tbuckley/cabot-search huggingface dataset:
Genomic mechanisms of resistance to neoadjuvant leuprolide plus abiraterone in locally advanced prostate cancer.
Authors: Adam G. Sowalsky, Huihui Ye, Rachel J. Schaefer, Olga S. Voznesensky, Zhenwei Zhang, Rosina Lis, Glenn J. Bubley, Mary-Ellen Taplin, Steven P. Balk
Journal: Journal of Clinical Oncology (2017)

98 Background: Blocking both gonadal and extragonadal androgens with leuprolide and abiraterone acetate (AA) is approved by the FDA to treat mCRPC. Applying this treatment in the neoadjuvant setting reduced intratumoral testosterone levels in our Phase 2 trial, but pathologic CR's were rare and minimal residual disease was observed in some patients. Methods: We performed laser capture microdissection to isolate pure foci of residual tumor cells from 19 patients who underwent RP following 24 weeks of leuprolide plus AA. We also isolated 19 foci of matched benign glands as germline controls. In 15 of the 19 cases, we dissected 2 spatially-distinct foci of residual tumor. We then performed whole exome sequencing to assess somatic mutations and copy number variations (CNVs). Results: A diversity of genomic resistance mechanisms were observed. Resistance to AA as predicted by mutation of the ligand binding domain of AR was observed in only one case. In contrast, the majority residual tumor foci harbored CNVs coinciding with gain of oncogenes or loss of tumor suppressor genes. Importantly, only a limited number of alterations were shared between foci from the same case, as most mutations were unshared. Shared CNVs frequently included arm-level single copy losses of 10q ( PTEN), 13q ( BRCA2), 5q ( CHD1), 17p ( TP53), 16q ( ZFHX3) and 8p ( NKX3-1), and gain of 8q ( MYC). Mutations not shared by foci in the same case included further biallelic inactivation of PTEN, BRCA2 and TP53, as well as point mutations and single copy losses of BRCA1 and RB1. Distinct, focal gains included AR, PIK3CA and BRAF, and mutations also accumulated in KMT2B, KMT2C and KMT2D. Conclusions: By sampling multiple foci of residual tumor, we identified mutations that likely emerged by subclonal selection by ADT, which cooperated with the shared, clonal mutations that contributed to de novo development of the index lesion. Strikingly, the spectrum of alterations mimics mCRPC with enrichment for alterations affecting cell cycle, DNA damage repair and chromatin modifier pathways. If these alterations permit the tumor to evade AR directed therapy and subsequently mediate relapse, adjuvant therapies targeted to these mutations may increase survival. Clinical trial information: NCT00924469.
Prior therapy and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC) in a hospital-based database.
Authors: Edoardo Francini, Kathryn P. Gray, Wanling Xie, Philip W. Kantoff, Lauren Christine Harshman, Mary-Ellen Taplin, Christopher Sweeney
Journal: Journal of Clinical Oncology (2017)

221 Background: Recent reports have shown that patients (pts) with low volume (LV) mHSPC and those who relapse after prior local therapy (PLT) have median overall survival (OS) longer than 5 years with androgen deprivation therapy (ADT) alone. Using data from our prospectively collected hospital-based database, we aimed to detail the outcomes of pts with mHSPC by combining PLT or de novo (DN) and LV or high volume (HV) of disease. Methods: A cohort of mHSPCpts treated with ADT between 1990 and 2013 was identified in the Dana-Farber Cancer Institute IRB approved database and categorized as DN or PLT and HV or LV, at time of ADT start. HV was defined as visceral metastases and/or ≥ 4 bone metastases (BM) with at least 1 BM beyond the pelvis and axis. The analysis endpoints included OS, defined as time from ADT start to death from all causes. Kaplan-Meier method estimated the time to events distribution with median (95% CI). Cox proportional hazards model evaluated patient and disease volume groups on disease outcomes and provided estimates of hazard ratio (95% CI) for the comparison by groups. Results: Of the 354 pts included and classified as LV or HV, 202 (57%) had PLT, while 152 (43%) presented with DN metastases. The distributions of the 4 groups are 38% (PLT/LV), 19% (PLT/HV), 14% (DN/LV) and 29% (DN/HV). Compared to pts in PLT/LV group, those in the other 3 cohorts had a significantly higher risk of death. In particular, a statistically significant gradient in OS was noted (Trend test P &lt; 0.001) within the groups in favor of PLT, primarily, and LV, secondarily. Conclusions: Consistent with the results seen in clinical trials, our hospital database informs us that disease volume and history of PLT define 4 distinct subgroups with different outcomes. This classification can be routinely used for counseling pts and future clinical trial design including oligometastatic disease. [Table: see text]
Accuracy of <sup>68</sup>Ga-PSMA-PET/CT for patient selection for lymphadenectomy in addition to salvage radical prostatectomy in locally recurrent prostate cancer after primary radiotherapy.
Authors: David Pfister, Isabel Heidegger, Frederik Verburg, Daniel Porres-Knoblauch, Axel Heidenreich
Journal: Journal of Clinical Oncology (2017)

