tbuckley/cabot-search huggingface dataset:
Two-arc volumetric modulated arc therapy to provide dosimetric advantages for pancreas stereotactic body radiotherapy.
Authors: Jason K Molitoris, Christopher Brown, Shifeng Chen, Kimberly Marter, Kristin Spaeth, William Regine, Michael David Chuong
Journal: Journal of Clinical Oncology (2016)

445 Background: Stereotactic body radiation therapy(SBRT) is increasingly used in locally advanced pancreatic cancer (LAPC). SBRT can be delivered using 3D conformal, static intensity modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT) techniques. Prior data suggest advantages of using VMAT over IMRT for single-fraction pancreas SBRT. We performed the first dosimetric comparison of IMRT with one and two arc VMAT for 5-fraction pancreas SBRT, a more commonly used regimen. Methods: We generated 5-fraction SBRT plans for 12 LAPC patients who were previously treated at our institution with standard fractionation. The prescription dose was 33 Gy delivered in 6.6 Gy fractions. Assuming breath hold, 3 plans were generated for each patient: 9-beam static IMRT, 1-arc VMAT (VMAT1), and 2-arc VMAT (VMAT2) targeting the primary tumor. Target coverage and normal tissue doses were compared between the delivery techniques. Results: Each plan met target coverage planning goals. More VMAT2 plans (100%) were able to meet all normal tissue constraints than VMAT1 (83.3%) or IMRT (75%). Duodenal dose was most lowest for VMAT2 compared to VMAT1 and IMRT for mean dose (8.66 vs. 9.00 vs. 8.99 Gy); D4% (25.9 vs. 26.6 vs. 26.3 Gy); V10Gy (38.02 vs. 39.33 vs. 40.11%), V15Gy (23.98 vs. 25.88 vs. 25.97%), V20Gy (12.73 vs. 13.84 vs. 14.95%), and V25Gy (5.96 vs. 6.85 vs. 6.78%)(all p &lt; 0.05). The tumors closest to the duodenum had statistically significantly improved V30Gy for VMAT2 compared to VMAT1 and IMRT (both p &lt; 0.001). VMAT1 and VMAT2 reduced dose to the stomach, spinal cord, and liver compared to IMRT; kidney dose, however, was lowest using IMRT. VMAT2 plans had the highest conformity, but required the most monitor units to deliver. Delivery time was significantly longer with IMRT, compared to VMAT1 and VMAT2 (8.25 vs. 2.16 vs. 3.33 mins). Conclusions: These data suggest that VMAT2 should be strongly considered for 5-fraction pancreas SBRT because of superior normal tissue sparing, more conformal target volume coverage, and faster treatment delivery time (compared to IMRT). Further evaluation is needed to clarify whether the dosimetric advantages of VMAT2 are clinically significant.
Clinical effectiveness of adjuvant chemotherapy (AC) with or without oxaliplatin following neoadjuvant chemoradiotherapy (nCRT) in stage II rectal cancer (RC).
Authors: Jonathan M. Loree, Hagen F. Kennecke, Erin Diana Powell, Rachel Anne Goodwin, Patricia A. Tang, Daniel Yick Chin Heng, Julie A. Price Hiller, Jose Gerard Monzon, Michael M. Vickers, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2016)

686 Background: Use of AC in RC following nCRT is controversial because of concerns regarding its potentially small magnitude of benefit. We aimed to 1) examine real-world patterns of AC use in stage II RC and assess its impact on outcomes and 2) determine whether the addition of oxaliplatin to fluoropyrimidines modifies effectiveness. Methods: Using a cohort of yp stage II RC patients from 5 Canadian centers that underwent curative surgery, we assessed the relationship between AC +/- oxaliplatin and overall (OS) and disease free survival (DFS). Cox models adjusting for age, gender, ECOG, and high risk features (T4 lesion, poor differentiation, inadequate lymph node sampling, lymphovascular/perineural invasion, and obstruction/perforation) were constructed. Results: Among 485 pts, 74% received AC of whom 19% received oxaliplatin-based treatment. Median follow up was 4.5 yrs. Pts in the AC group were younger (median age 61 vs 64; P= 0.003) and had higher rates of TME (82% vs 79%; P= 0.049), but they had similar demographics, ECOG, high risk features, preoperative CEA, margin status and nCRT regimen when compared to pts in the non-AC group (all P&gt; 0.05). Multivariate analyses demonstrated that receipt of any AC (OS HR 0.93 95% CI 0.58-1.50 P =0.77; DFS HR 0.91 95% CI 0.58-1.43 P =0.69), fluoropyrimidine AC (OS HR 0.82 95% CI 0.49-1.36 P =0.44; DFS HR 0.83 95% CI 0.51-1.34 P =0.44), or oxaliplatin-based AC (OS HR 1.37 95% CI 0.74-2.55 P =0.32; DFS HR 1.17 95% CI 0.66-2.05 P =0.59) did not improve outcomes versus no AC. In subgroup analyses that stratified pts by high risk features, presence of 1, 2, or 3 high risk factors, preoperative CEA and margin status, AC did not result in better OS or DFS in any subgroup. A further exploratory analysis that focused only on those receiving AC within 12 weeks of surgery did not reveal any consistent correlations between AC and survival. Conclusions: Use of fluoropyrimidine or oxaliplatin-based AC in this multi-institutional cohort of yp stage II RC pts after nCRT did not improve outcomes compared to observation. Conventional high risk features used to risk stratify stage II colon cancer for AC decision making have limited utility in RC after nCRT.
Exome sequencing of extreme phenotypes to identify variants predictive of response to chemotherapy in bladder cancer.
Authors: Shaheen Alanee, Sohela Shah, Kelly Lynn Stratton, Ilana Rebecca Garcia-Grossman, Emily Zabor, Irina Ostrovnaya, Vijai Joseph, Deepa Pendse, Dean F. Bajorin, Kenneth Offit
Journal: Journal of Clinical Oncology (2013)

