tbuckley/cabot-search huggingface dataset:
The clinical outcome of FAP+ cancer-associated fibroblasts in high-grade serous ovarian cancer.
Authors: Hanna Dahlstrand, Sara Corvigno, Artur Mezheyeuski, Joseph W Carlson, Josefin Fernebro, Gabriele Hölzlwimmer, Klein Klein, Elisabeth Avall-Lundqvist, Arne Ostman
Journal: Journal of Clinical Oncology (2018)

e17526 Background: Experimental studies suggest that fibroblast activation protein positive (FAP+) cancer-associated fibroblasts (CAFs) are negative regulators of T-cell function. Increased CD8+ T-cells is correlated to improved OS in high-grade serous ovarian cancer (HGSC). The effect of FAP+ CAFs on prognosis and treatment response in a clinical setting of HGSC is unknown. Methods: We analyzed FAP and CD8 by IHC in a pretreatment tissue microarray of HGSC (N = 116), stage IIC-IV, diagnosed in 2002-06. Marker status was correlated with OS, PFS and primary platinum resistance (PPR). The gene expression of FAP and CD8 was correlated to relapse-free survival (RFS) in HGSC in two public databases (TCGA and GSE9891). Results: High density of CD8+ cells was associated with longer OS (52.6 months vs 34.4 months, p = 0.02) as compared to low tumor infiltration of CD 8+ cells (HR 0.59; 95% CI 0.38-0.92, p = 0.02). High FAP expression was associated with shorter PFS (median PFS 11.4 vs 14.7 months, p = 0.04), an effect restricted to cases with high CD8+ cells. High FAP expression in the CD8-high group was associated with a shorter PFS (11.4 vs 18.2 months, p = 0.01) as well as PRR (p = 0.04). The results were confirmed in univariate (HR 3.25, CI 95% 1.21-8.75, p = 0.02) and in multivariate (HR 4.05, CI 95%1.09-15.13, p = 0.04) analyzes. In contrast, high intensity FAP was not associated with PFS or PPR in cases with low CD8+ cells. Analyses in two gene expression data sets confirmed the association between high FAP and shorter RFS in the group with high but in not low CD8 expression. Conclusions: FAP+ fibroblasts were associated with shorter PFS and primary platinum resistance in patients with high density CD8+ HGSC. Therapy targeting FAP may enhance the platinum sensitivity in a CD8+ high group of patients. This strategy may be also useful to explore in T-cell-directed immunotherapy in HGSC.
Development of a companion diagnostic assay for tissue hyaluronan detection and treatment with PEGPH20 in metastatic pancreatic ductal adenocarcinoma patients.
Authors: Sihem Khelifa, Jie Pu, Carrie Aldrich, Junming Zhu, Erika Walker, Zhanna Zhilina, Frank Vladich, Paco Delgado, Ammar Qadan, Thomas Müller, Ping Jiang
Journal: Journal of Clinical Oncology (2016)

e15749 Background: Ventana Medical Systems, Inc. is developing in collaboration with Halozyme Therapeutics an affinity histochemical companion diagnostic to aid in selecting patients with pancreatic ductal adenocarcinoma (PDA) that may benefit from PEGPH20 based therapy. Methods: A recombinant hyaluronan (HA) binding probe was optimized for use with the VENTANA OptiView DAB IHC Detection Kit on the automated BenchMark ULTRA platform (HA CDx Assay). HA is a non-sulfated glycosaminoglycan polymer that often accumulates in extra-cellular tumor matrices. The HA CDx Assay was developed for use in formalin-fixed, paraffin-embedded tissue samples of PDA in a series of studies addressing sensitivity, specificity, robustness, and precision. PEGPH20 is a pegylated form of recombinant human PH20 hyaluronidase degrading tumor-associated HA with high affinity and selectivity. The scoring algorithm was defined using statistical analysis of clinical outcome data and HA CDx Assay staining pattern observed in a set of HALO109-202 Phase 2 clinical trials samples. Inter-reader precision was established by 3 pathologists evaluating 100 PDA samples across the range of HA expression levels. Results: The Ventana HA CDx Assay met all pre-defined acceptance criteria. PDA are considered HA-high when the HA CDx Assay staining in the tumor extra cellular matrix (ECM) is ≥ 50% of the tumor surface. Inter-reader precision in determining HA status resulted in agreement rates greater than 94%. Conclusions: These results highlight the robustness and reproducibility of the Ventana HA CDx Assay. In HALO 109-202, patients identified by the Ventana HA CDx Assay algorithm as HA high demonstrated clinically meaningful improvements when treated with nab-paclitaxel and gemcitabine (AG) + PEGPH20 compared to those treated with AG alone. The clinical utility of the HA CDx assay will be further validated in additional patients in subsequent PEGPH20 studies, including a planned Phase 3 study beginning in 2016.
