tbuckley/cabot-search huggingface dataset:
Central Texas experience of IMRT-SIB for preoperative therapy for locally advanced rectal cancers.
Authors: Nitika Thawani, Shilpa Vyas, Rahila Essani, Deb Niloyjyoti, Subhakar Mutyala
Journal: Journal of Clinical Oncology (2015)

e14705 Background: Neoadjuvant chemoradiation followed by TME is current standard of care for locally advanced rectal cancers. We analyzed our experience of Intensity Modulated Radiation Therapy with simultaneous integrated boost (IMRT-SIB) with concurrent 5-FU based chemotherapy for locally advanced rectal cancers preoperatively. Methods: 49 consecutive patients from 07/2010 to 10/2014 treated with neoadjuvant chemoradiation for rectal cancers at our institution were included in the study. All patients received 45 Gy in 25 fractions to the pelvic nodes along with a simultaneous integrated boost of 50 Gy in 25 fractions to areas of gross disease with margins. IMRT planning was done with dose constraints for bladder, small bowel, bone marrow and femoral heads. All patients received 5-flourouracil based chemotherapy concurrently with radiation. Evaluation of toxicity was based on RTOG criteria. Results: All patients completed their prescribed course of radiation. Patient characteristics are described in Table 1.Median followup was 20.5 months (range 8-31 months). Partial to complete response(CR) was noted in all patients except 2. 14% (7/49) patients had pathological CR and 65.3% (32/49) had down staging of the locoregional disease. All acute toxicities were tolerable and subsided within 3 weeks of treatment completion. The incidence of > Grade 2 toxicity was: GI 35% (17/49), GU 18% (9/49), Skin 14% (7/49) and myelotoxicity 41% (20/49). 65% (32/49) patients achieved sphincter preservation. 5 patients needed chemotherapy dose modification. Conclusions: IMRT-SIB for preoperative radiation for rectal cancers has decreased toxicity, comparable pathological outcomes and shortened duration. This is so far the largest reported series for rectal cancer treatment with IMRT-SIB. The current results are promising and will possibly allow dose escalation in the future along with addition of targeted agents to better outcomes. Age (years) 58(31-87) Site ≤ 5cm from Anal Verge > 5cm from Anal Verge 23(47%) 26(53%) Stage IIA IIB IIIB IIIC 18(37%) 1(2%) 28(57%) 2(4%) Surgery TAE LAR APR 6(12%) 26(53%) 17(35%) Last Followup NED Locoregional recurrence Distant Metastasis Both locoregional and distant 37(76%) 3(6%) 9(18%) 1(2%)
Abstract P305: Alternative Ankle Brachial Index Calculation and CVD Events and Mortality: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Jonathan Unkart, Matthew Allison, Maria Rosario Araneta, Joe Ix, Mary McDermott, Michael Criqui
Journal: Circulation (2019)

