tbuckley/cabot-search huggingface dataset:
Small molecule pan-bcl-2 inhibitor AT-101 induces apoptosis in NSCLC by up-regulating noxa and enhances antitumor activity of docetaxel or targeted kinase inhibitors
Authors: P. Min, Y. Zhang, X. Ni, H. Wang, J. Wang, G. Wang, L. Leopold, M. Sorensen, D. Yang
Journal: Journal of Clinical Oncology (2009)

e14591 Background: AT-101 is an orally active pan Bcl-2 inhibitor currently under clinical development in Phase II trials. We investigated the effect of AT-101 alone or in combination with chemotherapies or targeted kinase inhibitors in NSCLC both in vitro and in vivo. Methods: Growth inhibition was measured by WST assays. The CalculSyn method was used to assess drug interaction by calculating the Combination Index (CI) value. The ability of AT-101 to potentiate the anti-cancer effect of chemotherapies or kinase inhibitors was evaluated in xenograft models. Results: A panel of 11 NSCLC cell lines with overexpression of Bcl-2, Bcl- X L or Mcl-1 proteins was treated with AT-101, docetaxel, pemetrexed, erlotinib, sorafenib, sunitinib, rapamycin, as a single agent and in combination. AT-101 inhibited the growth with IC 50 at 3–9 uM. When treating cells simultaneously with both agents, AT-101 demonstrated strong synergy with those agents in A549 or H460 cells with CI values &lt; 1.0. Protein analysis results indicated that AT-101 caused apoptosis by a time- and dose-dependent induction of Noxa expression in those cells. The expression of Bcl- X L was not influenced by AT-101. Pro-Caspase-3 was reduced with increasing doses of AT-101. In vivo, combined treatment of AT-101 with docetaxel, erlotinib, or sorafenib synergistically suppressed subcutaneous NSCLC A549 cells tumor growth compared with treatment with either agent alone. The synergist effects with the ErbB1 inhibitor Erlotinib is associated with the overexpression of the target protein ErbB1 in those cells. Only combination therapy resulted in significant tumor growth delay and no significant toxicities were observed. Conclusions: Our results demonstrate that AT-101significantly enhances the anti-tumor activity of chemotherapy and targeted agents and may represent a promising new anticancer agent with a novel molecular mechanism. Molecular targeted therapy with AT-101 may improve the outcome of current chemotherapy for NSCLC with Bcl-2, Bcl-xL and/or Mcl-1 overexpression. [Table: see text]
Multi-institutional evaluation of women at high-risk for developing breast cancer.
Authors: Marie Wood, Jennifer Chun, Tiffany Rounds, Shira Schwartz, Freya Ruth Schnabel
Journal: Journal of Clinical Oncology (2015)

e12580 Background: Well-established risk factors for breast cancer (BC) include family history, BRCA mutations and biopsies with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS). Several institutions have registries of these high-risk women but outcomes from these registries require large numbers and long follow-up. The purpose of this study was to compare clinical characteristics and outcomes between two high-risk populations. Methods: Women were enrolled in IRB-approved registries between 2003-2014 at the NYU Langone Medical Center (NYU) and University of Vermont (UVM). We compared variables including risk categories, uptake of prevention and cancer rates. Pearson’s Chi-Square and Fisher’s Exact Tests were performed. Results: There were 969 women in this study. We found a 99% concordance of variables collected between the two registries. There were significant differences in risk characteristics, uptake of prevention and cancer rates between registries (Table I). There was a significant difference in age between the two groups. There was low uptake of chemoprevention (8% for all women), with higher uptake among women with AH/LCIS (66%) when compared to those with strong family history or BRCA mutation. Women with BRCA mutations accounted for 76% of women undergoing risk-reducing surgeries. Conclusions: We demonstrate a high degree of concordance between registries suggesting no barriers to multi-institutional collaboration. Interestingly, there were significant differences in risk categories between the two populations and low uptake of chemoprevention. Future studies will include additional institutions and will allow us to draw meaningful conclusions about risk assessment, risk management, and ultimately, breast cancer prevention. Clinical characteristic. Variables UVM (N=493, 51%) % NYU (N=476, 49%) % p-value Median age (years) 46 (20-75) 51 (20-87) p<0.001 Risk Factors One or more 1° relatives with BC 440 89 253 53 p<0.001 BRCA positive 25 5 82 17 p<0.001 AH 62 13 219 46 p<0.001 LCIS 22 4 99 21 p<0.001 Uptake of Prevention Chemoprevention 26 5 53 11 p<0.001 Prophylactic Bilateral Mastectomy 1 0.2 41 9 p<0.001 Bilateral Salpingo-Oophorectomy 1 0.2 37 8 p<0.001 Developed BC 30 6 9 2 p<0.001
Prognostic and biologic impact of molecular markers in papillary renal cell carcinoma
Authors: S. B. Riggs, T. Klatte, D. B. Seligson, A. J. Pantuck, J. T. Leppert, J. S. Lam, N. Zomorodian, F. F. Kabbinavar, A. S. Belldegrun
Journal: Journal of Clinical Oncology (2007)