229 Background: Salvage radical prostatectomy, sRPE, is an option for patients in locally recurrent prostate cancer with curative intent. Patients with low PSA at time of salvage treatment and initially low-risk disease have a favourable outcome whereas locally advanced and lymph node positive patients do not. Imaging studies could be beneficial for patient selection of lymph node dissection in addition to sRPE. Here we show first results of the diagnostic accuracy of PSMA-PET/CT in this setting. Methods: We reviewed 87 patients with sRPE and PSMA-PET/CT prior to surgery. In all patients an extended sRPE with an extended lymphnode dissection including the internal, external iliac artery, fossa obturatoria as well as the A iliaca communis to the ureteral crossing, was performed. For diagnostic accuracy Sensitivity, Specifity, pos. and neg. predictive value was calculated per person and per lymph node. Results: 11 patients had a PSMA PET/CT prior to surgery. All scans showed positive results in the prostate but only one showed a positive lymph node. A total of 141 lymph nodes were dissected (median 13,5; 8-29 per patient). Pathological analysis showed 6 lymph nodes with a metastasis in 4 patients. No positive lymph node was identified correctly by PSMA PET/CT. Specificity and negative predictive value per patient / per lymph node were high with 85% / 99% and 60% / 95.7%, respectively. As no patient or lesion was identified correctly sensitivity and pos. predictive value could not be calculated. Accuracy was 55% / 95.7%. Conclusions: In this small patient group PSMA PET/CT has an insufficient per-patient accuracy for patient selection of lymph node dissection in addition to sRPE. For patient selection clinical data including primary risk profile and PSA kinetics prior to surgery are still more useful for this purpose.
Genetic associations of fatigue and other symptom domains after breast cancer treatment: Results from a prospective cohort study.
Authors: Kate Webber, Barbara Kaye Bennett, David Goldstein, Andrew R. Lloyd
Journal: Journal of Clinical Oncology (2014)

9537 Background: We have previously reported on the natural history of cancer related fatigue and other symptoms after adjuvant breast cancer therapy in a prospective cohort study. This paper reports genetic associations with symptom phenotypes in this cohort. Methods: Women with early stage breast cancer from six metropolitan teaching hospitals in Sydney were enrolled post-surgery but before adjuvant therapy and followed for up to 5 years, with optional participation in a genetic association substudy. Self-report questionnaires recorded physical and psychological health and disability. Symptom scales for pain, fatigue, depression, anxiety, neurocognitive disturbance and neurotoxicity were derived by prinicipal components analysis from self-report questionnaires at completion of treatment. Genetic associations were sought with functional single nucleotide polymorphisms (SNPs) in cytokine genes tumour necrosis factor (TNF)-α, interferon (IFN)-ɣ, Interleukin (IL)-10, neuropeptide Y(NPY) and the purinogenic transporter gene P2RX7. Results: 151 of the 218 participants provided samples for genetic analyses, of whom 109 were unambiguously Caucasian with corresponding self-report questionnaire data at completion of adjuvant therapy. Depression and anxiety were associated with both the IL-10 -1082 A/A genotype (both p=0.001), as well as the P2RX7 rs208294 A/A genotype (p=0.019 and 0.031). The IL-10 -1082 A/A genotype was also associated with higher levels of fatigue (p=0.032). Associations were found between high levels of neurocognitive dysfunction and homozygosity for the high expression G/G variant of TNF-α -308 (p=0.049). No significant associations between symptoms and NPY or IFN-ɣ were seen in this cohort. Conclusions: These findings support for the notion that susceptibility to mood disturbance, fatigue and neurocognitive dysfunction after cancer therapy has a genetic basis. Furthermore, as these associations have also been reported in non-cancer settings, the observed findings may represent inherent susceptibility to these symptoms rather than a response unique to cancer or its treatment.
Development of RTXM83 (a potential rituximab biosimilar): In vitro and in vivo comparability with MabThera.
Authors: Mauricio Seigelchifer, Esteban Corley, Gloria Fresnillo, Analia Pesce, Cedric Bes, Marie Elise, Amalia Florez, Susana Millan, Tamal Raha
Journal: Journal of Clinical Oncology (2014)

