tbuckley/cabot-search huggingface dataset:
Is care coordination associated with improved care quality for comorbid conditions in cancer survivors?
Authors: Claire Frances Snyder, Kevin D. Frick, Robert J. Herbert, Amanda L. Blackford, Bridget A. Neville, Klaus Lemke, Antonio C. Wolff, Michael Anthony Carducci, Craig Earle
Journal: Journal of Clinical Oncology (2012)

6026 Background: Many cancer survivors have comorbid conditions, adding complexity to their already complicated care and requiring greater care coordination. We assessed the role of care coordination in comorbid condition care for cancer survivors. Methods: Using SEER-Medicare, we examined 7 published indicators of quality comorbid condition care in survivors of loco-regional breast, prostate, or colorectal cancer who were diagnosed in 2004, in fee-for-service Medicare, and survived ≥3 years. Comorbid condition care was evaluated during the transition from initial cancer treatment to survivorship (i.e. days 366-1095 post-diagnosis). Coordination risk was categorized as Likely, Possible, or Unlikely using an index developed and tested as part of the ACG case-mix adjustment and predictive modeling tool. The index factors in the number of unique providers, number of specialties, the percentage majority source of care, and generalist visits. We tested the hypothesis that lower coordination risk would be associated with better comorbid condition care using logistic regression, adjusting for socio-demographics, cancer type, and comorbidity. Results: The sample included 8661 survivors (53% prostate, 22% breast, 26% colorectal; mean age 75; 65% male, 85% white). Our hypothesis was not supported. Compared to patients with Unlikely coordination issues, patients with Likely coordination issues were more likely to receive appropriate care on 4 indicators and less likely on 1. Possible coordination issues were associated with better care on 1 indicator and worse care on 1 indicator. To explore this finding further, we conducted post-hoc analyses examining the role of each component of the coordination risk index. Having more unique providers was generally associated with better comorbid condition care, in contrast to the calculation of the index which considers more unique providers a greater risk for coordination issues. Conclusions: These findings suggest that traditional metrics of care coordination may not be valid for survivors of cancer. Understanding the role of care coordination in cancer survivorship care requires development and application of alternative coordination measures.
The Promise of Targeting Macrophages in Cancer Therapy
Authors: J. Martin Brown, Lawrence Recht, Samuel Strober
Journal: Clinical Cancer Research (2017)

Abstract Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this review, we outline the importance of tumor-associated macrophages (TAM), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs, and their role in blunting the efficacy of cancer treatment by radiation and anticancer drugs, both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally, we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy. Clin Cancer Res; 23(13); 3241–50. ©2017 AACR.
A phase II trial of an oral CDK 4/6 inhibitor, PD0332991, in advanced breast cancer.
Authors: Angela DeMichele, Amy Sanders Clark, Daniel Heitjan, Sophia Randolph, Maryann Gallagher, Priti Lal, Michael D Feldman, Paul J. Zhang, Allison Schnader, Kelly Zafman, Susan M. Domchek, Keerthi Gogineni, Stephen Michael Keefe, Kevin R. Fox, Peter J. O'Dwyer
Journal: Journal of Clinical Oncology (2013)