15525 Background: Papillary renal cell carcinoma (PRCC) is the second most common histological subtype among patients undergoing surgery for kidney cancer, but the molecular profile of this entity is not well characterized. The goals of this study were (1) to evaluate differences in expression between type 1 and 2 PRCC, and (2) to analyze the prognostic impact of molecular markers. Methods: We examined clinicopathological and molecular parameters of 42 patients treated with nephrectomy with the final pathology being PRCC. A tissue microarray consisting of the tumor specimens was constructed. Immunohistochemical staining was performed with antibodies directed against CAIX, CAXII, CXCR3, Gelsolin, HIF-1a, Ki-67, Vimentin, EpCAM, p21, p27, p53, pS6, pAkt, PTEN, VEGF-A, VEGF-C, VEGF-D, VEGF-R1, VEGF-R2, and VEGF-R3. Staining was analyzed by one anatomical pathologist (DS) who was blinded to outcome. Mann- Whitney’s U-test was used to compare marker expressions between type 1 and 2. Endpoint was disease-specific survival (DSS). Expression cut-offs were detected by using recursive partitioning. The Kaplan-Meier curves were compared using the log-rank test. Results: At last follow-up, 21 patients (50%) had died including 12 (29%) of RCC. The median follow-up for the patients alive was 8 years. Type 1 PRCC had significantly higher expression of nuclear p27, nuclear pAkt, and p53 compared with type 2. Since none of these 3 markers provided prognostic information, survival analyses were performed together for both types. Using the cut-offs identified with recursive partitioning, higher expression of Ki-67 (p=0.02), lower gelsolin (p&lt;0.001), lower p21 (p=0.01), higher cytoplasmic p27 (p=0.01), higher endothelial VEGF-A (p=0.01), lower epithelial VEGF-D (p=0.04), and lower endothelial VEGFR-3 (p=0.01) were adverse prognostic factors. Conclusions: Out of 19 molecular markers, a specific molecular profile for PRCC was identified. pAkt, p27, and p53 can assist in subdividing type 1 and type 2 PRCC. Ki-67, gelsolin, p21, p27 and proteins of the VEGF family were found to be important prognostic factors among these patients. Although prognostic relevant, the VEGF proteins cannot be used to differentiate type 1 and 2 PRCC. No significant financial relationships to disclose.
Testosterone (T), luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels in testicular cancer survivors (TCSs) 11 and 19 years after orchiectomy.
Authors: Mette Sprauten, Marianne Brydoy, Hege Sagstuen Haugnes, Carl Wilhelm Langberg, Olav Dahl, Olbjorn Harald Klepp, Roy M. Bremnes, Milada Cvancarova, Sophie D. Fossa, Jan Oldenburg
Journal: Journal of Clinical Oncology (2013)