300 Background: Little is known about germline variants predictive of response to chemotherapy in bladder cancer (BC). We investigated germline variants in patients (pts) treated with neoadjuvant gemcitabine/cisplatin (GC) under the hypothesis that responders and non-responders may differ in rare alleles predictive of treatment outcome. Methods: The Hiseq platform (≥ 20x coverage) was used to sequence the exomes of muscle-invasive (≥cT2) BC pts representing “extreme phenotypes” defined by response to neoadjuvant GC (complete responders vs. non responders). Responders were pT0N0 at cystectomy and remained disease free &gt;1 year. Non-responders had residual disease in the bladder at cystectomy and metastatic disease either at cystectomy or within 1 year. Rare, potentially deleterious single nucleotide variants (SNVs) unique to these phenotypes were confirmed with Sequenom and validated in an independent group of BC pts treated with GC in the neoadjuvant or first line setting. One-sided Fisher’s exact test and multivariate logistic regression were used to estimate association between SNVs and response. Results: The discovery cohort had 6 responders (4 male) with a mean age of 62 and 9 non-responders (6 male) with a mean age of 63. Filtered exome sequences identified 93 rare/potentially deleterious SNVs unique to non-responders and 45 unique to responders of which 84 and 35 were confirmed by Sequenom, respectively. The independent validation cohort consisted of 173 pts, mean age 60, 72% male, and 53% responders (complete or partial). Among 119 SNVs genotyped in this cohort, only 3 responder and 9 non-responder SNVs were identified in ≥ 3 pts. None of the responder SNVs were associated with response. One non-responder SNV (rs150721903) was significantly associated with resistance to GC (OR: 9.7, 90% CI: 1.7-56.8, p=0.011), and remained significant after adjusting for risk score (p= 0.017). rs150721903 is a missense variant in an uncharacterized protein on chromosome 8. Conclusions: Exome sequencing of extreme phenotypes identified a variant that predicts resistance to GC, demonstrating the feasibility of this pharmacogenomics approach. Further evaluation of this SNV is warranted.
ImmTAC-gp100: A novel, targeted therapy for malignant melanoma.
Authors: B. K. Jakobsen
Journal: Journal of Clinical Oncology (2010)