Bolus infusion of cisplatin, 5-fluorouracil, and leucovorin as alternative first-line therapy for advanced gastric cancer.
Authors: Rafael Correa Coelho, Pedro Duarte Abreu, Mariana Ribeiro Monteiro, Ana Paula Stramosk, Roberto Almeida Gil, Mariana Siqueira, Bruno dos Santos Vilhena Pereira, Cristiano Guedes Duque, Alexandre de Mendonca Palladino, Marcia Silveira Graudenz, Carlos J C Andrade
Journal: Journal of Clinical Oncology (2017)

e15511 Background: Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death worldwide.Classic regimens in first line setting for advanced GC combine platinum compounds and fluoropirimidines ± antracyclines or docetaxel. At Brazilian National cancer Institute (INCA), there are limitations in hospital beds and infusion pumps, so the combination between cisplatin (CDDP) + 5-Fluorouracil (5-FU) in an infusion protocol has been out of possibility. An institutional project with an adapted protocol involving CDDP + 5-FU + Leucovorin (CFL) in bolus demonstrated good results and CFL became routine at INCA for more than 10 years. Methods: Retrospective cohort study evaluating 109 patients with advanced GC treated in first line setting with CDDP 80mg/m 2 (D1) + 5- FU 400mg/m 2 (D1,D8,D15,D22)+ Leucovorin (LV) 20mg/m 2 (D1,D8,D15,D22) in 28-day cycles from January 2008 to December 2014. Results: The median age was 54 years (24y-80y), 53.6% were male, 70% white and 20% mulatto, 49.1% formal smokers and 15.5% formal drinkers. Tumor staging at initial diagnosis was: E IIA 2.7%, E IIB 2.7%, E IIIA 1.8%, E IIIB 5.5%, E IIIC 5.5% and E IV 81.8%. Performance status ≤ 2 was present in 97.3% and G3 disease in 63.6%. The most common metastatic sites were: lymph nodes 31.8%, peritoneum 24.5%, liver 21.8% and lung 2.7%. The median of cycles received per patient was 4. Complete responses were achieved in 6.4%, partial responses in 14.5% and stable disease in 14.5%. Median PFS was 6.3 months (5.08 – 7.58) and median OS was 8.3 months (6.79 – 9.87). Seventy five (68.8%) patients were alive in 1-year and 26 (23.9%) in 2-years. Dose reduction was necessary in 9.1% and the most common toxicities were: nausea 27.3%, vomiting 19.3% fatigue 13.6%, diarrhea 10.6%, mucositis 4.2% and neutropenia 4.2%. Of all adverse events, grade 3 and 4 corresponded to 11.36% and 1.51%, respectively. Three patients had neutropenia G4. Only 26 patients (23.8%) received second line treatment. Conclusions: Chemotherapy protocol in bolus combining CDDP, 5-FU and LV could be an alternative for CDDP and 5-FU infusion protocol.
Combination of WEE1 and AURKA inhibition in HPV negative head and neck squamous cell carcinoma.