Introduction: The ankle brachial index (ABI) is independently associated with cardiovascular disease (CVD) events and mortality. The recommended ABI calculation for the ankle pressure involves taking the higher (ABI-TRAD) of the dorsalis pedis (DP) or posterior tibial (PT) arteries in the lower of the two legs. However, little is known about using the lower (ALT-ABI) of the DP/PT in evaluating CVD endpoints. Methods: Using a multiethnic cohort free of known CVD disease at baseline, participants with complete ABI assessment were followed for incident CVD events, CVD mortality and all-cause mortality. ABI was assessed as categories: low (≤0.9), borderline (0.9-1.0), low-normal (1.0-1.1), normal (1.1-1.4) and high (≥1.4) and continuously using ALT-ABI. Leg symptoms were assessed with the San Diego Claudication Questionnaire. We used cox models to assess associations between ALT-ABI and outcomes adjusting for age, gender, race/ethnicity, ASCVD risk score and leg symptoms. Results: Of the 6,669 participants with complete ABI measures, the mean ALT-ABI was 1.03 +/- 0.12 versus ABI-TRAD of 1.10 +/- 0.11. The mean age of participants was 62 years and 1,625 (24.4%) reported some type of leg pain with walking. At a median follow up of 14.2 years, 1,214 deaths, 657 CVD events, and 288 CVD-specific deaths had occurred. Of the 824 individuals with low ALT-ABI, 581 (70.5%) had an ABI &gt; 0.9 using ABI-TRAD. As seen in the Table, lower values and categories of ALT-ABI were associated with increased risk of CVD events, CVD and all-cause mortality. Conclusions: Using ALT-ABI identified more individuals with an ABI ≤ 0.9. The ALT-ABI is significantly associated with CVD outcomes, even in asymptomatic individuals. Significant risk increases were present even in those with a low-normal ALT-ABI. While clinical guidelines recommend further workup and risk reduction in individuals with leg symptoms and an ABI-TRAD ≤ 0.9, this method of ABI calculation and cutoff may misidentify individuals at-risk for adverse CV outcomes.
Age-related variation in gene alteration frequency in metastatic prostate cancer.
Authors: Zachary Rockow Chalmers, Garrett Michael Frampton, Jeffrey S. Ross, Maha H. A. Hussain, Sarki Abdulkadir
Journal: Journal of Clinical Oncology (2019)

178 Background: Despite advances in therapy, metastatic prostate cancer (mPCA) remains lethal. Younger men with mPCA have a significantly greater risk of mPCA-related death compared to men diagnosed later in life. This suggests that early-onset mPCA is a uniquely aggressive subtype of disease, however, the genomic drivers have not been explored. Here, we analyze data from 2,196 mPCA specimens profiled as part of routine clinical care. Methods: Comprehensive genomic profiling was performed by hybridization capture of exonic regions from either 236, 315 or 324 cancer-related genes and select introns from 19 genes commonly rearranged in cancer. Libraries were sequenced to high, uniform coverage and assessed for all classes of genomic alterations. Tumor mutational burden (TMB) was determined from 1.1 Mb of sequence and microsatellite instability (MSI) from 114 loci. Results: 336 (15.3%) men were &lt; 60 years old (yo), and 1,860 (84.7%) were ≥60 yo at time of biopsy. Lymph node, liver, and bone were the three most common metastatic sites in both groups, accounting for 75% of all specimens. Patients &lt; 60 yo harbored significantly fewer AR and PTEN point mutations when compared to patients ≥60 yo (OR = 0.48, p &lt; 0.001; OR = 0.51, p = 0.01). Copy number alterations in PTEN and CDKN2A/B were significantly more common among young patients (OR = 1.46, p = 0.003; OR = 1.91, p = 0.04). AR copy number alterations were significantly less common among young patients (OR = 0.57, p &lt; 0.001). Although uncommon in mPCA, markers of genomic instability including MSH2 mutations and MSI were both significantly less common among patients &lt; 60 yo (0.00% vs. 1.29%, p = 0.04; 0.89% vs. 3.06%, p = 0.03). There were no significant differences in the frequency of TP53, APC, BRCA2, ATM, and CDK12 point mutations, MYC copy number alterations, or TMPRSS2-ERG fusions. The average TMB was not significantly different between young and old patients, with 3.26 and 5.79 mutations per Mb, respectively (p = 0.19). Conclusions: Younger men with mPCA appear to represent a genomically distinct disease subtype. To better define this population, we are prospectively investigating the genomic, genetic, and environmental risk factors through an ongoing PCF funded clinical trial.
AMA and Planned Parenthood sue to halt new US restrictions on abortion
Authors: Janice Hopkins Tanne
Journal: BMJ (2019)

The American Medical Association, Planned Parenthood, the Oregon Medical Association, and 22 state attorneys general have filed a lawsuit to block new restrictions on abortion proposed by the Trump administration.1