e19036 Background: The human immune system can theoretically identify malignant cells by ‘scanning' peptide antigens presented on the cell surface by Class I HLA molecules. Indeed, many cancer patients will generate CD8 cyto-toxic T cell responses to tumour- specific antigens. However, the majority of patients fail to clear tumours, since T cell avidity for self-antigens tends to be weak, and cancer cells employ escape mechanisms for avoiding destruction by T cells. We report here the engineering of novel, bi-functional protein therapeutics termed ImmTACs (Immune Mobilising mTCR Against Cancer) which redirect the immune system to target and destroy tumour cells with a high degree of potency and specificity. In particular, we describe ImmTAC-gp100, specific for the tumour-associated melanoma peptide antigen gp100280-288 presented in the context of HLA-A2, an allele found in approximately 50% of the Caucasian population. Methods: ImmTAC-gp100 is a bifunctional molecule, comprising a soluble, high affinity ‘monoclonal' T cell Receptor (mTCR) specific for gp100, fused to an anti-CD3 scFv domain. The anti-CD3 moiety activates a polyclonal T cell response when targeted to melanoma cells expressing the gp100 antigen, largely through activation of effector memory CD8 lymphocytes, which can be measured by cytokine release and cell killing assays. Results: We demonstrate that ImmTAC-gp100 can target and kill melanoma cells expressing as few as 10-20 epitopes per cell with pico-Molar potency, and that the agent is able to inhibit tumour growth in mouse xenograft models. ImmTAC-gp100 is specific for cells expressing the gp100 antigen, and does not activate T cells unless both TCR and anti-CD3 portions of the molecule are simultaneously bound to target, ensuring that it will give rise to minimal toxicity in the clinic. The in vitro potency translates to a dose of less than 1mg in humans. Currently we are completing preclinical activities prior to initiating a phase I dose-escalation trial in late stage melanoma patients in the last quarter of 2010. Conclusions: ImmTAC-gp100 offers a novel therapeutic approach to the treatment of melanoma with the potential to provide major benefits over current treatments including quantity per dose and an improved safety profile. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Immunocore Ltd. Adaptimmune Ltd. Adaptimmune Ltd.
Tumor infiltrating lymphocytes (TILs) and the expression of programmed death ligand 1 (PD-L1) as predictors for the response rate of preoperative systemic therapy (PST) and prognosis in triple-negative breast cancer (TNBC).
Authors: Nobumoto Tomioka, Manabu Azuma, Kanako Hagio, Mayuko Ikarashi, Masako Satoh, Mitsugu Yamamoto, Ken-ichi Watanabe, Katsushige Yamashiro, Masato Takahashi
Journal: Journal of Clinical Oncology (2015)

157 Background: The status of tumor infiltrating lymphocytes (TILs) is known to be prognostic for triple negative breast cancer (TNBC) due to its correlation with chemosensitivity. Moreover, to regulate the pathway of immune-checkpoint molecules is also expected to improve the prognosis of TNBC. The relevancy of these two factors could be attractive concerning on the immune interaction which might play an important role in the prognosis of TNBC. Methods: Patients with TNBC are 277 among 2371 who were underwent surgery between January 2002 and December 2011. Out of 90 patients received preoperative systemic therapy (PST), 32 patients’ specimens of core needle biopsy were available for review for TILs. The TILs was scored as “% stromal” by pathologist who feels comfortable with through the scan for single whole section according to the recommendations by an International TILs Working Group 2014. The expression of programmed death ligand 1 (PD-L1) was assessed by immunohistochemistry, which was defined 3 stages as negative or positive (weak or strong) by the pathologist in our facility. The statistical analysis for variance was done by Mann-Whitney U-test or Kruskal-Wallis test, and for survival by Kaplan Meier method was evaluated by Logrank test. Results: TILs’ score was defined as follows (%; numbers of patients): (5; 2), (10; 8), (20; 9), (30; 7), (40; 1), (50; 1), (60; 1), (70; 2), (80; 0), (90; 1). Statistical validations for variance of TILs’ score were significant on the regression rate of tumor size: (T-pT)/T; &lt; 2/3 v.s. 2/3 &lt; (p= 0.0097), and pathological therapeutic grade: 1 vs 2 or 3 (p= 0.0285). When we set the threshold at 30% of TILs’ score, DFS with TILs’ score &lt; 30% was worse significantly (p= 0.0383) but not on OS (p= 0.0772). Unfavorable group on DFS (TILs’ score &lt; 30%) was divided again into two groups by the status of PD-L1 significantly (negative or weak v.s. strong; p= 0.0319). Conclusions: The status of TILs and PD-L1 could elucidate the candidate for the therapeutic approaches to immune-checkpoint molecules, which could make improvement of the prognosis of TNBC.
Comparison of PSA slope and nadir between hypofractionated SBRT and conventionally fractionated EBRT.
Authors: Mekhail Anwar, Vivian K. Weinberg, Albert Chang, I-Chow Joe Hsu, Mack Roach, Alexander Gottschalk
Journal: Journal of Clinical Oncology (2013)