4562 Background: Hypogonadism, i.e., low T-, high LH- and/or FSH-levels, is frequently observed in TCSs and is associated with cardiovascular disease, osteoporosis and reduced quality of life. Little is known about the impact of aging on hypogonadism in TCSs. Methods: T, LH, and FSH levels were retrieved twice from 874 TCSs median 11 (S11) and 19 (S19) years after orchiectomy and categorized based on cut-offs calculated from 570 healthy controls (C), separately for each decadal age group. Treatment was categorized into surgery (S), radiotherapy (RT) or cisplatin-based chemotherapy (CT). Impact of treatment and aging on T, LH and FSH levels was assessed by comparing proportions of TCSs grouped into the C quartiles by ordinal logistic regression and expressed with odds ratios (OR) and 95% confidence interval (CI). Results: TCSs had lower T and higher LH and FSH levels than C at S11 and S19 (p&lt;0.05, except for LH after S at S11) (Table).Approximately 50% of TCSs had T levels in the lowestquartile at S11 and S19. The proportion of TCSs with T below the 2.5% cut-off threshold for C increased from S11 to S19, for the S (9.7 - 12.5%), RT (9.4 - 16.3%) and CT group (12.5- 19.9%). Conclusions: TCSs had lower T and higher LH and FSH levels than C of similar age indicating an impact of treatment. Importantly, proportions of TCSs in the highest LH quartile and below the 2.5% cut-off for T-level increased from S11 to S19, indicating an accelerated hormonal aging. Continued follow-up of hormone levels is important. [Table: see text]
A retrospective assessment of outcomes of chemotherapy-based versus radiation-only adjuvant treatment for completely resected stage I–IV uterine carcinosarcoma (UCS) with rhabdomyosarcoma (RMS) differentiation.
Authors: Vicky Makker, Sara Jane Kravetz, Jacqueline Gallagher, Oana Orodel, Alexia Iasonos, Deborah DeLair, Qin Zhou, Carol Aghajanian, Martee Leigh Hensley
Journal: Journal of Clinical Oncology (2013)

5595 Background: UCS with RMS differentiation are aggressive cancers with poor survival, and without an established standard treatment (txt). We aimed to determine the progression-free survival (PFS) and overall survival (OS) in patients (pts) who received either platinum-based chemo with or w/o radiation therapy (pelvic or IVRT), or RT alone (pelvic or IVRT). Methods: MSKCC EMR from 1990 to 2012 was reviewed for pt age, diag. date, primary surgery, residual disease at completion of primary surgery, FIGO stage, txt details, dates of progression, death, site(s) of first recurrence. Univariate analysis for PFS/OS utilized Kaplan Meier method. Differences between PFS/OS and categorical variables of stage + txt type were assessed using log-rank test. All analyses utilized SAS version 9.2. Pts who received chemo with or w/o RT or RT alone were included in the analysis. Results: 53 pts met study criteria. 41/53 (77.4%) pts received chemo: 30/41 (73.2%) paclitaxel-carboplatin (TC); 3/41 (7.3%) ifosfamide (I)-platinum; 3/41 (7.3%) weekly cisplatin followed by TC; 2/41 (4.9%) other platinum-doublets; 3/41 (7.3%) IT. 34% of the chemo pts also received pelvic or IVRT. 12/53 (22.6%) pts received only pelvic RT+/-IVRT. FIGO stage: I =16 (30%); II =5 (9%); III =14 (26%); IV =18 (34%). Median PFS for the entire cohort: 11.7 mos (95% CI 6.4, 14.1). Median OS for the entire cohort: 21.8 mos (95% CI 14.9, 31.8). Median PFS by stage: 14.3 mos for early stage (stages I and II) vs 9.9 mos for late stage (stages III and IV), p=0.0217. Median OS by stage: not reached in the early stage cohort. Median OS for the late stage: 19.9 mos, p=0.0106. Median PFS by txt: 10.7 mos for the Pelvic RT+/- IVRT group vs 13.5 mos for chemo+/-Pelvic RT+/- IVRT group, p=0.5126. Median OS treatment: 23.9 mos for the chemo+/-Pelvic RT+/- IVRT group vs 17.4 mos for the Pelvic RT+/- IVRT group, p = 0.5191. Conclusions: PFS and OS outcomes in our cohort of pts with UCS with RMS differentiation were similar to survival outcomes among pts treated with platinum-based chemo on GOG 150 and GOG232B. The role of adjuvant RT in addition to chemo warrants further investigation.
Management of secondary immunodeficiencies with immunoglobulins (IG) under clinical practice conditions.
Authors: Marcel Reiser, David Pittrow, Martin Stangel, Ralf Gold, Michael Borte, Maria Fasshauer, Wilhelm Kirch, Doerte Huscher, Ulrich Baumann, Manfred Hensel
Journal: Journal of Clinical Oncology (2014)

