tbuckley/cabot-search huggingface dataset:
Smoking and the risk of anal cancer recurrence: The Addenbrookes Hospital experience.
Authors: Anna Bowzyk Al-Naeeb, Gill Barnett, Charles Wilson
Journal: Journal of Clinical Oncology (2014)

439 Background: Anal cancer, a tumour induced by the human papilloma virus (HPV) is highly responsive to chemoradiation. Smoking appears to be an important cofactor in its development, possibly through immunomodulatory mechanism and has been reported to have a negative effect on prognosis. Objective is to evaluate the relation between smoking and the outcome in patients receiving radical chemoradiotherapy (50.4 Gy/ 28f with concomitant 5FU/Mitomycin) for squamous carcinoma of the anus. Methods: 109 patients treated with radical intent from January 2009- Feb 2013 were retrospectively analysed. Details of staging, smoking history, HIV status, response to treatment, follow up time and recording of persistent or recurrence were collected. High risk disease (HR) was defined as any T3/T4 disease or TxN2+, standard risk (SR) as T1/2 N0-1. Results: 68 females and 41 males with an age range 38-83 (median 61).Data about smoking status was available in 74 patients: 28 smokers, 8 ex-smokers, and 38 non-smokers. 54/109 (49%) had high risk disease (HR), and the distribution was balanced across the groups. 4 patients were HIV positive. Median follow up time was 23 months. Complete clinical response was achieved in 101/109 (93%), 1 patient died (cause unknown), and 7 had persistent disease. Of these 6 were smokers (2 SR, 3HR, 1 HR and HIV+) 1 was a non-smoker (1 HR). 9 patients developed recurrent disease: 5 smokers (2 SR, 3 HR), 1 ex-smoker (HR), 3 unknown (2HR, 1SR). 11/16 patients who had a local failure were persistent smokers. Using ordinal logistic regression, smoking increases the risk of recurrence with an Odds ratio of 17.4 (p=0.008). Conclusions: This retrospective series suggest that smoking is associated with a higher risk of local recurrence following chemoradiotherapy. One of the hypothesis is that tissue hypoxia may impact on the oxygen dependent effect of chemoradiation. Patients should be encouraged to stop smoking and smoking may need to be considered as a factor defining a higher risk category which may benefit from dose escalation.
Improving provider adherence to evidence-based supportive care practices for patients with myeloma.
Authors: Carrie Tompkins Stricker, Beth Faiman, Diana Harris, Nicole Rozario
Journal: Journal of Clinical Oncology (2016)

218 Background: Rapidly emerging therapeutics for multiple myeloma (MM) have diverse and sometimes life-threatening toxicities, underscoring the need for proactive screening, assessment, and management to mitigate symptoms and adverse events [AEs] (i.e., “supportive care (SC) practices”). Little is known about the real-world systematic use of such strategies in routine MM clinical care. A 3 center pilot study aims to describe documented adherence to evidence-based SC practices, and then intervene with a novel ePRO and supportive care planning system (CPS) technology designed to improve adherence. Methods: 90 patients and 90 controls with MM from 3 sites are being evaluated in this pilot study. A scorecard to measure provider use of evidence-based SC practices, at the patient level, was developed by an interdisciplinary team, using an iterative process of literature review and a modified Delphi technique to gain metric consensus. The scorecard is applied to medical records of intervention subjects and controls over an 8-12 week period. Results: Scorecards have been completed to date for 20 historical controls &amp; 7 intervention subjects; remaining to be complete by meeting. For controls, screening for specific symptoms was fairly consistent, but documentation of detailed assessments (e.g., severity, functional impact) and management strategies was poor. For intervention subjects to date, screening almost always was documented, and both detailed assessment and intervention was better than for controls in most cases. See table. Conclusions: For controls, providers regularly documented symptom/AE screening, yet detailed assessments and evidence of interventions were inconsistently documented. Barriers may include the limited availability of effective interventions for symptoms such as CIPN &amp; fatigue, as well as time barriers to effective symptom assessment and management, and its documentation. Almost all metrics were better in intervention subjects to date. Although documentation may not reflect actual practice, improvement in detailed assessment and management strategies is likely needed, and a novel CPS technology may improve this state of affairs; evaluation ongoing. [Table: see text]
The interval to biochemical failure versus biochemical failure as predictors for cause specific and overall survival following dose-escalated external beam radiation therapy for prostate cancer.
Authors: N. S. Kapadia, F. Y. Feng, K. B. Olson, H. M. Sandler, D. A. Hamstra
Journal: Journal of Clinical Oncology (2011)