Authors: Janaki Parameswaran, Jong Woo Lee, Teresa Sandoval-Schaefer, Jaseok P. Koo, Barbara Burtness
Journal: Journal of Clinical Oncology (2017)

e14105 Background: Aurora Kinase A (AURKA) is overexpressed in HNSCC, and correlates with poor prognosis. It has been identified as a potential therapeutic target, yet the response rate for the AURKA inhibitor MLN8237 is only 9% in treatment refractory HNSCC. We hypothesized that although AURKA inhibitors lead to defective spindle assembly, they may also reduce mitotic entry, undermining cytotoxic effect. We predicted that adding a WEE1 inhibitor to an AURKA inhibitor would mitigate this effect and enhance cell death Methods: Cell viability assays were performed on FaDu ( p53 mut.), Detroit562 ( p53 mut.), and UNC7 ( p53 WT) HPV negative HNSCC cell lines treated with AZD1775 (AZD), MLN8237 (MLN), and combination of AZD+MLN. Oncosphere formation assays were used to confirm findings of cell death, and western blot analysis and confocal microscopy were used to investigate mechanism of synergy. The above drugs were also given at varying doses via oral gavage to FaDu xenografted nude mice. Results: There was clear synergy of AZD and MLN in-vitro. Combination Indices were determined by the Chou-Talalay method: FaDu 0.4, Detroit562 0.5, and UNC7 0.6 (synergy = &lt; 0.8). Oncopshere assays showed inability of AZD+MLN treated cells to re-differentiate. FaDu cells treated with MLN had increased p-CDK1 and reduced phospho-histone H3 (pHH3), suggesting reduced mitotic entry. AZD+MLN treated cells had reduced p-CDK1 and increased pHH3, similar to AZD treated cells; they also had spindle disarray with poor chromatin organization on confocal microscopy indicating mitotic catastrophe. In mice, the combination of AZD+MLN inhibited tumor growth, with no apparent toxicity. Mice treated with either drug alone had tumor volumes over 1000mm3 and were sacrificed at day 21; those treated with AZD 90mg/kg and MLN 30mg/kg had tumors volumes around 300mm3 on day 28. Conclusions: AZD and MLN synergistically enhance cell death in HNSCC cell lines and significantly inhibit tumor growth in mouse xenograft models. The ability of AZD to overcome intrinsic resistance to MLN may underlie mechanism of synergy. We recommend further investigation of AURKA and WEE1 inhibition in other cancers with high AURKA expression, and in patients with HNSCC.
Treatment decision making after introduction of PD-L1 reflex testing in NSCLC up front.
Authors: Karin Holmskov Hansen, Lotte Holm Land, Tine Schytte
Journal: Journal of Clinical Oncology (2018)

e21149 Background: PD-L1 testing was established in Denmark (DK) after the approval of Nivolumab (Niv) and Pembrolizumab (Pem) in second line (2L) treatment of Non-Small Lung Cancer (NSCLC) due to the requirements of PD-L1 tumor proportion score (TPS) ≥ 1% except for Niv in squamous NSCLC Reflex testing up front in the diagnostic work was established Marts 2017 in DK due to the approval of Pem in 1L NSCLC (PD-L1 TPS ≥ 50%). Re-biopsy can be challenging at progressive disease (PD) and the information from the reflex test can be used in clinical decisions in 2L. New biopsy is offered at PD in pts with unknown PD-L1 TPS and if possible in recurrent disease (RD). PD-L1 TPS, stage (TNM), performance status (PS) and co-morbidity is crucial in clinical decision making Methods: Pts examined for PD-L1 expression from 1th of Mar. until 31th of Dec. 2017 at Odense University Hospital were identified. TPS is defined as the percentage of tumor cells expressing PD-L1 assessed by immunohistochemistry (IHC) using antibody 22C3. In this retrospective study the primary treatment of NSCLC pts was assessed in patients with TPS ≥50 and 1% ≤ TPS < 50% respectively Results: Of 500 pts (lung cancer and other cancer forms) tested for PD-L1 TPS 179 (36%) had TPS ≥50%, 120 (24%) had 1% ≤ TPS < 50%, 181 (37%) TPS < 1% and 20 (4%) of biopsies were non-evaluable In 171 NSCLC with TPS ≥ 50% 40 pts (23%) received immunotherapy (IT), 20 pts (12%) 1L chemotherapy (CT) with or without (+/-) palliative radiotherapy (RT) up front, 52 pts (30%) treated with curative intention (CI), 23 pts (14%) only palliative RT and 24 pts (13%) no treatment at all. EGFR mutation was found in 7 pts (4%) and 5 pts (3%) were treated in another region In 102 NSCLC with 1% ≤ TPS < 50% 34 pts (33%) with newly diagnosed or recurrent disease received 1L CT +/- palliative RT up front, 30 pts (29%) treated with CI, 15 pts (15%) only palliative RT and 12 pts (12%) no treatment at all. In 5 pts (5%) PD-L1 TPS assessment was in order to decide 2L treatment. Only 1(20%) received IT and 4 (80%) CT in 2L Conclusions: In PD-L1 TPS ≥ 50% only 23% of all tested NSCLC in our study are candidates for IT in 1L. The reflex testing helps the clinician to identify the pts that benefit from 1L IT. It gives important knowledge for further treatment decision making in pts with PD or RD too
Efficacy of radium-223 in bone-metastatic prostate cancer patients with and without homologous repair deficiency (HRD) mutations.