e14020 Background: RTXM83, a proposed biosimilar to rituximab, has an identical amino acid sequence and similar physicochemical and in vitro functional properties to reference drug, MabThera (sourced from EU). This study was designed to demonstrate comparability between RTXM83 and MabThera, both in vitro and in vivo. Methods: Mass fingerprinting and mass spectrometry analysis; UV CD spectroscopy; Glycan and charge variant analysis; SDS-PAGE analysis and SE HPLC analysis; CDC and ADCC assays; FcRIII and c1q assays; PK/PD study. Results: The results indicate similar primary structural attributes, as evident from peptide mass fingerprinting and mass spectrometry analysis. Far and near UV CD spectroscopy indicates comparable secondary and tertiary structure between the two molecules. Glycan and charge variant analysis also indicate similar post translational modifications. The product related impurity profile, as indicated by SDS-PAGE analysis and SE HPLC analysis, indicates similar purity. Both molecules demonstrated similar binding affinity to CD20 receptor and their ability to recruit the complements, c1q and finally demonstrated similar potency in in vitro complement dependent cytotoxicity (CDC) assay. The similarity in effector function was determined by evaluating the binding with Fc?RIII followed by in vitro antibody dependent cell cytotoxicity (ADCC). Both molecules showed similar potency in in vitro apoptosis assay. The in vitro binding affinities to neonatal receptors are also similar, predicting similar half-life in vivo. The in vivo PK/PD study was conducted in cynomologus monkeys and the results indicate that the AUC, T1/2, Cmax of RTXM83 are within 80-120% range of the reference drug, MabThera. While evaluating the PD parameters, it was observed that the time of onset, magnitude and duration of PD response (CD20 and CD40 cell depletion) was similar between RTXM83 and Mabthera. Conclusions: herefore, all data generated to date are establishing a high comparability (high similarity) between Mabthera and RTX83, meeting all requirements for clinical approval of our product.
Intramuscular (IM) depot methylprednisolone in established rheumatoid arthritis: A randomised placebo-controlled trial
Authors: E H Choy, G H Kingsley, B Khoshaba, N Pipitone, L Dolan, P Pitt, B Dasgupta, G S Panayi, D L Scott
Journal: Annals of the Rheumatic Diseases (2004)
A pilot study of local injection of TNFerade biologic in addition to neo-adjuvant chemoradiation for the treatment of primary and recurrent rectal cancer
Authors: K. A. Camphausen, M. Quezado, D. Citrin, J. F. Pingpank, B. Wood, H. R. Alexander, G. Seidel, M. Eugeni, Y. Shutack, S. K. Libutti
Journal: Journal of Clinical Oncology (2007)