4585 Background: Prostate cancer (PCa) recurrence can be identified by biochemcial failure (BF) many years prior to clinical recurrence. A short IBF (<18 months) has been proposed as a surrogate for cause specific survival (CSS). Since dose-escalated RT influences both the rate and timing of BF we sought to validate the association between short IBF and both CSS and overall survival (OS). Methods: From 1998-2008, 718 patients (median age 69.3 (IQR: 63-74) were treated with definitive external beam radiation therapy (RT) with or without androgen deprivation therapy (ADT) at the University of Michigan (minimum dose 75 Gy, median follow-up 64 months). BF was defined by the Phoenix definition (nadir +2 ng/ml). Log-rank and Cox-proportional hazard regressions were used to assess the association of BF, the IBF, and other clinical factors with CSS and OS. Results: There were 149 BFs (21%), and no low-risk patients had a short IBF while for intermediate- and high-risk disease it accounted for 14% and 40% of all BFs, respectively. BF had no significant impact on OS (p=0.36) even in patients with NCCN high-risk disease (p=0.8). However, in those with recurrence a short IBF predicted decreased CSS (p<0.0001 HR: 5.6 [2.4-13.0]) and OS (p<0.0001, HR: 4.8 [2.3-10.3]). Further, the 10-year rate of OS was 74% in those without BF, compared to 77% in those with a long IBF (p=0.1, HR: 0.7 [0.4-1.1]) and only 33% in those with a short IBF (p<0.0001, HR: 3.7 [2.3-5.9]). On multivariate analysis, after accounting for age, co-morbid illness, PSA, T-stage, Gleason score, and the use of ADT, a short IBF increased the risk of prostate cancer death (p<0.0001, HR: 18.1 [8.4-39]) and all cause mortality (p=0.0027, HR: 1.5 [1.2-2.1]) while late BF did not. Conclusions: We validated the relationship between the IBF and CSS in patients treated with dose-escalated RT. The IBF is associated with OS while BF by itself is not. Prompt salvage therapy should be considered for all patients with a short IBF while those with a long IBF might be appropriately managed with a more conservative approach. Further evaluation of the IBF as a surrogate end-point for clinical trials is warranted.
Changes in breast tumour receptor status with time: A prospective study assessing the impact of obtaining confirmatory biopsy at metastatic recurrence on patient management
Authors: C. Simmons, N. Miller, W. Geddie, D. Gianfelice, M. Oldfield, M. Clemons
Journal: Journal of Clinical Oncology (2008)

1052 Background: Metastatic recurrence of breast cancer is usually diagnosed by a combination of clinical and radiological assessments. Decisions about systemic treatment are often based on receptor expression in the primary tumour. Retrospective studies evaluating pts who have undergone a biopsy of metastatic lesions (ML) suggest that ER/PR/Her2 status may differ between the primary and ML in up to 1/3 of cases. This finding has not been validated prospectively. Objectives: To measure prospectively ER/PR/Her2 discordance between primary tumour and ML in breast cancer pts presenting with a suspected new metastatic recurrence. Secondary objectives were to measure the impact of any discordance on pt management, assess pt acceptability and feasibility of obtaining a confirmatory biopsy. Methods: Eligible pts were identified at the time of first clinical/radiological suspicion of metastatic recurrence. Biopsies of MLs were obtained and samples were analysed for disease confirmation and determination of ER/PR by IHC and Her2 by FISH. The pts oncologist was surveyed pre- and post-biopsy to determine if the biopsy results impacted treatment plan. Pts completed questionnaires to determine acceptability of the biopsy procedure. Results: 30 pts underwent successful biopsy of MLs. Sites of biopsy were: bone 11, soft tissue 10, liver 3, pleural effusion 4, lung 1, CSF 1. Despite high clinical suspicion of metastases, 3/30 pts (10%) had benign disease on biopsy. In another pt the biopsy demonstrated low-grade lymphoma. Of the 26 patients with matched primary and ML, 38% had a change in hormone receptor status, and 8% had a change in Her2neu status (2/26 becoming Her2 positive). Biopsy results led directly to a significant change of management in 20% of pts, (6/30, P = 0.002). The biopsy procedure was acceptable for most pts. Conclusions: This study demonstrates prospectively the presence of a significant discordance rate between primary and MLs that is of sufficient magnitude to alter pt management in 20% of cases. The impact of biopsy results for the pts with benign findings cannot be overstated. Tissue confirmation should be considered standard of care in pts with clinical/radiological suspicion of metastatic recurrence. No significant financial relationships to disclose.
Is there a standard of care for intermediate and advanced stages of cutaneous T-cell lymphoma mycosis fungoides (CTCL-MF)?
Authors: R. P. Stephan, L. Dao, J. Heybroek
Journal: Journal of Clinical Oncology (2011)