Barbara McAneny, president of the American Medical Association, called the restrictions “a gag rule” that was “illegal, unethical, and dangerous.” She said it “would decimate the Title X [family planning] programme and limit the advice physicians can give their patients.” It put physicians in “an untenable situation, prohibiting us from having open, frank conversations with our patients about all their healthcare options—a …
An investigator initiated multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE).
Authors: Yasutoshi Kuboki, Tomohiro Nishina, Eiji Shinozaki, Kentaro Yamazaki, Kohei Shitara, Wataru Okamoto, Takeshi Kajiwara, Toshihiko Matsumoto, Takahiro Tsushima, Nobuo Mochizuki, Miki Fukutani, Masako Nakamoto, Hiromi Hasegawa, Ayako Sugama, Shogo Nomura, Akihiro Sato, Atsushi Ohtsu, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2015)

3544 Background: In global phase III RECOURSE trial, TAS-102 significantly improved overall survival (OS), progression-free survival (PFS) and disease control rate (DCR) over placebo for metastatic colorectal cancer (mCRC) patients (pts) refractory to standard therapies. In preclinical models, TAS-102 with bevacizumab (BEV) demonstrated enhanced activity against CRC cells compared with either drug alone. This phase I/II study was conducted to determine the recommended phase II dose (RP2D) and evaluate the efficacy, safety and pharmacokinetics of this combination in pts with mCRC refractory to standard therapies. Methods: Eligibility criteria were: mCRC pts who were refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin, anti-angiogenesis therapy and anti-EGFR antibody (if KRAS wild-type) and had no prior regorafenib treatment. Phase I was designed to determine RP2D in the dose de-escalation design of TAS-102 (35 mg/m2 BID on days 1–5 and 8–12 q4w for level 1 and 30 mg/m2BID for level −1) with a fixed BEV dose (5 mg/kg q2w). Primary endpoint was centrally assessed PFS at 16 weeks in pts treated with RP2D. Using a single stage binomial design, this study required 21 pts, with a centrally assessed PFS rate at 16 weeks of 50% deemed promising and 25% unacceptable (alpha = 0.1; beta = 0.2). Results: From February to July 2014, 25 pts were enrolled. In phase I, dose-limiting toxicity was not observed in 6 pts at level 1, which was determined as the RP2D. Centrally assessed PFS rate at 16 weeks (n = 21) was 42.9% (80% C.I.: 27.8–59.0%). Median PFS and DCR by central assessment were 3.7 months and 64.0%, and by investigator assessment were 5.4 months and 72.0%, respectively (n = 25). Median OS was not reached. The most common grade 3 or worse adverse events were neutropenia (68%), febrile neutropenia (8%), thrombocytopenia (4%) and anorexia (4%) without unexpected safety signals. Drug–drug interaction was not indicated by PK analysis. Conclusions: The combination ofTAS-102 with BEV showed promising antitumor activity with acceptable toxicity for mCRC pts; biomarker analysis will be presented. Clinical trial information: UMIN000012883. Clinical trial information: 000012883.
PACE: Analysis of acute toxicity in PACE-B, an international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) to conventionally fractionated or moderately hypofractionated external beam radiotherapy (CFMHRT) for localized prostate cancer (LPCa).
Authors: Nicholas John Van As, Douglas Brand, Alison Tree, Peter James Ostler, William Chu, Andrew Loblaw, Daniel Ford, Shaun P. Tolan, Suneil Jain, Alexander Stephen Martin, John Staffurth, Stephanie Brown, Stephanie M. Burnett, Aileen Duffton, Clare Griffin, Vicki Hinder, Kirsty Morrison, Olivia Frances Naismith, Emma Hall
Journal: Journal of Clinical Oncology (2019)