519 Background: The G1/S checkpoint of the cell cycle is frequently dysregulated in breast cancer (BC). Initial efficacy of PD0332991, a potent oral inhibitor of cyclin-dependent kinases (CDKs) 4/6 was shown in a variety of solid tumors and in combination with letrozole in a randomized phase II trial. Methods: We performed a phase II, single arm trial of PD0332991 in women with advanced BC. The primary objectives were safety and efficacy. Eligible patients had histologically-confirmed, stage IV BC with primary or metastatic tumor positive for retinoblastoma (Rb) protein expression, measureable disease by RECIST and adequate organ function/performance status. PD0332991 was given at 125 mg orally, days 1 – 21 of a 28-day cycle. Tumor was assessed every 2 cycles. A two-stage statistical design was employed. Secondary objectives included predictive biomarker assessment. Results: 36 patients were enrolled; 28 who completed cycle 1 are reported: 18 (64%) HR+/Her2-, 2 (7%) HR+/Her2+ and 8 (29%) HR-/Her2-. 90% had prior chemotherapy for metastatic disease (median 3 lines); 78% had prior hormonal therapy (median 2 lines). Grade 3/4 toxicities were limited to transient neutropenia (50%) and thrombocytopenia (21%). One episode of neutropenic sepsis occurred in cycle 1 in patient with 6 prior chemo regimens. All other toxicities were grade 1/2. Treatment was interrupted in 7 (25%) and dose reduced in 13 (46%) pts for cytopenias. For response data see table. Responses occurred at dose levels as low as 50 mg. Median PFS (months, 95% CI) was 4.1 (2.3,7.7) for ER+/Her2-, 18.8 (5.1,∞) for ER+/Her+ and 1.8 (0.9,∞) for ER-/Her2-. 27/28 patients discontinued study for progressive disease (PD); 1 due to patient preference. Conclusions: Therapy with PD0332991 alone is well-tolerated and demonstrates response or prolonged stable disease (SD) in patients with BC despite prior hormonal and chemotherapy. Expansion within subtypes and molecular predictors of response are being investigated. Clinical trial information: NCT01037790. [Table: see text]
NCCTG trial of concomitant or sequential IL-12 in combination with rituximab in previously treated non-Hodgkin lymphoma patients
Authors: S. M. Ansell, S. M. Geyer, T. E. Witzig, D. F. Jelinek, P. J. Kurtin, I. N. M. Micallef, P. Stella, P. Etzell, C. Erlichman, A. J. Novak
Journal: Journal of Clinical Oncology (2004)

6591 Background: Rituximab is a chimeric murine/human monoclonal antibody that binds to CD20 on B-lymphocytes. Interleukin-12 (IL-12) facilitates cytolytic T-cell responses and enhances the lytic activity of NK cells. This study was performed to determine the efficacy and toxicity of the combination of IL-12 and rituximab in patients with B-cell non-Hodgkin lymphoma (NHL). Methods: 52 patients with previously treated, histologically confirmed CD20+ low-grade B-cell NHL or mantle cell NHL have been enrolled in this phase 2 study. Patients were randomized to one of two arms: concurrent treatment with rituximab+IL-12 (Arm A) or rituximab with subsequent treatment with IL-12 after documented non-response, defined as less than a partial response (Arm B). Treatment consisted of rituximab 375 mg/m2 on days 1, 8, 15, and 22; and IL-12 300 ng/kg given SQ twice weekly starting on day 2 of cycle 1 for Arm A or upon progression or non-response for Arm B. We focus here on the interim analyses of the first 21 evaluable patients in each arm. Results: To date, 14 of 21 patients on Arm A and 9 of 21 patients on Arm B have discontinued treatment. 8 patients on Arm B have progressed, and have gone on to receive IL-12. On Arm A, 8 patients had grade 3 and 2 patients grade 4 toxicities vs. 2 patients on Arm B with grade 3 toxicities. Of the first 21 evaluable patients accrued to Arm A, 8 responses (38%) have been observed to date. Eight responses (38%) have also been observed on Arm B. All responses observed in Arm B were due to rituximab and none from subsequent treatment with IL-12. Based on these results, accrual to Arm B was closed. However, the subset of mantle cell NHL patients on Arm A had a higher response rate (3/5 patients). As a result, mantle cell NHL patients will continue to be accrued to Arm A. Conclusions: The combination of IL-12 and rituximab was well tolerated. The sequential administration of IL-12 at the time of disease progression after treatment with rituximab did not result in any clinical responses. The concomitant use of IL-12 and rituximab had moderate disease activity in this study; however, promising clinical activity was seen in patients with mantle cell NHL. No significant financial relationships to disclose.
Survival and prognostic factors of radioiodine refractory pulmonary metastatic differentiated thyroid carcinoma (DTC).
Authors: Johanna Wassermann, Marie-Odile Bernier, Jean-Philippe Spano, Charlotte Lepoutre-Lussey, Jean-Marc Simon, Fabrice Ménégaux, Catherine Hoang, André Aurengo, Laurence Leenhardt
Journal: Journal of Clinical Oncology (2013)