e18537 Background: Patients with CTCL-MF are treated with a variety of approaches by varying clinical specialists. None of the current approaches is curative. This study was conducted to understand the most common treatment practices for later stages of CTCL-MF in the United States. Methods: An internet-based treatment panel of 50 oncologists and dermatologists provided over 1100 independent decisions from all disease stages. Those decisions for intermediate (stage IIb) and advanced (stages III / IVa and IVb) were used to determine the representative treatment practices in the US. Results: Treatment decisions reported here were for predominantly Caucasian and male patients (60 to ≥80% for each characteristic). Systemic drug therapy, either a single drug alone or combined with another drug, was used as the primary treatment modality for most with advanced CTCL-MF. While it also was the most common selection for intermediate disease, the variety of selections indicates the difficult nature of treating this stage of MF (Table). For stage III/IVa disease, denileukin diftitox was by far the most common drug used (59%). While denileukin diftitox was also the most common choice for stage IVb, it was only used in 22% of the cases; CHOP (20%) and vorinostat (17%) were used almost as often. This heterogeneity is indicative of the refractive nature of stage IVb CTCL-MF. Conclusions: While systemic drug therapy is the preferential selection, there is still great heterogeneity in the selection of modality as well as the specific therapeutic(s) used. Taken together, these results suggest that a specific standard of care has not been identified for advanced CTCL-MF. Additional efforts aimed at identifying new efficacious therapies for advanced CTCL are needed. However, lack of a current treatment standard is an impediment to selection of the appropriate control arm in clinical trials. Treatment modality usage in CTCL-MF by disease stage. Stage IIb (n=104) Stage III/IVa n=192) Stage IVb (n=56) Systemic drug therapy 25% 72% 63% Localized XRT 20% 0% 0% Phototherapy 13% 2% 0% Skin-directed + systemic drugs 13% 6% 7% Localized (topical) drug 10% 0% 0% Multiple systemic drugs 0% 6% 18% Photopheresis 2% 11% 5%
The basal phenotype as a clinically relevant indicator of trastuzumab resistance in HER2+ breast cancer.
Authors: Michael Phillip Choi, Alice P. Chung, Shikha Bose, Bingchen Han, Ying Qu, Xiao Zhang, Xiaojiang Cui, Armando E. Giuliano
Journal: Journal of Clinical Oncology (2014)

154 Background: Trastuzumab (Herceptin) resistance remains a clinical challenge but the mechanism is not well understood. Recently, studies have identified a subset of Her2+ breast cancer called basal HER2 that expresses basal genes. We investigated the effect of basal gene expression on Herceptin response in HER2+ breast cancer cell lines and on prognosis in HER2+ breast cancer patients. Methods: Non-basal (BT474, SKBR3) and basal (HCC1569, HCC1954, JIMT-1) HER2+ cell lines were chosen based on basal cytokeratin expression. Cell proliferation was assessed after treatment with vehicle, Herceptin (H), Paclitaxel (P), H+P, Akt Inhibitor (AI), and H+AI. HER2 signaling was examined using immunoblotting of p-Akt and p-ERK. Because breast cancer stem cells (BCSC) are linked to basal breast tumors and treatment resistance, we assessed BCSC activity using mammosphere formation and aldehyde dehydrogenase (ALDH) positivity. Immunohistochemical staining of HER2+ breast cancers for basal markers CK5/6, CK14, and EGFR was correlated with clinicopathologic features and survival in 88 patients with Stage 1-3 HER2+ breast cancer treated with Herceptin. Results: Basal HER2 cells were resistant to Herceptin compared to non-basal HER2 cells but this resistance was overcome by Akt inhibition. Immunoblotting showed that non-basal HER2 cells had decreased p-Akt after Herceptin treatment which was not seen in basal HER2 cells. There was no difference in p-ERK levels after Herceptin therapy in all cell lines. Basal HER2 cells had increased mammosphere formation and ALDH positivity suggesting higher stem cell activity compared to non-basal HER2 cells. Of the HER2+ patients, 33/88 (37.5%) expressed at least one basal marker. Basal Her2 tumors were associated with higher grade (p = 0.04) and more ER/PR negativity (p &lt; 0.01). CK14 expression correlated with worse overall survival by log-rank test (p = 0.02), while EGFR showed a similar trend (p = 0.06). Conclusions: Basal HER2 breast cancer cell lines have Herceptin resistance which may be due to constitutively active Akt signaling and increased stem cell activity. Clinically, basal marker expression predicts Herceptin resistance and worse outcomes in HER2+ breast cancer patients.
Thymidylate synthase expression in adenosquamous carcinoma of lung.
Authors: C. Shu, H. Cheng, A. Wang, M. Mansukhani, C. A. Powell, B. Halmos, A. C. Borczuk
Journal: Journal of Clinical Oncology (2011)