e17596 Background: Patients with acquired (secondary) immunodeficiencies (SID) carry an increased risk of recurrent, life-threatening infections. Methods: “Assessment of Immunoglobulins in a long-term non-interventional study” (SIGNS, ClinicalTrials.Gov is NCT01287689) is an ongoing prospective observational monitored study that, among others, documents in six-monthly intervals patients with SID who receive IG substitution therapy. Results: As of 19 January 2014, 299 patients (of a total of 616 in the database) had SID. 52% were males, mean age was 64.2 ±13.9 years. 125 (42%) patients had CLL, 77 (26%) indolent lymphoma, 42 (14%) multiple myeloma, and 54 (18%) another condition such as HIV infection (2.3%), non-Hodgkin lymphoma (6%) or a post-transplant condition (2.3%). Mean disease duration since diagnosis was 5.0 ±5.1 years. 123 patients (42%) had received chemotherapy or immunotherapy in the past 12 months, the majority in combination with rituximab (29%). 165 patients (56%) were newly treated with IG. In the 12 months prior to baseline, 90 patients (30%) had experienced no infections (17% in IG naïve and 36% in IG previously treated patients), 13 had serious bacterial infections (13 pneumonia, 1 IG naïve patient in addition with sepsis) and 193 (65%) general infections. At 6-month follow up, 64% of patients were free of infections, and the rate remained at about 60% at all six-monthly observations in the 2 years after baseline. Current state of health in SF-36 was described by patients in 3% as very good, in 34% as good, in 46% as intermediate, in 15% as bad and in 2% as very bad. After 6 months, 28% reported their global health as improved, 56% as stable and 16% as worsened. Conclusions: In SID patients treated with IG, the rate of general and serious bacterial infections was decreased in comparison to pretreatment. It is lower than reported in published controlled trials which are now outdated (at least 20 years old). Self-described state of health of SID patients is mostly good or intermediate.
The primary clinical trial of dendritic cell vaccine pulsed with apoptosis tumor cell in patients with malignant cancers
Authors: K. Qian, Y. Wang, H. Shi, G. Yajun Wang, Heng Ye, Haiyan Min, Xiao Lu, Yongling Ning
Journal: Journal of Clinical Oncology (2007)