112 Background: Patients with early stage prostate cancer have a challenge in selecting from a variety of curative radiotherapy options, including external beam radiotherapy (EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Rapid post-treatment PSA decline and low PSA nadir have been associated with improved clinical outcomes. The purpose of this study was to compare the PSA measurements over time between conventionally fractionated EBRT and SBRT in newly diagnosed localized prostate cancer. Methods: 104 patients with low to low-intermediate risk prostate cancer (GS 3+3, PSA &lt; 20 or 3+4, PSA &lt; 15) treated with standard fractionated EBRT (&gt; 70.2 Gy, &lt; 76 Gy) without hormones to the prostate only were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997-2012). Patients were excluded if they failed therapy by the Phoenix definition. All included patients had at least 1 year of follow up and 3 serial PSAs. 35 patients that were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. Of these, 47 and 19 patients treated with EBRT and SBRT, respectively, had a yearly increase in PSA follow-up over 3 years. PSA nadir and rate of change in PSA over time (e.g. slope) were calculated from the completion of RT to 1, 2 and 3 years post RT. Results: The median PSA nadir and slope for patients treated with EBRT was 0.80, 0.50, 0.40 ng and ‑0.07, ‑0.02, ‑0.01 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadir and slope were 0.73, 0.50, 0.24 ng and ‑0.09, ‑0.06, ‑0.05 ng/ml/month. The PSA slope for SBRT was greater than EBRT (p = 0.001) at 2 and 3 years following RT, although similar during the first year. These results were consistent when limited to patients with more complete PSA follow-up each year, with PSA nadir significantly lower 3 years after treatment with SBRT compared with EBRT (p = 0.03). Conclusions: Patients treated with SBRT experienced a more rapid decline in PSA 2 and 3 years following completion of RT than with EBRT, and for those with continuous long term followup, a lower PSA nadir, consistent with delivery of a higher bioequivalent dose.
Patient involvement in multidisciplinary treatment planning (MTP).
Authors: Irene Prabhu Das, Heather Rozjabek, Mary L. Fennell, Katherine Mallin, E. Greer Gay, Kathleen M. Castro, Andrew K. Stewart, Steven Clauser
Journal: Journal of Clinical Oncology (2013)

145 Background: Patient involvement in treatment decision-making has been well-studied. However, little is known about how patients are involved in the MTP process prior to their consideration of treatment options. Methods: An online survey was administered to 1,261 Commission on Cancer (CoC)-accredited programs to describe current MTP practice. Survey items addressed team structure and process, case presentation, and patient involvement. A total of 797 (63%) facilities responded. Multiple aspects of patient involvement focusing on the initial case presentation and post-meeting follow-up regarding information provision and communication are examined. Initial descriptive analyses are presented. Results: 97% of facilities reported patients are not invited to attend MTP meetings. Reasons for not inviting patients included: patients may find it overwhelming (62%), physicians not able to speak freely (58%), liability (43%) and privacy (42%) concerns. Of the facilities that do invite patients, 1/3 reported that patients often or always attend. Treatment recommendations from MTP meetings are shared with patients at 75% of facilities, 42% share treatment plans, and 28% give a meeting summary to patients. Nine percent of facilities do not give patients any information from the meeting. Prior to treatment, a written treatment plan is developed at 43% of facilities, and among these, 15% give the plan to patients. Regarding communication about MTP meetings, facilities reported pre-meeting discussions with attending physicians (95%) and patient navigators (21%). Post-meeting follow-up by 93% of facilities is usually done by physicians, 26% by patient navigators and 16% by PA/NPs, and 66% follow-up within 1 week. Conclusions: Initial findings suggest that even if facilities do not invite patients to MTP meetings, they engage patients in various ways at pre- and post-MTP meetings, providing information and having discussions. Physicians are integral in communicating with patients throughout the MTP process. Further study on the multiple facets of patient involvement in MTP is needed to better understand its influence on treatment decision-making.
Evaluation of circulating-tumor DNA (ctDNA) as a source material for molecular phenotyping of colorectal tumors.
Authors: Petra Minarikova, Lucie Benesova, Barbora Belsanova, Tereza Halkova, Jiri Cyrany, Jan Bures, Stepan Suchanek, Miroslav Zavoral, Marek Minarik
Journal: Journal of Clinical Oncology (2015)