Authors: Pedro Henrique Isaacsson Velho, Fahad Qazi, Sayeedul Hasan, Michael Anthony Carducci, Mario A. Eisenberger, Phuoc T. Tran, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2018)

e17023 Background: Inactivating mutations in genes mediating homologous recombination DNA-repair (HRD) are present in 20-30% of men with metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a bone-seeking α-emitter that induces double-strand (ds)DNA breaks, thereby killing prostate cancer cells in the bone. We hypothesized that radium-223 would have greatest efficacy in men with germline or somatic HRD mutations where dsDNA breaks would go unrepaired, representing a form of ‘synthetic lethality’. Methods: We conducted a retrospective study of 22 consecutive mCRPC patients that received standard-of-care radium-223 at Johns Hopkins between 02/2013 and 08/2017 who had germline and somatic DNA sequencing data available. We assessed > 30% alkaline phosphatase (AlkPhos) declines and time-to-AlkPhos-progression (co-primary endpoints), as well as > 50% PSA responses, overall survival (OS) and time-to-next-systemic-therapy (secondary endpoints) in men with and without pathogenic HRD mutations. Results: Of the 22 patients, 7 men (32%) had a germline/somatic HRD mutation (2 in BRCA2; 1 each in ATM, ATR, CHEK2, FANCI, FANCL) and 15 (68%) did not. Men with HRD mutations had numerically lower ages (65y vs 73y, P= 0.33), more soft-tissue metastases (57% vs 27%, P= 0.34) and higher PSA levels (113 ng/mL vs 47 ng/mL, P= 0.41), but had similar AlkPhos levels (107 U/L vs 110 U/L, P= 0.48). Compared to HRD(–) men, HRD(+) patients showed a trend towards greater AlkPhos responses (71% vs 40%, P= 0.08 [1-sided χ2 test]), longer time-to-AlkPhos-progression (median 7.1 vs 6.0 mo, HR 0.56, P= 0.32 [log-rank test]), and longer OS (median 36.9 vs 17.6 mo, HR 0.40, P= 0.25). There were no differences between HRD(+) and HRD(–) men in terms of PSA responses (0% vs 7%, P= 0.85) or time-to-next-systemic-therapy (HR 1.41, P= 0.62). Conclusions: In this exploratory study, bone-metastatic mCRPC patients with inactivating HRD mutations demonstrated a non-significant trend towards improved AlkPhos responses, delayed AlkPhos progression, and greater OS. These results should motivate prospective validation of the ‘synthetic lethality’ hypothesis between HRD mutations and radium-223 activity.
The association between caregiver burden, resilience, and self-rated health in a national sample of caregivers of patients with cancer.