10563 Background: Thymidylate synthase (TS) expression is higher in squamous (SQ) cell carcinoma than in adenocarcinoma (AD) of lung. Higher TS level has been related to the poor efficacy of pemetrexed in SQ carcinoma. There is limited data on TS expression in adenosquamous (AS) carcinoma, a distinct subtype of lung cancer, containing both squamous and glandular differentiation. Methods: TS protein levels were evaluated by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded (FFPE) specimens from 163 patients, including 17 SQ, 19 AS, and 121 AD tumors by two independent investigators. Based on the cross-product of the intensity score and percentage of positive cells an H-score (range of 0-200) was generated. For the AS samples, the squamous and glandular components were also separately assessed. In order to assess whether TS expression was correlated more intra- versus inter-specimen, permutation method was used to calculate the correlation coefficients. The results were compared based on the random permutation with the actual coefficient between two components within the same specimen (rho=0.4832505) (Permutation p-value < 0.5). One way ANOVA was conducted to compare the mean values of the three groups: SQ, AS, and AD. Results: The average H-score of TS expression in AS, SQ and AD samples were 64.7%, 66.5% and 32.5% respectively (p=0.0001). Consistent with previous reports, TS expression was significantly higher in SQ than AD carcinoma. Interestingly, TS expression in AS carcinoma was near-identical to SQ carcinoma, rather than falling between AD and SQ carcinoma. In AS samples the expression of TS was more closely correlated within the two components than would be expected by random chance alone, suggestive of a tumor-specific rather than a histology-dependent determinant of TS expression. Conclusions: The current study identifies high TS expression in AS carcinoma of lung similar to SQ tumors and the expression of TS appears to be driven more by individual tumor determinants than histological pattern. Given that TS is the main target of pemetrexed and the similarity of TS expression between SQ carcinoma and AS carcinoma, it is possible that pemetrexed may also have inferior clinical activity in AS carcinoma of lung.
Significance and reliability of pathologic marker Ki-67 in patients with neuroendocrine cancers.
Authors: S. Singh, Y. Feinberg, C. Rowsell, C. Law
Journal: Journal of Clinical Oncology (2011)

264 Background: Molecular markers, especially Ki-67, in neuroendocrine cancers (NETs) have become increasingly important. Debate exists as to the optimal role of ki-67 in the treatment of this uncommon cancer. This study was designed to examine the significance of ki-67 as a clinical predictor and its reliability in the treatment of NETs. Methods: A retrospectively assembled integrated database with prospectively collected data of patients undergoing multidisciplinary management for NETs between 2000 to 2009 was analysed. Clinical and outcomes data were collected. Ki-67 was then categorized to Group A (≤2%), B (3-15%) and C (&gt;15%). We compared the original Ki-67 value to the reviewed value. We then used a kappa statistic to calculate the inter-rater agreement between the original and reviewed determination of Ki-67. Fisher's exact test was used to compare categorical variables. Survival was evaluated using the log-rank test. All analyses were carried out using SAS 9.1.3. Results: A total of 184 patients were seen at our clinic. Ki-67 correlated with metastases at presentation (36, 52, 63% for Groups A, B, C respectively, p&lt;0.05), while influencing treatment with chemotherapy even in the absence of metastases (14, 29, 57% for Groups A, B, C respectively, p&lt; 0.002). Ki-67 predicted overall survival (p=0.0005) in favor of Group A. 99 patients had an original Ki-67 reported from the referring center and then a review by an expert pathologist at the multidisciplinary clinic. In Group A, there was 94.4% agreement, with 3.7% of cases upgraded at review to Group B and 1.9% of cases upgraded to Group C. In Group B, there was 94.3% agreement, with 5.7% of cases downgraded to Group A, and 0% upgraded. In Group C, there was 90% agreement, with 10% of cases downgraded to Group B and none to Group A (kappa = 0.89). Conclusions: Our previous report had demonstrated that Ki-67 influenced decisions regarding treatment options. In our updated population of NETs patients, Ki-67 continued to predict biology, influence treatment, and predict survival. In addition we demonstrated high reproducibility of Ki-67. It appears that with modern techniques Ki-67 can be highly reproducible and reliable tool in improving outcomes in this patient population. No significant financial relationships to disclose.
The genome landscape of indigenous African cattle
Authors: Jaemin Kim, Olivier Hanotte, Okeyo Ally Mwai, Tadelle Dessie, Salim Bashir, Boubacar Diallo, Morris Agaba, Kwondo Kim, Woori Kwak, Samsun Sung, Minseok Seo, Hyeonsoo Jeong, Taehyung Kwon, Mengistie Taye, Ki-Duk Song, Dajeong Lim, Seoae Cho, Hyun-Jeong Lee, Duhak Yoon, Sung Jong Oh, Stephen Kemp, Hak-Kyo Lee, Heebal Kim
Journal: Genome biology (2017)