1 Background: External beam radiotherapy (EBRT) is a curative treatment for LPCa. Large randomised controlled trials (RCTs) have shown moderately hypofractionated regimens (2.5–3 Gy/fraction(f)) as non-inferior to conventionally fractionated regimens (2 Gy/f). PACE-B aims to demonstrate non-inferiority of SBRT compared to CFMHRT for biochemical or clinical failure. Compared to CFMHRT, SBRT reduces patient (pt) attendances but compressed overall treatment time may influence acute toxicity severity. Methods: PACE is a phase III open-label multiple-cohort RCT. Men with LPCa, stage T1-T2, ≤ Gleason 3 + 4, PSA ≤ 20 ng/mL, unsuitable for surgery or preferring EBRT, were eligible for the PACE-B cohort. Between 08/12-01/18, 874 pts (38 centres) were randomised (1:1) to SBRT or CFMHRT. SBRT dose was 36.25 Gy/5f in 1-2 weeks (wks), CFMHRT as 78 Gy/39f over 7.5 wks, or 62 Gy/20f in 4 wks. Androgen deprivation therapy was not permitted. Clinician reported acute toxicity was assessed at baseline, 2-weekly during CFMHRT and at 2, 4, 8 &amp; 12 wks post-treatment. Key toxicity outcomes were worst grade 2+ Radiation Therapy Oncology Group (RTOG) genitourinary (GU) and gastrointestinal (GI) acute toxicities, compared by Chi-square test with alpha 0.05 divided between the two measures. Results: By per protocol analysis n=430 received CFMHRT, n=414 received SBRT. Key characteristics seen in the CFMHRT and SBRT groups respectively were: mean age: 69.5 vs 69.3 years; T-stage ≥T2b: 51.8% vs 56.6%; Gleason Score 3+4: 80.2% vs 85.0%; PSA 10-20 ng/mL: 30.9% vs 31.6%. RTOG G2+ toxicity was not significantly different for GI events (CMFHRT 52/430 (12.1%) vs SBRT 42/414 (10.1%), p=0.368), nor GU events (CFMHRT 117/430 (27.2%) vs SBRT 96/414 (23.2%), p=0.179). Conclusions: Despite an accelerated treatment schedule, RTOG assessments show similar rates of acute GI and GU toxicity for SBRT and CFHFRT. Pt follow-up in PACE-B continues and results of late toxicity and biochemical/clinical failure are awaited. Clinical trial information: NCT01584258.
How TNM stage affects surveillance intensity after treatment for breast cancer.
Authors: Daniel Wu, Emad S. Allam, Katherine S. Virgo, Ling Chen, Julie A. Margenthaler, Frank E. Johnson
Journal: Journal of Clinical Oncology (2015)

6547 Background: The mean lifetime cost of surveillance for a woman diagnosed with breast cancer at age 45 is estimated to be > $35,000. Based on trials comparing low and high intensity surveillance, ASCO and NCCN have published recommendations encouraging low intensity strategies. We aimed to determine whether ASCO experts carry out surveillance differently for patients with breast cancer of varying TNM stages. Methods: We created a web-based survey instrument with 4 idealized patient vignettes depicting patients with TNM stages 0 to IIIA. Respondents were asked how often they would recommend 12 specific diagnostic modalities for each vignette during post-treatment years 1-5. The survey was e-mailed to the 3245 ASCO members who had identified breast cancer as their major clinical focus. We used repeated measures ANOVA for analysis. Results: 1,012 (31%) of the 3245 ASCO members surveyed responded. There were 915 (90%) evaluable responses. Office visit was most frequently recommended. Responders also commonly recommended complete blood count (CBC), liver function tests (LFTs), and mammogram. There was statistically significant variation in recommended surveillance intensity for all 12 modalities according to TNM stage. Conclusions: We have demonstrated significant variability in surveillance after curative-intent treatment. Modalities not recommended by ASCO guidelines, such as CBC and LFTs, are frequently recommended by physicians. The frequency of recommended modalities varied depending on the TNM stage of the described patients, but ASCO guidelines do not stratify according to TNM stage. Our results suggest both overuse and underuse of surveillance modalities. Innovative solutions to promote physician and patient education can help physicians follow evidence-based surveillance guidelines and help patients to participate in these decisions. There is a need for new randomized controlled trials to evaluate newer surveillance modalities to guide clinical practice. Frequency of recommended use of office visits: mean ± SD. Year TisN0M0 T2N0M0 T1N1M0 T3N2M0 1 2.8 ± 1.2 3.3 ± 1.3 3.3 ± 1.2 4.1 ± 2.2 2 2.5 ± 1.2 3.0 ± 1.1 3.0 ± 1.1 3.3 ± 1.2 3 2.1 ± 1.3 2.4 ± 1.1 2.5 ± 1.2 2.7 ± 1.3 4 2.0 ± 1.4 2.2 ± 1.1 2.3 ± 1.3 2.5 ± 1.3 5 1.9 ± 1.5 2.1 ± 1.3 2.2 ± 1.3 2.4 ± 1.3
Effectiveness of transcranial magnetic stimulation in neurooncological patients.
Authors: Dmitriy P. Atmachidi, Alla Ivanovna Shikhlyarova, Eduard E. Rostorguev, Tatiana P. Protasova, Elena P. Korobeynikova
Journal: Journal of Clinical Oncology (2015)