642 Background: Patients with advanced stages of colorectal cancer have elevated levels of circulating-tumor DNA (ctDNA) in peripheral blood. Its presence can facilitate acquisition of DNA material for tumor molecular profiling without the invasive procedures. In this work we present utility of ctDNA for the determination of tumor phenotype within the basic division into the mutator phenotype (microsatellite instability, MSI and chromosomal instability, CIN) or methylator phenotype (CpG island methylator phenotype, CIMP). Methods: Tumor biopsy tissue and 5mL of peripheral blood samples were prospectively collected from 148 patients with colorectal tumors. In addition, plasma was extracted from peripheral blood immediately upon collection. Samples were then transported to the molecular laboratory where DNA and ctDNA were isolated from tissue and plasma, by a modified spin-column ctDNA extraction. Somatic mutations in tumor suppressors denoting CIN phenotype were detected by denaturing capillary electrophoresis (DCE), microsatellite instability was detected by MSI Analysis System, Version 1.2 (Promega corporation, Madison, WI) and DNA methylation (CIMP phenotype) was obtained by multiplex ligation-dependent probe amplification (MRC Holland, NL). Results: The samples included 75 adenomas and 70 carcinomas. The detected rates in tissues were: 4% for MSI, 32% for CIN and 7% for CIMP in adenomas and 10% for MSI, 36% for CIN and 32% for CIMP in carcinomas. In adenomas, none of the detected molecular types could be confirmed in ctDNA. In carcinomas, the concordance between tissue and ctDNA was 25% for MSI, 23% for CIN and 60% for CIMP. The success rates were related to the ctDNA concentration yields with a minimum requirement of ~0.2ng/uL. Conclusions: ctDNA may serve as alternative source for molecular classification of colorectal tumors (MSI, CIN and CIMP). A low concordance between tissue and ctDNA was found for CIN and MSI in comparison to 60% of CIMP-phenotypes found in both tissue as well as ctDNA. The results are predominantly dictated by disease stage and the corresponding levels of ctDNA. Supported by a Czech Ministry of health grant no. 14383.
Back pain, the usefulness (or not!) of clinical tests and your invitation to Langkawi, Malaysia in October
Authors: Gavan White
Journal: British Journal of Sports Medicine (2017)

As I work on this Sports Doctors Australia issue of BJSM , my home city of Perth is sundrenched as in the postcards and the Qantas advertisements. The Australian Open Tennis tournament is dominating television coverage. Amid the amazing cohort of athletes I note that many have had back problems—a topic we focus on in this issue.

Back pain and management of this is an area with varied opinions. It seems that almost every healthcare practitioner has her/his favourite or preferred methods for assessment and treatment. The management of acute back injury has a lot of research that shows little difference in benefit from a range of treatments. We are slowly, but definitely, getting high- quality research that guides us.

Unfortunately, the preferences of practitioners can be slow …
Prognostic significance of regional lymph nodes status in stage IV colorectal cancer.
Authors: Shahid Ahmed, Anne Leis, Selliah Kanthan, Anthony L.A. Fields, Bruce Reeder, Adnan Zaidi, Kamal Haider, Tahir Abbas, Nayyer Iqbal, Punam Pahwa
Journal: Journal of Clinical Oncology (2016)

721 Background: Lymph node involvement is one of the most important prognostic variables in early stage CRC and an indication for adjuvant therapy. However, the prognostic significance of regional nodal metastases and the ratio of metastatic to examined lymph nodes (LNR), in stage IV CRC remain unknown. The current study aims to determine prognostic importance of nodal status and LNR in patients with stage IV CRC who undergo primary tumor resection (PTR). Methods: Retrospective cohort study involving patients with synchronous metastatic CRC diagnosed in Saskatchewan, during 1992-2010 and underwent PTR. Cox Proportional multivariate analyses were performed to determine prognostic significance of nodal status and LNR. Results: 2,294 patients were diagnosed with synchronous metastatic CRC during the study period. Of those 1257 underwent PTR, 148 patients did not have information about nodal status and were excluded. Median age of 1109 eligible patients was 70 yrs (22-98) and M:F was 1.2:1. 26% patients had rectal cancer, 96% had T3/T4 tumor, and 82% had node positive disease. The median LNR was 0.36 (0-1.0). 54% received chemotherapy. Median overall survival of patients who had LNR of ≥ 0.36 and received chemotherapy was 29.7 months (95% CI: 26.6-32.9) compared with 15.6 months (13.6-17.6) with LNR of &lt; 0.36 [p &lt; 0.001]. On multivariate analyses, among prognostic variables use of any chemotherapy, HR: 2.36 (2.0-2.79); metastasectomy, HR: 1.95 (1.63-2.32); nodal status, HR 1.34 (1.14-1.59); LNR ≥0.36, HR: 1.59 (1.38-1.84); and T status, 1.23 (1.07-1.40) were correlated with survival. Test for interaction was positive for LNR and high grade cancer, HR: 1.17 (1.031-1.33). In a sub-cohort of patients who underwent metastasectomy both LNR using a cut-off of 0.36 and nodal status, independent of chemotherapy and other prognostic variables were correlated with survival, HR of 2.38 (95%: 1.64-3.47) for LNR ≥ 36 and 1.57 (95% CI: 1.05-2.34) for node positive disease. Conclusions: Our results suggest that regional nodal status and LNR are important prognostic factor independent of chemotherapy in stage IV CRC patients undergoing PTR. Future studies are required to elucidate the mechanism by which nodal status affect survival in stage IV CRC.