6093 Background: The challenging key point of management of radioiodine refractory DTC patients is to define those who could benefit from experimental drugs in clinical trials. Methods: We reviewed clinical and pathological data of patients with refractory pulmonary metastatic DTC treated in our center from 1990 to 2011. Survival was estimated with the method of Kaplan-Meier. Associated prognostic factors were studied in Cox model based analyses. Results: Among 167 pulmonary metastatic DTC, 46% (n=76) met a criterion of radioiodine refractory disease: at least one metastases without I131 uptake: 61% (n=46); progressive disease despite I131: 22% (n=17) and absence of complete response despite a cumulated dose &gt;600mCi: 17% (n=13). There were 63% of female (n=48) and the median age was 64 years (range 18-87). The initial treatment was total thyroidectomy in 92% (n=70), lymph node dissection in 71%, (n=54) and radioiodine therapy in 100% of patients. Pathological features were papillary histology in 61% (n=46), follicular histology in 29% (n=22) and poor differentiated histology in 10% (n=8). pT stage was 1ab, 2, 3, and 4 in 11%, 13%, 63% and 13% respectively, pN stage after lymph node dissection was 0, 1a and 1b in 33%, 7% and 60% respectively. Metastasis were present at diagnosis in 45% (n=34) of cases. The refractory feature was established at the time of diagnosis and in the follow-up in 18% and 82% of cases respectively. When the disease was considered as refractory, the median overall survival was 5.5 years. The refractory feature at the initial diagnosis was the only independent prognostic factor correlated with poor survival (p&lt;0.001). Conclusions: Patients who are considered as radioiodine refractory at the initial diagnosis of DTC have poor prognosis and should be considered for clinical trials in case of progression.
Satisfying the fatty acid demand of prostate cancer: De novo synthesis versus uptake as alternative and potentially cooperative prostate cancer phenotypes.
Authors: Sandra Marlene Gaston, James Kearns, George W. Adams, Soroush Rais-Bahrami, Jeffrey Nix, Peter N Kolettis, James E Bryant, Dennis Otali, William E. Grizzle
Journal: Journal of Clinical Oncology (2017)

107 Background: Malignant transformation increases cellular demand for fatty acids (FA). Many cancers show increased expression of fatty acid synthase (FASN); FASN catalyzes the de novo synthesis of the FA palmitate. While research has focused on FASN and de novo tumor FA synthesis, observations suggest that alternate mechanisms for FA acquisition are also important, including studies showing that cancer cells can be rescued from FASN inhibition by exogenous palmitate. Using a biopsy-based approach, we identified a PrCa subtype with outlier (&gt;10 fold) overexpression of fatty acid binding protein 5 (FABP5). FABP5 facilitates the utilization of palmitate and other FAs from outside the cell; a FABP5 overexpression phenotype may confer a selective advantage when dietary FAs are abundant or when FASN is targeted as a therapy. Methods: 244 prostate biopsy patients were prospectively enrolled. Tissue prints were collected from each core for RNA and DNA preparation. mRNA was analyzed using Affymetrix arrays and TaqMan qrtPCR assays. Immunohistochemistry (IHC) was performed using archival radical prostatectomy (RP) specimens. Results: mRNA analyses revealed a PrCa subtype with &gt;10 x overexpression of FABP; this phenotype was observed in 7% of 268 cores with Gleason sum (GS) 7-10 PrCa. We also observed a second subtype with &gt;10 x overexpression of FASN in 9% of GS 7-10 cores. With few exceptions these two PrCa subtypes showed an “either-or” pattern with top-quartile overexpression of FABP5 or FASN but not both (Spearman r = - 0.385; P &lt; 0.0001). IHC confirmed variable expression, including “patchwork” PrCas with high Gleason pattern (GP) areas overexpressing FABP5 next to low GP areas overexpressing FASN. The net result may be a selective advantage for the high grade cancer if FABP5 allows it to exploit the FA being synthesized by the adjacent low grade focus Conclusions: Identification of a PrCa subtype with high levels of FABP5 overexpression suggests a previously unrecognized mechanism by which some PrCas can increase FA supply without de novo synthesis; such a PrCa subtype might be particularly sensitive to dietary interventions and relatively insensitive to FASN inhibitors.
Antimesothelin vaccine CRS-207 plus chemotherapy as front-line treatment for malignant pleural mesothelioma (MPM).
Authors: Raffit Hassan, Evan W. Alley, Hedy Lee Kindler, Scott Joseph Antonia, Thierry Marie Jahan, Mona Jacobs-Small, Jennifer Hull, Katherine McDougall, Ed Lemmens, Aimee Murphy, John J. Grous, Thomas Dubensky, Dirk G. Brockstedt
Journal: Journal of Clinical Oncology (2014)