14585 Background: Rectal cancer presents unique therapeutic considerations due to competing concerns regarding sphincter preservation and local recurrence. Treatments using pre-operative chemoradiation are employed to decrease local recurrence and improve the probability of sphincter preservation. Agents, which improve the pathologic response rate may be of further benefit. Methods: TNFerade biologic is a replication deficient adenovirus expressing human TNF-alpha driven by a radiation inducible promoter. TNFerade biologic (4X10e10 pfu) is injected locally into rectal tumors once a week for 5 weeks. Patients receive concurrent chemoradiation utilizing oral capecitabene (937.50 mg/m 2 BID, Monday-Friday) and external beam radiotherapy (1.8 Gy/day, 5 days per week to a total dose of 45 Gy). A boost dose of 5.4–9 Gy is delivered to sites of gross disease. After treatment, patients recover for 6–9 weeks before surgery. Patients are scored prior to the start of neo-adjuvant therapy for the feasibility of a sphincter preserving operation versus an abdominal perineal resection (APR). Following surgery the specimen (entire area submitted for processing) is examined for the percent of viable tumor remaining. The goal of the study is to show a target pathologic response rate of &lt;10% viable tumor in more than 30% of patients treated. Results: Six patients have been treated (4M, 2F). There has been no toxicity attributable to the TNFerade biologic, and the chemoradiation has been well tolerated with only mild, expected toxicities. Five of the six patients have undergone surgery (one is awaiting surgery). Three of these five patients were thought to require an APR prior to treatment due to the size and location of their tumor. All five patients have successfully undergone sphincter- preserving operations. On examination of the five specimens, 3 had less than 5% viable tumor while 2 had greater than 50% viable tumor. All resections were margin negative. The target pathologic response rate of &lt;10% viable tumor was achieved in 60% of the patients evaluated. Conclusion: The addition of TNFerade biologic to pre-operative chemoradiation was well tolerated and a prospective randomized trial comparing the addition of this agent to chemoradiation is warranted. No significant financial relationships to disclose.
Suicide Following Deliberate Self-Harm
Authors: Mark Olfson, Melanie Wall, Shuai Wang, Stephen Crystal, Tobias Gerhard, Carlos Blanco
Journal: American Journal of Psychiatry (2017)

Objective: The authors sought to identify risk factors for repeat self-harm and completed suicide over the following year among adults with deliberate self-harm. Method: A national cohort of Medicaid-financed adults clinically diagnosed with deliberate self-harm (N=61,297) was followed for up to 1 year. Repeat self-harm per 1,000 person-years and suicide rates per 100,000 person-years (based on cause of death information from the National Death Index) were determined. Hazard ratios of repeat self-harm and suicide were estimated by Cox proportional hazard models. Results: During the 12 months after nonfatal self-harm, the rate of repeat self-harm was 263.2 per 1,000 person-years and the rate of completed suicide was 439.1 per 100,000 person-years, or 37.2 times higher than in a matched general population cohort. The hazard of suicide was higher after initial self-harm events involving violent as compared with nonviolent methods (hazard ratio=7.5, 95% CI=5.5–10.1), especially firearms (hazard ratio=15.86, 95% CI=10.7–23.4; computed with poisoning as reference), and to a lesser extent after events of patients who had recently received outpatient mental health care (hazard ratio=1.6, 95% CI=1.2–2.0). Compared with self-harm patients using nonviolent methods, those who used violent methods were at significantly increased risk of suicide during the first 30 days after the initial event (hazard ratio=17.5, 95% CI=11.2–27.3), but not during the following 335 days. Conclusions: Adults treated for deliberate self-harm frequently repeat self-harm in the following year. Patients who use a violent method for their initial self-harm, especially firearms, have an exceptionally high risk of suicide, particularly right after the initial event, which highlights the importance of careful assessment and close follow-up of this group.
Prognostic factors influencing the selection of bevacizumab combined with chemotherapy in patients with HER2-negative metastatic breast cancer in routine clinical practice: Oncosur-Avalox—Observational cross-sectional study.
Authors: Luis Manso, Andres Garcia-Palomo, Ramon Perez-Carrion, Jose Ignacio Chacon, Xabier Mielgo Rubio, Isabel Gallegos Sancho, Javier Cassinello, Rosa Llorente, Elena Galve Calvo, Cristina Llorca, Inaki Alvarez, Antonio Fernandez, Gustavo Catalan, Maria Jose Garcia Lopez, Maria Dolores Torregrosa, Esperanza Blanco, Coralia Bueno, Antonia Perello, Miguel Méndez, Hernan Cortes-Funes
Journal: Journal of Clinical Oncology (2013)