13509 Background: We evaluated the feasibility, safety, and immunogenicity of mature, apoptosis tumor cells-pulsed dendritic cell (DC) vaccines administered by intradermal injection. Methods: We performed a randomized study in 16 patients with malignant tumors, including 4 cases for gastric cancer, 3 cases for prostate cancer, 2 cases for breast cancers, one case for lung cancer, esophageal carcinoma, liver cancer , colorectal cancer, kidney cancer, ovarian cancer, endometrial cancer respectively.The vaccine used mature DCs (CD11c++, HLA-DR++, CD83+, and CD86+++) generated from peripheral blood monocytes in the presence of GM-CSF and IL-4. After 5 days, DCs were matured with a defined cocktail of cytokines (IL-1+ TNF-a+PGE2) and simultaneously pulsed with apoptosis autologous tumor cells or heterologous tumor cell lines, for 2 days.Patients were administrated four DC vaccinations (5×10 6 per time) at 7 th day, 14 th day, 21 st day and 42 nd day by intradermal injection(ID). Toxicity effect, life quality, immune function and clinical efficacy were monitored during the whole therapy. Results: Fourteen (82.4%) of 17 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited less than grade 1 toxicities including rash, transient fever, transient debilitation and injection site reaction. The life quality of most patients had improved to certain degree, including sleep, appetite, mental status, and a good recovery from surgery and chemotherapy. Moreover, the serum level of IL-2 of 10/14 patients increased more than several times to twenty times, and 6/10 patients had a long increase for more than forty days. Serum level of IL-12 were increase in 11/14(9/11 patients increased for more than forty days) patients, Serum level of IFN-? were increase in 11/14(5/11 patients increased for more than forty days ) patients. Conclusions: Administration of this apoptosis tumor cell-pulsed mature DC vaccine by ID routes is feasible and safe. This administration seems to result in superior immunological sensitization as measured by in vitro serum level of immune cell factor such as IL-2, IL-12 and IFN-?. No significant financial relationships to disclose.
Parents gave baby alcohol and antihistamines in case of induced illness
Authors: Clare Dyer
Journal: BMJ (2017)

The parents of a baby boy secretly administered alcohol and antihistamines to him over several months in hospital while puzzled doctors put him through extensive tests to try to find out what was wrong, a High Court judge has ruled.

Mr Justice MacDonald said that the baby’s mother or father, or both, gave him amounts of alcohol which could have been fatal had it not been for the emergency treatment he received as a hospital inpatient.

The case is the latest example to come into the public domain of fabricated or induced illness (FII), formerly known as Munchausen syndrome by proxy. The Royal College of Paediatrics and Child Health issued guidance …
Government’s childhood obesity plan does not go far enough, say MPs
Authors: Jacqui Wise
Journal: BMJ (2017)

To tackle childhood obesity the government must regulate to reduce the impact of deep discounting and price promotions of unhealthy food and drink, says the House of Commons Health Committee.1

The committee’s report criticises the government’s childhood obesity plan for England, which was published last August amid accusations that it had been watered down.23 Although the committee welcomed the government’s measures in the plan, it was disappointed that several key areas for action were missing.

Sarah Wollaston, chair of the health committee, said, “Vague statements about seeing how the current plan turns out are inadequate for the seriousness and urgency of this major public health …
First-line monotherapy with nivolumab (NIVO; anti-programmed death-1 [PD-1]) in advanced non-small cell lung cancer (NSCLC): Safety, efficacy and correlation of outcomes with PD-1 ligand (PD-L1) expression.
Authors: Scott N. Gettinger, Matthew David Hellmann, Frances A. Shepherd, Scott Joseph Antonia, Julie R. Brahmer, Laura Quan Man Chow, Jonathan Wade Goldman, Rosalyn A. Juergens, Hossein Borghaei, Neal Ready, David E. Gerber, Faith Ellen Nathan, Yun Shen, Christopher Harbison, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2015)