Authors: Matthew Golub, David Avram, Lacey Clement, Alaina Carr, Elizabeth Riley Kessler, Kristin Kilbourn
Journal: Journal of Clinical Oncology (2018)

e22138 Background: Providing care for a patient with cancer can have a deleterious effect on the health of the caregiver. Self-rated health (SRH) is an important caregiver health metric, and prior research has identified caregiver burden (CB) and psychological resilience (PR) as predictors of SRH in non-cancer caregiver samples. The purpose of this study was to examine the association between CB, PR, and SRH in caregivers of patients with cancer. Furthermore, we sought to explore a potential interaction between CB and PR on SRH. Methods: We developed a psychosocial survey and recruited a national sample of cancer patient caregivers through Qualtrics Panels, an online data recruitment service. A standard multiple regression model was developed in which SRH was the outcome variable and CB, PR, and a burden-resilience interaction variable were the predictors. Additional predictors included age, gender, marital status, employment status, years caregiving, and emotional social support. Results: The analytic sample included 467 participants. In this sample, 61% were female, 88% were white, 77% were married, and 72% reported having employment. The primary patient diagnoses reported by caregivers were breast cancer 21%, lung cancer 15%, and gastrointestinal cancers 15%. The overall model was significant F(9, 457) = 65.55, p < .001, and accounted for 28% of the variance in SRH (R2= 27.99). Significant predictors of SRH included CB β = -.01, p < .001, PR β = .04, p < .001, age β = -.01, p < .001, having a committed relationship β = .35, p < .001, employment β = .45, p < .001. The burden-resilience interaction variable was not a significant predictor of SRH. Conclusions: These findings are consistent with prior research in non-cancer caregiver samples in that demographic characteristics, CB, and PR were all significant predictors of SRH. Interestingly, burden and resilience appear to have independent and not joint connections to SRH, which suggests that mitigating burden and promoting resilience could have a positive impact on SRH in cancer caregivers. Furthermore, helping these caregivers nourish existing committed relationships and secure or maintain employment could improve health outcomes.
Cytomegalovirus (CMV) disease in peripheral blood (PB) allogeneic hematopoietic cell transplant (HCT) with post-transplant cyclophosphamide (PT-Cy).
Authors: Scott Ryan Goldsmith, Michael Slade, Steven J Lawrence, Rizwan Romee
Journal: Journal of Clinical Oncology (2016)

e18538 Background: PT-Cy has been identified as an effective and inexpensive agent for graft-vs-host disease (GVHD) prophylaxis for T-cell replete haploidentical HCT (haplo-HCT) recipients. It is being implemented more frequently in non-haploidentical (non-haplo) HCT. There is limited information regarding CMV disease in PT-Cy recipients, mainly pertaining to haplo-HCT. Methods: We conducted a retrospective analysis by chart review of all patients who had received PB allo-HCT with PT-Cy between 2009 and 2016. CMV disease was defined by end-organ damage due to CMV infection. Patients at high risk for CMV reactivation were defined by donor and/or recipient seropositivity. Cumulative incidence (CI) of CMV reactivation was determined treating death without reactivation as a competing event using Gray’s test. Criteria for initiating antiviral therapy were standardized. Results: We identified 104 haplo-HCT and 38 non-haplo-HCT recipients who met criteria. Baseline characteristics were comparable. 81.6% of non-haplos and 68.2% of haplos were at high risk for CMV. Median follow-up for non-haplos was 289d, and 270d for haplos. The CI of CMV reactivation at 30 and 100 days among non-haplos was 37% and 55%, and 36% and 54% among haplos (p = 0.89). Median time to reactivation in non-haplos was 28d, and 24d in haplos. Among non-haplos with reactivation, 11 (50%) required antiviral therapy, compared to 46 (81%) haplos with reactivation (p = 0.006). Four (11%) non-haplos and 16 (15%) haplos developed CMV disease (p = 0.46). This corresponded to 13% and 23% of those at high risk, respectively (p = 0.26). Two non-haplos had CMV pneumonia, one case fatal, and 2 had CMV enterocolitis and died from concurrent bacteremia/sepsis. Among haplos, 7 had CMV disease involving only the GI tract, 6 had only pneumonia, 2 had both systems affected, and 1 had meningitis, retinitis, and pneumonia. Death in 4 haplos was attributable to CMV, all due to CMV pneumonia. Conclusions: CMV infection and disease occur frequently in both haplo-HCT and non-haplo-HCT utilizing PB grafts and PT-Cy. Antiviral usage was significantly more frequent in haplo-HCT despite similar incidence of end-organ disease.
C-reactive protein (CRP) as a predictive marker for survival in patients with advanced non-small cell lung cancer (NSCLC) treated with first line pembrolizumab monotherapy.