7532 Background: CRS-207 is live-attenuated Listeria monocytogenes engineered to express the tumor-associated antigen mesothelin which is highly expressed in malignant pleural mesothelioma (MPM). CRS-207 stimulates potent innate and adaptive cellular immunity. Chemotherapy may act synergistically in combination with CRS-207 by altering the tumor environment to be more susceptible to immune-mediated killing. Methods: Key eligibility criteria included patients who were chemotherapy-naïve, had unresectable MPM, good performance status (ECOG 0 or 1) and adequate organ function. Eligible patients received 2 prime vaccinations with CRS-207 (1 × 109 CFU; 250 mL IV over 2 hours) 2 weeks apart, followed by up to 6 cycles of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) 3 weeks apart and 2 CRS-207 boost vaccinations 3 weeks apart. Subjects were followed every 8 weeks until disease progression. Clinically stable patients could continue CRS-207 maintenance vaccinations every 8 weeks. Objectives of the study were safety, immunogenicity, objective tumor responses and tumor marker kinetics. Results: Sixteen subjects (88% male; median age: 69) have been enrolled and as of Feb 1 2014, 13/16 are still on treatment. Median time on treatment was 134 days (range: 0-330 days). No treatment-related serious adverse events or unexpected toxicities have been observed. The most common adverse events related to CRS-207 were Grades 1/2 infusion-related fever, chills/rigors, hypotension and nausea/vomiting. Of 15 subjects evaluable for response, 60% (9/15) had confirmed partial response (PR) post CRS-207 and chemotherapy and 27% (4/15) had stable disease (SD). Treatment, follow-up and immune response evaluations are ongoing. Conclusions: CRS-207 can be safely combined with standard of care chemotherapy and showed encouraging anti-tumor activity with 9 out of 15 subjects having confirmed durable PR and 4 SD. These results are considerably better than those expected with chemotherapy alone and warrant further evaluation. Clinical trial information: NCT01675765.
<i>APC</i> germ-line allele-specific expression in familial adenomatous polyposis
Authors: E. Castellsague, S. González, I. Blanco, E. Guinó, C. Lázaro, S. Gruber, G. Capella
Journal: Journal of Clinical Oncology (2009)

e22037 Background: About 13% of Familial Adenomatous Polyposis (FAP) families and 70% of Attenuated FAP families remain with unknown molecular pathogenic cause after APC and MYH mutational analyses. Also, mutations can affect specific allele expression (ASE) at the germline level. The aim of the study was to determine the presence of germline ASE in the APC gene in FAP and AFP with and without detectable APC or MYH mutations. Methods: Germline RNA from fresh frozen and/or cultured lymphocytes of 17 APC/MYH-negative Polyposis (7 FAP, 10 AFAP) families (21 individuals) and 35 APC-mutated Polyposis (30 FAP, 5 AFAP) families (60 individuals) was analyzed. Fourteen controls were also studied. ASE was investigated by single nucleotide primer extension (SNuPE) of rs2229992 APC coding SNP. Results: In controls ASE was 1.04± 0.3. We found that 17% (3 of 17) APC/MYH(-) FAP and AFAP families showed ASE (range=1.17–1.39) and ASE co-segregated with disease. ASE was more intense in short-cultured lymphocytes except for two cases and completely reversed by puromycin treatment. Eleven of 35 (31%) APC-FAP/AFAP harbored ASE (range=1.20–7.76), and the mutant allele was underexpressed in each case. ASE was restricted to splicing (4 families), nonsense (3 families) and frameshift (3 families) mutations outside of exon 15. Puromycin reversed ASE in all cases analyzed. Conclusions: APC ASE is present in a significant proportion (17%) of APC/MYH(-) FAP or AFAP. ASE, due to nonsense-mediated decay (NMD), is present in APC-FAP and is associated with specific mutation location, similar to reports for other hereditary syndromes. No significant financial relationships to disclose.
The impact of the extent of gastric resection on advanced gastric cancer treated with systemic chemotherapy.
Authors: Yusuke Sasaki, Yutaka Watanabe, Ichiro Ohkita, Jojo Hirota, Jun Konno
Journal: Journal of Clinical Oncology (2017)

