This phase II study was conducted to evaluate an efficacy and safety of NK012 in patients with recurrent or metastatic colorectal cancer. Methods: This was a multicenter, open-label, single-arm phase 2 study. Patients with a history of oxaliplatin-based treatment against metastatic colorectal cancer, or recurrence within 6 months after the last dose of adjuvant oxaliplatin had been enrolled. NK012 (28 mg/m2) was administered intravenously every 3 weeks. Administrations continued until disease progression. Objective clinical response was evaluated according to RECIST 1.1. The primary endpoint was overall response rate (ORR). Results: In the 58 patients registered, 53 patients received NK012. Median number of previous oxaliplatin-based therapy was 11.0 courses. 4.2% of patients had a history of previous irinotecan. Median treatment period was 3 courses. ORR was 3.8 %, and DCR (CR+PR+SD) was 56.0%. Median PFS and OS were 99.0 and 451 days, respectively. Major adverse drug reactions were absolute neutrophil count (ANC) decreased, of which grade 4 or more manifested in 81% of patients. Ratio of Grade 4 ANC decreased was higher in patients who had received previous oxaliplatin for more than 6 months. Grade 3 diarrhea manifested in 5.7%, but no diarrhea of Grade 4 manifested. Conclusions: Efficacy of NK012 against recurrent or metastatic colorectal cancer was comparable with that of irinotecan monotherapy previously reported, and disease control by NK012 was suggested. Unlike irinotecan, the major ADR was myelosuppression, with mild gastrointestinal toxicity. These safety profiles implicate a possibility of combination with less-myelotoxic anticancer agent(s) like 5-FU/LV and of being preferable to FOLFIRI. Further optimization of dosage and schedule of NK012 administration and its combination strategy would be worthwhile.
Factors which predict treatment outcome for patients with locally advanced (T4) breast cancer
Authors: E. Montagna, V. Bagnardi, N. Rotmensz, N. Fazio, E. Scarano, A. Cardillo, R. Torrisi, G. Viale, A. Goldhirsch, M. Colleoni
Journal: Journal of Clinical Oncology (2008)

22099 Background: Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either non inflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify those characteristics which predict treatment outcome Methods: Clinical and pathological features of 279 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall 155 patients (56%) presented with NIBC (cT4a-c, N0–2, M0) and 124 patients (44%) with IBC (cT4d, N0–2, M0) Results: Median follow-up time was 26 months (range 1–88). At the multivariate analysis, patients with ER and PgR absent disease had a significantly worse Disease Free Survival (DFS) than patients with ER and/or PgR positive disease (Hazard Ratio: 2.35, 95% CI 1.36–4.08 for NIBC; HR: 2.32, 95% CI 1.13–4.79 for IBC). The worst DFS was observed for the subgroup of patients with endocrine non responsive and HER2 positive breast cancer (2-yr DFS: 20% in NIBC and 29% in IBC; HR 2.45, 95% CI 1.24–4.87 for NIBC; HR 3.28, 95% CI 1.13–9.51 for IBC, when compared to endocrine responsive disease). A high Ki-67 labelling index (> 20% of the invasive tumour cells) significantly correlated with poorer DFS, overall (HR 2.47, 95% CI 1.51–4.03) and in the cohort of patients with NIBC (HR 3.06, 95% CI 1.65–5.69) Conclusions: Patients with endocrine non-responsive LABC had the most dire treatment outcome. HER2 overexpression and high degree of Ki-67 staining were also indicators of higher risk of relapse. These factors should be considered in therapeutic algorithms for LABC. No significant financial relationships to disclose.
Women from non-English speaking backgrounds living in Australia present with later stage breast cancer: A population study
Authors: C. K. Lee, L. Browne, P. Bastick, W. Liauw
Journal: Journal of Clinical Oncology (2007)

17043 Background: Ethnicity may influence both the incidence and prognosis of breast cancer. We have conducted an analysis to determine if women from non-English speaking backgrounds (NESB) living in New South Wales (NSW), Australia, present with later stage breast cancer compared to women from English speaking backgrounds (ESB); and to determine whether there is an impact on their survival. Methods: Data from the NSW Cancer Registry (1980 to 2004) was used to identify women with their first presentation of breast cancer. Stage of breast cancer was classified as early (insitu or localized) versus late (regional nodal or distant metastatic spread) according to registry definitions. Country of birth was used as a surrogate for language status. Stage at diagnosis was compared between ESB versus NESB women. Logistic regression was used to determine the odds of late stage disease and Cox regression to determine survival outcomes Results: 60,676 of 75,583 cases were considered suitable for analysis. Of these 16.64% were NESB. Accounting for potential confounding variables, NESB women were more likely to have late stage disease than ESB women (OR= 1.12; 95% CI, 1.07 to 1.17). Analysis by geographical region of birth revealed women born in Middle Eastern region were most likely to have late stage disease at presentation (OR 1.41; 95% CI, 1.25 to 1.60). In multivariable analysis of all-cause mortality NESB women had a superior overall survival (HR 0.90; 95% CI 0.87 to 0.94) compared to ESB women, however, there was no difference in breast cancer specific survival between these groups by univariate analysis (logrank p=0.46). Conclusions: In New South Wales, Australia, NESB women have a delayed presentation with breast cancer as indicted by more advanced stage. However, stage-adjusted, breast cancer specific survival in NESB women is similar to the ESB women. Further studies are required to determine the reasons for delayed detection for NESB women. No significant financial relationships to disclose.
Phase II study of intraperitoneal topotecan as consolidation chemotherapy in ovarian cancer
Authors: M. D. Robertson, T. W. Malpass, K. D. McGonigle, P. L. Weiden, H. Muntz
Journal: Journal of Clinical Oncology (2004)