The history of African indigenous cattle and their adaptation to environmental and human selection pressure is at the root of their remarkable diversity. Characterization of this diversity is an essential step towards understanding the genomic basis of productivity and adaptation to survival under African farming systems. We analyze patterns of African cattle genetic variation by sequencing 48 genomes from five indigenous populations and comparing them to the genomes of 53 commercial taurine breeds. We find the highest genetic diversity among African zebu and sanga cattle. Our search for genomic regions under selection reveals signatures of selection for environmental adaptive traits. In particular, we identify signatures of selection including genes and/or pathways controlling anemia and feeding behavior in the trypanotolerant N’Dama, coat color and horn development in Ankole, and heat tolerance and tick resistance across African cattle especially in zebu breeds. Our findings unravel at the genome-wide level, the unique adaptive diversity of African cattle while emphasizing the opportunities for sustainable improvement of livestock productivity on the continent.
Polymorphisms of thymidylate synthase as prognostic factor in rectal cancer.
Authors: V. Arrazubi, J. Suarez, D. Guerrero, K. Cambra, M. L. Gomez Dorronsoro, F. Arias, E. Balen, L. Teijeira, R. Vera
Journal: Journal of Clinical Oncology (2011)

433 Background: Neoadjuvant fluoropyrimidine-based chemotherapy (ChT) plus radiotherapy (Rt) is a standard approach for locally advanced rectal cancer. Polymorphisms of thymidylate synthase (TS), the target for fluoropyrimidines, are recognized prognostic factors in colon cancer. The aim of this study was to evaluate the prognostic value of the polymorphisms of TS in rectal cancer after neoadjuvant ChT plus Rt. Methods: We studied one-hundred consecutive patients with stage II/III rectal cancer between November 2001 and March 2009. Patients underwent surgery 6-8 weeks after neoadjuvant Rt (5,040 cGy) plus fluoropyrimidine-based ChT. DNA was extracted from paraffin embedded biopsies. TS1494del6 and 5′-28bp repeat +G/C SNP polymorphisms were determined. Results: Sixty-seven percent were men and median age was 67 years. ypT stage was: T0 9%, T1 2%, T2 27%, T3 60% and T4 2%; 32% had locoregional adenopathies. The median follow-up was 45 months and relapse occurred in 20% of patients. Polimorphisms could be determined in 98% of pt: -6bp/-6bp 10%, - 6bp/+6bp 39%, +6bp/+6bp 51% and 2R/2R 72%, 2R/3R 21%, 3R/3R 6%. The grade of pathological tumour regression was not associated with polymorphisms. Relapses occurred in 40% of patients -6bp/-6bp, 22% of patients -6bp/+6bp and 21% of patients +6bp/+6bp. The difference in disease- free survival (DFS) between the first and the third groups was stadistically significative (p=0.049). No relation between 5′-28bp repeat +G/C SNP polymorphism and DFS was found. Conclusions: Our data suggest that the TS1494del6 polimorphism may be an important prognosis factor in rectal cancer receiving neoadjuvant chemoradiotherapy. No significant financial relationships to disclose.