194 Background: In previous clinical trials of adjuvant chemotherapy for gastric cancer, severe toxicity and discontinuation of chemotherapy was more common in patients receiving total gastrectomy (TG) than in those with distal gastrectomy (DG). However, data on the significance of the extent of gastric resection for stage IV gastric cancer treated with systemic chemotherapy are not available. Methods: This is a retrospective review of patients who were received chemotherapy with S-1 and cisplatin for stage IV gastric cancer at our institution between June 2009 and August 2015. The patients were classified into three groups according to the extent of gastrectomy (TG, DG and no gastric resection (NG)) before chemotherapy. Patient characteristics, survival and toxicities of chemotherapy were compared between three groups. Results: Among the 83 patients, 24 underwent TG, 19 DG, and 40 NG. Patient characteristics were well balanced between three groups. There was no significant difference in the requirement for dose reduction between TG, DG and NG patients (29% vs 11% vs 20%, respectively, p= 0.32). However, the rate of discontinuation because of toxicity was significantly higher in TG than in DG or NG patients (46% vs 16% vs 25%, respectively, p= 0.04). The main reasons of discontinuation were anorexia (43%), myelosuppression (23%), nausea (18%) and diarrhea (16%). The median progression-free survival was 8.9, 6.1 and 5.3 months ( p= 0.25), and the median overall survival was 16.0, 16.0 and 9.8 months ( p= 0.40) in the patients with TG, DG and NG, respectively. Conclusions: There was a high frequency of discontinuation of systemic chemotherapy in the advanced gastric cancer patients who underwent TG, but it was not associated with prognosis.
Use of dual donor T-cell chimerism to predict prognosis after double cord blood allogeneic transplantation.
Authors: Muhamed Baljevic, Kai Cao, Richard E. Champlin, Chitra Hosing, Nina Shah, Simrit Parmar, Katayoun Rezvani, Amanda Leigh Olson, Elizabeth J. Shpall, Betul Oran
Journal: Journal of Clinical Oncology (2015)

7093 Background: Double cord blood transplantation (dCBT) is an important strategy to overcome dose limitation of single CBT. By day 21, over 80% of patients (pts) have single unit dominance maintaining long-term hematopoiesis. However, outcomes of pts who have persistence of both CB units after dCBT is unknown. Methods: We retrospectively analyzed 105 pts who engrafted after dCBT between 2003 through 2014 and had donor T cell chimerism (TCC) of at least 10% from each CB unit at day 100 +/- 30 after transplant (dCTT). Pts alive and free of disease progression at day 100 were evaluable. Results: Of 105 pts, 10 (9.5%) had dTCC. Median age was 43 (range; 1-73). Disease diagnosis was AML in 57.1% and ALL in 21.9%. Disease status at dCBT was 1st or 2nd complete remission in 67.6% and active disease in 32.4%. Conditioning was myeloablative in 73.3% and reduced intensity in 26.7%. Immunosuppressive therapy included mycophenolate mofetil and tacrolimus; all pts received anti-thymocyte globulin. One of the CB units were manipulated by ex-vivo expansion in mesenchymal stem cell co-culture in 72.4% of the pts. The median dose of CD34+ and total nucleated cells infused was 0.36x106/kg (0.12-5.35) and 0.51x107/kg (0.3-1.29), respectively. Singe TCC (sTCC) and dTCC pts were comparable except for more frequent ≥ 4/6 HLA matching between 2 CB units (66.3% vs. 90%, p = 0.1), and less use of CB manipulation in dTCCC (74.7% vs. 50%, p = 0.1). Transplant outcomes were similar between groups with 3-year (yr) overall survival and progression free survival of 40% vs. 41.4% and 40% vs. 32.3%, respectively. Seven of 10 pts with dTCC were evaluable for long-term assessment [ > 6 months (mo)]: 1 pt had autologous recovery with progression after 6 mo of dCBT. Unit dominance was observed in 4 pts, within 4 to 20 mo after dCBT; 1 of them progressed 5 mo after unit dominance and another died of fungal infection at 15 mo. Two AML pts had long-term dTCC with units contributing 58%/42% and 84%/16% at 4 and 3.2 yrs after dCBT. Both were alive in remission at last follow-up. Conclusions: The unique situation of TCC from both CB units around day 100 is not associated with worse transplant outcomes in pts receiving dCBT. These provocative results need to be confirmed in larger studies.