5077 Background: Intravenous (IV) topotecan is approved for the treatment of ovarian cancer. Previous studies with intraperitoneal topotecan have shown 20 mg/m2 to be well tolerated. This is an interim analysis to evaluate the feasibility, safety, and effectiveness of intraperitoneal topotecan as consolidation chemotherapy in patients with ovarian cancer. Methods: Patients with stage III/IV ovarian cancer in clinical complete response (CR) after surgical cytoreduction and IV chemotherapy with carboplatin and paclitaxel who had negative macroscopic disease documented at second-look surgery were eligible. Intraperitoneal topotecan 20 mg/m2 in 1 L normal saline was infused into the peritoneum once every 21 days for 4 to 6 cycles. Dose reduction was determined based on grade 3/4 toxicities. Hematopoietic growth factors were used at the discretion of the treating physician. Results: To date, 10 patients have been enrolled. Eight patients received 4 cycles, 1 patient received 6 cycles, and 1 patient withdrew by personal request after 1 cycle. Of the total 39 cycles, 2 (5%) were delayed due to slow recovery of neutropenia and 14 (36%) were administered with dose reductions due to prior grade 3/4 neutropenia or thrombocytopenia; mean delivered dose was 17 mg/m2. Major toxicities included episodes of neutropenia (3 grade 3 and 1 grade 4) or thrombocytopenia (1 grade 3 and 1 grade 4). Filgrastim was administered to 80% of patients in 29 (74%) cycles, and epoetin alfa was administered to 50% of patients in 16 (41%) cycles. Other adverse events (grade 1/2) that occurred in more than half of patients included nausea and abdominal distention. All 10 patients have maintained CR for a median of 14 months (range, 5 to 23 months). Conclusions: Consolidation intraperitoneal topotecan 20 mg/m2 is feasible and well tolerated in a select group of patients with ovarian cancer. We continue to enroll patients in this trial. Future results will determine whether intraperitoneal topotecan may play a role as consolidation therapy in some ovarian cancer patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Advance directives (ADs) among members of the American Society of Clinical Oncology (ASCO)
Authors: J. E. Schroeder, M. A. Mathiason, C. M. Meyer, K. A. Frisby, E. Williams, R. S. Go
Journal: Journal of Clinical Oncology (2008)

20611 Background: Oncologists frequently discuss end-of-life planning with their patients. Yet little is known regarding how many of the oncologists actually have written ADs in their own medical records. We aimed to determine the proportion of ASCO members who had completed ADs and identify barriers to AD completion. Methods: We obtained a list of ASCO members who were from the U.S. and had M.D. or equivalent degree from the ASCO membership book. Between June and December 2007, we successfully sent a Web-based survey via e-mail to 7590 members. We defined having a written AD as having either a living will and or a power of attorney for health care. Results: As of December 26, 2007, we obtained a total of 525 usable replies for a response rate of 6.9%. The responders had a mean age of 50.6 years (range, 29–87) and were predominantly males (72.5%), in community practice (59.8%), with adult medical oncology as primary practice (80.7%). Although 87.0% reported that they had discussed their wishes regarding future life-sustaining medical care with those closest to them, only 59.0% had a written AD. Among those with ADs, 36.1% had informed their primary care physician, and 39.7% were certain that their ADs were in their medical records. Family (52.6%) and experience at work (68.1%) were the most common cited reasons for having an AD. Respondents with AD had a more comprehensive review of one’s own end-of-life wishes(P=0.001), discuss ADs with their own patients more frequently (P=0.025), and felt more knowledgeable (P=0.001) and more comfortable (P=0.036) in helping patients completing ADs. Among those without AD, most (74.0%) reported having end-of-life discussions with family members or loved ones. Perceived lack of time was the most common barrier cited by those without AD (49.3%). In multivariate analysis, age 50 plus (P<0.001), having had a comprehensive review (P<0.001), being male (P=0.017), and practice in the community setting (P=0.033) were independently associated with having an AD. Conclusions: Although limited by a low response rate, this study is the largest survey of oncologists regarding ADs. Despite work experience with patients who have a high mortality rate, oncologists do not adequately communicate (via a written AD) end-of-life planning decisions to their own primary care physicians. No significant financial relationships to disclose.
Determination of factors predicting for estrogen receptor positive (ER+) breast cancers in <i>BRCA1</i> mutation carriers
Authors: A. H. Comander, B. M. Gallagher, K. Krag, Y. Wang, H. Li, R. Gelman, L. C. Collins, S. J. Schnitt, J. E. Garber, N. Tung
Journal: Journal of Clinical Oncology (2009)