8025 Background: NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has demonstrated durable responses and tolerability in heavily pretreated patients (pts) with advanced NSCLC. This phase I study evaluated the efficacy and safety of NIVO monotherapy in pts with chemotherapy naïve advanced NSCLC. Methods: Pts (N=52) with squamous (SQ) or non-SQ advanced NSCLC received NIVO 3 mg/kg IV Q2W until progression or unacceptable toxicity (post-progression treatment was permitted per protocol). Response (RECIST v1.1) was evaluated overall, by histology and by tumor PD-L1 expression (PD-L1+: ≥5% tumor cells expressing PD-L1). Results: Objective response rate (ORR) was 21%, with 3 confirmed complete responses; 9/11 responders (82%) achieved response by first scan (wk 11). Median duration of response (mDOR) was not reached (NR; range, 7.6+, 85.6+ wks); 9 pts (82%) had ongoing responses at last tumor assessment, with a minimum follow-up of 8 mos in all pts. Two pts had unconventional immune-pattern responses with 35% and 43% maximum reductions in target lesions, respectively, and simultaneous appearance of new lesions (not reported as responders). Median overall survival (mOS) was 98.3 wks (range, 1.0, 104.4+). Objective responses were observed in both PD-L1+ and PD-L1– pts, with ORR higher in pts with PD-L1+tumors. Eight pts (15%) experienced grade 3–4 treatment-related adverse events, including rash (n=2), increased amylase/lipase, increased AST/ALT, hyperglycemia, cardiac failure, lung infection, and pneumonitis (n=1 each). Conclusions: First-line NIVO demonstrated durable responses, encouraging survival and a tolerable safety profile in pts with advanced NSCLC. Although response rates were higher in PD-L1+ pts, OS was encouraging in both PD-L1+ and PD-L1– pts. Updated OS and safety data will be presented. Clinical trial information: NCT01454102. ORR mDOR mOS n/N (%) wks (range) All pts 11/52 (21) NR (7.6+, 85.6+) 98.3 (1.0, 104.4+) Non-SQ 9/39 (23) NR (7.6+, 85.6+) NR (1.0, 104.4+) SQ 2/13 (15) NR (46.9+, 77.3+) 73.1 (13.3, 87.3+) PD-L1+ 8/26 (31) NR (7.6+, 85.6+) NR (1.0, 103.3+) PD-L1 2/21 (10) NR (13.0+, 24.1+) 98.3 (8.0, 104.4+)
Molecular profiling of adenocarcinoma of esophagogastric junction.
Authors: Yun-Suhk Suh, Deukchae Na, Euihyun Kim, Ju-Seog Lee, Jeesoo Chae, Jimin Min, Boram Choi, Seong-Ho Kong, Hyuk-Joon Lee, Jong-Il Kim, Charles Lee, Woo Ho Kim, Han-Kwang Yang
Journal: Journal of Clinical Oncology (2017)

65 Background: Biologic understanding of adenocarcinoma of esophagogastric junction (AEJ) and similarity to gastric or esophageal adenocarcinoma has been long standing controversial issue, especially according to Siewert classification. The purpose of our study is to evaluate molecular characteristics of AEJ compared to esophageal (EAC) or upper third gastric adenocarcinoma (UT) using next generation sequencing. Methods: We analyzed classifier genes between EAC and body/fundus gastric adenocarcinoma (GCBF) from The Cancer Genome Atlas (TCGA) cohort. Based on classifiers, class prediction model was developed with Bayesian compound covariate predictor (BCCP). According to Siewert classification, SNUH cohort is comprised of each 16 pairs of tumors and normal gastric mucosae of AEJII, III and UT groups for which whole exome and transcriptome sequencing was carried out. SNUH cohort (n = 48) and AEJ/cardia cancer of TCGA cohort (n = 48) were tested using class prediction model. Results: Between EAC (n = 78) and GCBF (n = 102) in TCGA cohort, we identified 5,520 differentially expressed genes ( P&lt; 0.001), and chose each top and bottom 200 genes using fold-change rank as classifiers for prediction model. Cross validation for prediction model revealed 90.2% of sensitivity and 89.7% of specificity. AEJ/Cardia cancer in both cohorts showed spectrum transition of predictor gene expression, and 75% in TCGA cohort (AEJ/Cardia) and 81.2% in SNUH cohort (AEJ) is classified as GCBF type using cut-off as 0.5 of BCCP. In SNUH cohort, 68.8% of AEJII , 80.0% of AEJIII sparing gastroesophageal junction (GEJ) and all AEJIII involving GEJ was classified as GCBF type. GCBF type shows significantly higher proportion of undifferentiated and diffuse type than EAC. Conclusions: Molecular prediction using BCCP revealed spectrum transition of AEJ, and 75-81.2% of AEJ/cardia cancer was classified as GCBF. Especially, 68.8 of AEJII and more than 80.0% of AEJIII can be considered as GCBF irrespective of involvement of GEJ.