e12020 Background: Combining bevacizumab (BEV) with chemotherapy (CT) improves survival in HER2-negative metastatic breast cancer (MBC). We investigated the influence of age, ECOG, hormonal status, number of sites, location of metastases and patient decision on the selection of BEV combined with CT in MBC. Methods: Observational cross-sectional multicenter study in patients with HER2- negative MBC who have received first-line CT with BEV. Results: 219 patients were included: median age 51(44-63) yr; ECOG: 0=53%; 60.4% pre-menopausic; 23.9% triple-negative (TN);76.2 % hormone receptor positive (HR+).Metastatic disease: ≥3 sites=39.2% (TN: 22%; HR+: 43.9%); location: 45.2% bone, 37.4% liver, 30.1% lung. Most frequent BEV combinations were paclitaxel/BEV(60.7%) and docetaxel/BEV(12.8%); median no. of CT cycles: 6 (5- 8). A disease-free survival (DFS) ≥12 months was achieved by 82.8%; TN: 78.9%; HR+: 83.3%. Overall response rate (ORR) was 62.7%: 53.6% partial response (PR), 9.1% complete response (CR); 25.4% stable disease (SD) and 7.2% disease progression (4.8% non evaluated). TN:ORR 54.2% (47.9% PR), clinical benefit 80% (27.1% SD); HR+:ORR 65.8% (55.7% PR), clinical benefit 89.9% (24.1% SD). 66.2% presented at least one toxicity, mainly grade 1-2; 32% BEV-related: only 3 grade 3 toxicities; no grade 4. Receiving adjuvant hormonal therapy was associated to DFS ≥12 months (p&lt;0.05). ER+ tumors (OR:0.326;95%CI:0.16-0.65;p=0.002) and patient decision after consider doctor opinion (OR:0.026;95%CI:0.01-0.74; p=0.085) were independent factors associated with the selection of paclitaxel-BEV in the overall population (TN or HR+). Liver metastases were significantly related to paclitaxel-BEV administration (p&lt;0.01). Conclusions: First-line CT with BEV is an effective and safe scheme for patients with TN and HR+ MBC. ER+ tumors and patient decision after consider doctor opinion were identified as independent factors for the selection of paclitaxel-BEV therapy. The presence of liver metastases was significantly associated to the administration of a paclitaxel-BEV regimen.
Effect of NKTR-214 on the number and activity of CD8+ tumor infiltrating lymphocytes in patients with advanced renal cell carcinoma.
Authors: Michael E. Hurwitz, Adi Diab, Chantale Bernatchez, Cara L. Haymaker, Harriet M. Kluger, Michael T. Tetzlaff, Ivan Gergel, Mary Tagliaferri, Michael Imperiale, Sandra Aung, Ute Hoch, Jonathan Zalevsky, Patrick Hwu, Mario Sznol, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2017)

454 Background: Patients with low baseline CD8+ T-cells within the tumor microenvironment (TILs) have a poor response to immune checkpoint inhibitors. Agents designed to specifically activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs. NKTR-214 is a CD-122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) and preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells. Methods: A dose escalation, open-label, trial was initiated to assess the safety of NKTR-214 and explore immune changes in the blood and tumor microenvironment in patients with advanced solid tumors. NKTR-214 was administered IV in an outpatient setting with initial dosing at 0.003 mg/kg. Pre and post treatment blood and tumor samples were analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by immunohistochemistry. Results: Among 25 patients dosed, 15 had RCC (10@0.006mg/kg, 4@0.009mg/kg, and 1@0.012mg/kg). Treatment with NKTR-214 was well tolerated and the MTD was not reached. One patient experienced DLTs (Gr3 syncope and hypotension) at 0.012 mg/kg. There were no immune-related AEs. Of 12 patients evaluable for response, 75% had SD at their first on treatment scan. Of 5 patients, who were immune checkpoint naïve with ≥ 1 prior TKI treatments, 3 experienced tumor shrinkage, 1 with PR per RECIST 1.1 (unconfirmed). Interrogation of the tumor microenvironment revealed many significant immunological changes post treatment, including increase in total and proliferating NK, CD8+, and CD4+ T cells. There was good correlation between increase in activated CD4+ and CD8+ T cells in peripheral blood with an increase in T cell infiltrates within the tumor tissue. Conclusions: NKTR-214 increased immune infiltration in the tumor and anti-tumor activity in patients who previously progressed on TKIs, with a favorable safety profile. The ability to alter the immune environment and increase PD-1 expression on effectors T cells may improve the effectiveness of anti-PD-1 blockade. A trial combining NKTR-214 and nivolumab is enrolling. Clinical trial information: 02869295.