2042 Background: Development of technologies of neurooncological treatment has not solved the problem of treatment for malignant brain tumors. Neurological and somatic complications reduce the length and quality of life of patients. Development of systemic therapeutic approach showed the effectiveness of multisystem influence factors. They include low-intensity extremely low frequency variable and static magnetic fields (ELFMF and SMF). The purpose of this study was to improve the results of complex treatment for malignant brain gliomas using transcranial magnetic stimulation (TMS). Methods: 30 patients received TMS during adjuvant chemoradiotherapy (CRT) on days 1-20 of the treatment: ELFMF to hypothalamus projection with frequency 0.03; 3; 9 Hz, induction from 5 to 0.8 mT, exposure 7 min.; and in 20 min. – SMF to the area of operation with induction 20 mT, exposure 15 min. X-ray computed tomography was performed using Toshiba-AsteionVR 2002. Toxicity was evaluated according to CTC-NCIC criteria, cerebral symptoms and somatic status (ECOG-WHO performance status) – according to the scale, Karnofsky Performance Score and identification of integral reactions of the body. Results: Remission maintained in CRT+TMS in 93.3±4.6 patients vs. 40+9.1% in the control, 2-year survival increased by 2.4 times. Rate and severity of toxic complications, especially neurological ones (cerebral symptoms, disturbances of speech and motor functions) reduced significantly. Dynamics of somatic status improved (0.32 vs. 0.18), as well as Karnofsky index (9.3 vs. 2.6% in the control, p<0.05). Rate of stress development decreased by 10.8 times after TMS, antistress responses prevailed. Conclusions: TMS in complex treatment for malignant brain gliomas provides protective effect on homeostatic regulation systems, increases body resistance, optimizes rehabilitation and improves quality of life of patients.
Dapsone‐ and nitroso dapsone‐specific activation of T cells from hypersensitive patients expressing the risk allele HLA‐B*13:01
Authors: Qing Zhao, Khetam Alhilali, Abdulaziz Alzahrani, Mubarak Almutairi, Juwaria Amjad, Hong Liu, Yonghu Sun, Lele Sun, Huimin Zhang, Xiaoli Meng, Andrew Gibson, Monday O. Ogese, B. Kevin Park, Jianjun Liu, David A. Ostrov, Furen Zhang, Dean J. Naisbitt
Journal: Allergy (2019)