11045 Background: Most breast cancers that occur in BRCA1 mutation carriers tend to lack ER, progesterone receptors and Her2/neu. Foulkes et al.(Clin Can Res 2004; 10: 2029) reported an increase in BRCA1-associated ER+ tumors with increasing age. Little is known about the clinical factors that predict for ER status in this population. Understanding these factors and whether ER+ cancers are sporadic may have important implications for chemoprevention and treatment strategies. Methods: BRCA1mutation carriers who developed an invasive breast cancer from 1973–2008 were identified through the Cancer Risk and Prevention programs at 4 Boston-area hospitals. Clinical characteristics were abstracted from medical and research records. ER status was obtained from pathology reports, and ER staining was repeated when data was missing or when ER was listed as “weak”. Logistic regression was used to model ER positivity for the first invasive breast cancer. Potential predictors included menopausal status, age at cancer diagnosis, prior use of hormone replacement therapy, Ashkenazi-Jewish descent, age at first live birth, tobacco use, and alcohol use. Results: 170 BRCA1 mutation carriers were identified; 56 with ER+ and 114 with ER- first invasive cancers. Menopausal status was found to be a significant predictor of ER status; 18/56 (32%) with ER+ breast cancer were postmenopausal vs.14/114 (12%) with ER- cancer (odds ratio = 0.30, p = 0.002). Age &gt;= 50 was significant in univariate analysis, 14/ 56 (25%) ER+ vs. 11/ 114 (10%) ER- cancers (p=0.01), but not in multiple regression. Conclusions: While most breast cancers in BRCA1 carriers are ER-, we found postmenopausal BRCA1carriers significantly more likely to develop an ER+ tumor than premenopausal carriers. As mutation carriers are likely to become surgically menopausal before age 50, and menopause and age are correlated, additional data will be needed to sort out the relative contribution of each factor to ER status. An understanding of this issue could have important implications for chemoprevention strategies. Molecular analysis of the ER+ breast cancers in our BRCA1+ cohort is underway to investigate whether ER+ breast cancers are manifestations of the BRCA1 mutation or sporadic. No significant financial relationships to disclose.
From the Editor-in-Chief of Endocrine Reviews on the Occasion of the 2016 Centennial of the Endocrine Society
Authors: Leonard Wartofsky
Journal: Endocrine Reviews (2016)

Thyroxine was first isolated just over 100 years ago by Edward Kendall on Christmas Day 1914, and its structure was determined allowing its synthesis only a short time later by Charles R. Harington in 1926. Yet, when we consider thyroid health in our patients, prominent among the issues that come to mind are the difficulties in achieving patient satisfaction and their sense of wellbeing on replacement levothyroxine therapy. Patients complain, despite our reassurances that their serum free T4 and TSH levels are “normal,” ie, within the reference range. Indeed, what constitutes a normal TSH level has been controversial for several decades, with uncertain variations related to sex, aging, and other physiological states like pregnancy. Myriad studies confirm that even minor variations in thyroid function, subclinical hypothyroidism, or subclinical hyperthyroidism may have a significant impact on mental function, heart, bone, and even on mortality. Insights into these issues have evolved over the past decade with a flurry of research initiatives that begin to clarify the fact and nature of gene mutations and other genetic factors that underlie individual variations in thyroid function. In my view, a very important summary and analysis of this subject by Medici, Visser, Visser, and Peeters appeared in the April 2015 (Volume 36) issue of Endocrine Reviews. The authors discussed the basis for how we as individuals have unique genetically determined hypothalamic-pituitary-thyroid set points that may differ from, or vary within, the population’s normal ranges for TSH or free T4, which may relate as well to gene mutations of deiodinases or hormone binding proteins. They summarize the candidate gene and linkage studies identifying polymorphisms linked to thyroid dysfunction, based on genome-wide association studies, whole-genome sequence-based analysis, fine mapping, and analysis of variations in copy number, and they note those susceptibility genes for other autoimmune disorders that may play a role in thyroid dysfunction as well. The authors also consider the relevance of the impact of environmental factors such as smoking, iodine exposure, and infectious microorganismsongeneticmutations, and thisbrings tomindwhether there may be an association between the currently observed “epidemic” of thyroid cancer and growing concerns today about the effects of endocrine-disrupting chemicals. As we celebrate the Society’s Centennial, we can recall the pioneering work of earlier investigators of thyroid physiology and pathophysiology over the past century. And it is heartening to believe that the direction of future research as described by Medici et al has the potential to definitively establish the genetic basis of thyroid dysfunction and thereby allow clinicians to provide truly personalized care to our patients with thyroid disorders.