Authors: Yuji Shibata, Tadasuke Shimokawaji, Tetsuro Kondo, Terufumi Kato, Haruhiro Saito, Kouzo Yamada
Journal: Journal of Clinical Oncology (2018)

e21106 Background: Pembrolizumab have shown longer activity in patients with advanced NSCLC especially when PD-L1 expression was high. But even with high PD-L1 expression, more than half of them failed to response. We focused on CRP, inflammatory protein measured routinely in clinical practice, to find out its role as predictive biomarker for pembrolizumab. Methods: We analyzed advanced NSCLC patients with PD-L1 high expression (EGFR mutation (-), EML-4-ALK fusion (-)) who were treated with pembrolizumab as first-line therapy in our clinical practice. Patients received pembrolizumab (200mg/body, q3W) until progressive disease or unacceptable toxicity. During treatment period we measured serum biochemistry and blood cell count regularly. We evaluated the association the factors such as serum marker including inflammatory protein, age, performance status, histology, smoking status, prior radiation therapy and presence or absence of immune-related adverse events after treatment with the effect such as antitumor response, progression-free survival (PFS) and overall survival (OS). Results: A total of 31 patients treated with pembrolizumab from March 2017 to February 2018 were analyzed for this research. Their characteristics were: median age 72 (range 37-84), male/female 24/7, adenocarcinoma/squamous cell carcinoma/pleomorphic carcinoma/neuroendocrine carcinoma/NOS 17/5/3/1/5, clinical stage IIIB/IV/recurrence 3/21/7, median CRP level at pretreatment 1.15mg/dL (0.07-15.27). Among the candidate biomarker, there were no association except for CRP. Serum CRP level at pretreatment was not predictive, but change of serum CRP level at 6 weeks after anti-PD-1 therapy initiation was most predictive in the analysis. Elevated CRP group showed longer PFS and OS than depressed group (PFS: p = 0.08, HR 0.29, OS: p = 0.08, HR 0.28, log-rank test). Conclusions: Our analysis suggests that serum CRP elevation at 6 weeks of treatment predict for longer survival when pembrolizumab was given as first-line treatment. This finding might be related to inflammation status of patients and efficacy of anti-PD-1 inhibitor.
Evaluation of the treatment strategies for medication-related osteonecrosis of the jaws (MRONJ) and the factors affecting treatment outcome: A multicenter retrospective study with propensity score matching analysis.
Authors: Saki Hayashida, Sakiko Soutome, Souichi Yanamoto, Shigeyuki Fujita, Takumi Hasegawa, Takahide Komori, Yuka Kojima, Hironori Miyamoto, Yasuyuki Shibuya, Nobuhiro Ueda, Tadaaki Kirita, Hirokazu Hirokazu, Mitsuyo Shinohara, Masahiro Umeda
Journal: Journal of Clinical Oncology (2018)

e22517 Background: Medication-related osteonecrosis of the jaw (MRONJ) is an adverse event of bone modifying agent (BMA) such as bisphosphonate or denosumab, which may inhibit the treatment of primary disease and remarkably influence the patient’s quality of life. The treatment methods for MRONJ, nonsurgical and surgical, are controversial, with no agreement as to which method provides the best outcome and should therefore be recommended. This multicenter retrospective study aimed to investigate the treatment methods and outcome in a large number of patients with MRONJ in Japan, utilizing propensity score matching analysis. Methods: A total of 361 patients with MRONJ, at eight hospitals, were registered in this study retrospectively. Various demographic and treatment-related variables were examined and analyzed to determine their correlation with the treatment outcome. After propensity score matching for treatment methods (nonsurgical vs. surgical treatment), 176 patients were analyzed by logistic regression. Results: It was shown that those with low-dose administration of an antiresorptive agent and surgical treatment had better outcomes. Furthermore, in 159 patients who underwent surgical treatment, those who underwent extensive surgery experienced significantly better treatment outcomes than those who underwent conservative surgery. Drug holiday of BMA during treatment of MRONJ had no advantage for outcome. Conclusions: This is the first study to compare treatment methods for MRONJ using propensity score matching analysis. The results indicated that extensive surgical treatment should be performed as first-choice therapy for patients with MRONJ. Clinical trial information: 000021760.