Abstract Background Research into drug hypersensitivity associated with the expression of specific HLA alleles has focussed on the interaction between parent drug and the HLA with no attention given to reactive metabolites. For this reason, we have studied HLA‐B*13:01‐linked dapsone hypersensitivity to (a) explore whether the parent drug and/or nitroso metabolite activate T cells and (b) determine whether HLA‐B*13:01 is involved in the response. Methods Peripheral blood mononuclear cells (PBMC) from six patients were cultured with dapsone and nitroso dapsone, and proliferative responses and IFN‐γ release were measured. Dapsone‐ and nitroso dapsone‐specific T‐cell clones were generated and phenotype, function, HLA allele restriction, and cross‐reactivity assessed. Dapsone intermediates were characterized by mass spectrometry. Results Peripheral blood mononuclear cells from six patients and cloned T cells proliferated and secreted Th1/2/22 cytokines when stimulated with dapsone (clones: n = 395; 80% CD4 + CXCR3 hi CCR4 hi , 20% CD8+CXCR3 hi CCR4 hi CCR6 hi CCR9 hi CCR10 hi ) and nitroso dapsone (clones: n = 399; 78% CD4+, 22% CD8 + with same chemokine receptor profile). CD4 + and CD8 + clones were HLA class II and class I restricted, respectively, and displayed three patterns of reactivity: compound specific, weakly cross‐reactive, and strongly cross‐reactive. Nitroso dapsone formed dimers in culture and was reduced to dapsone, providing a rationale for the cross‐reactivity. T‐cell responses to nitroso dapsone were dependent on the formation of a cysteine‐modified protein adduct, while dapsone interacted in a labile manner with antigen‐presenting cells. CD8 + clones displayed an HLA‐B*13:01‐restricted pattern of activation. Conclusion These studies describe the phenotype and function of dapsone‐ and nitroso dapsone‐responsive CD4 + and CD8 + T cells from hypersensitive patients. Discovery of HLA‐B*13:01‐restricted CD8 + T‐cell responses indicates that drugs and their reactive metabolites participate in HLA allele‐linked forms of hypersensitivity.
Contralateral prophylactic mastectomy (CPM) use and utility in New Zealand (NZ) breast cancer patients.
Authors: Abbey Jebb, Ian Campbell, Rachel Shirley, Mark Barrios, David James Porter
Journal: Journal of Clinical Oncology (2015)

e17671 Background: CPM use is increasing internationally, despite uncertain evidence of survival benefit in sporadic cancers, and with falling contralateral breast cancer (CBC) rates. CPM use in NZ is currently undescribed. Methods: Information for all patients with invasive unilateral breast cancer (UBC) diagnosed between June 2000 and December 2012 was provided by NZ cancer registers. Patients having a mastectomy of the healthy contralateral breast concurrently or within a year of definitive surgery for UBC were classed as having had a CPM. Patient and cancer characteristics were compared using Fisher’s exact test, and survival outcomes determined by log rank test. Results: 244 of 10,374 patients with UBC underwent CPM. CPM use increased over time, from 2 patients (0.6%) in 2000 to 46 patients (4.9%) in 2010. Compared with women not having surgical prophylaxis, CPM patients were significantly younger at diagnosis (mean 51.2 years, cf. 57.8 years), and more often European (80.7%, cf. 68.7%) or Maori (10.7%, cf. 8.8%). 44.4% had family history of breast or ovarian cancer affecting a first degree relative (cf. 19.1%), and 58.1% had a relative of any degree affected (cf. 29.4%). 4.5% having CPM were BRCA mutation positive (cf. 0.4%). CPM was more commonly performed in patients with multifocal cancer (68.9%, cf. 18%), lobular carcinoma (18.6%, cf. 11%), and tumours of higher pathological T stage (T3 or T4 cancer in 9.8%, cf. 6.8% in T1 or T2). Groups were similar regarding nodal status (node positive 37.7%, cf. 36.8%), tumour grade (grade 3 33.3%, cf. 28.7%) and receptor status (ER positive 78.2%, cf. 80.2%; and HER2 expression positive 18.1%, cf. 16.1%). The use of endocrine therapy did not significantly differ between groups (55.6% cf. 60.6%). With median follow-up of 4.6 years, CPM use did not significantly change survival outcomes (overall survival HR 0.94, p = 0.74; breast cancer specific survival HR 1.25, p = 0.32) or incidence of metastases (12.4% cf. 12.0%, p = 0.85). 48 patients without CPM (0.5%) developed CBC, whereas 1234 developed metastases (ratio 26:1). Conclusions: CPM use is increasing in NZ despite a very low incidence of CBC. CPM has not improved patient survival or reduced the risk of developing metastatic disease.