tbuckley/cabot-search huggingface dataset:
Characterization of responders versus nonresponders to the anti-estrogen agent fulvestrant: A retrospective cohort study.
Authors: Santosh Bhusal
Journal: Journal of Clinical Oncology (2012)

117 Background: Patients with breast cancer often benefit from targeted endocrine therapy with estrogen receptor antagonists. However, the duration of therapeutic response to these agents is variable. We investigated several clinical variables that may potentially affect the duration of response to fulvestrant in the setting of metastatic disease. Methods: A retrospective cohort analysis was done in 137 patients who received fulvestrant between 2000 and 2011 at Moll Cancer Center at Fairview Hospital and Cleveland Clinic Cancer Center. Several patient variables e.g. degree of estrogen receptor positivity, BMI etc. were analyzed. The RECIST 1.1 criteria was used to measure disease activity. Clinical benefit (i.e., responsiveness) was defined as complete response, partial response or stable disease at 24 weeks of therapy. 57 patients had clinical benefit whereas 80 did not. The clinical variables were then compared between the two groups using Chi square test, Fisher's exact test and Wilcoxon’s rank sum test. A multivariable logistic regression model was then used to assess the association. Results: Patients who were responders exhibited a significantly higher proportion of bone and/or soft tissue only metastases than non-responders (51% vs. 24 %, p= 0.001). They also appeared to be older (mean age ± SD: 64.1 ± 12.2 vs. 60.2 ± 13.2, p=0.044) and had prior aromatase inhibitor sensitiveness (83% vs. 56, p=0.006). However, in multivariate and logistic regression analyses, the site of metastases was found to be the only significant predictor of response. Patients with bone and/or soft tissue only metastases were more likely to be responders than patients with visceral metastases (OR= 2.883 [95 % CI= 1.313 - 6.328], P= 0.012; OR: 3.325 [95% CI, 1.600-6.908], p=0.001, respectively). Conclusions: In metastatic breast cancer, patients with bone and/or soft tissue only metastases were more likely respond to fulvestrant therapy than those with visceral metastases.
Evaluation of levels of proliferating macrophages in patients at a county hospital and those with early recurrences.
Authors: R. Mukhtar, A. Moore, O. Nseyo, A. Au, F. L. Baehner, D. H. Moore, M. Campbell, L. Esserman
Journal: Journal of Clinical Oncology (2010)

1110 Background: Outcomes disparities persist in breast cancer, with certain minorities and women of low socioeconomic status more likely to develop high-risk cancers. The underlying mechanism is unknown, but may be related to biology rather than neglect. We have found in a cohort of UCSF breast cancer patients that abnormally proliferating macrophages, or “promacs,” are associated with hormone receptor negative and high-grade cancers, and shorter disease-free survival. We hypothesized that minority women, those of low socioeconomic status, and those with recurrence or death within 5 years of diagnosis would have increased tumor promacs. Methods: We identified consecutive breast cancer patients with available tissue blocks at Highland Hospital (Oakland, California) between 1996-2000. Promac thresholds were set using a cohort of 110 patients from UCSF, evenly divided by grade. Sections were double stained with CD68 and PCNA and cells positive for both were considered promacs. A single pathologist determined tumor grade and number of promacs per high-powered field (hpf). We used chi-squared and student's t-tests for categorical and continuous variables, and Kaplan-Meier survival analyses. Results: Of the 70 cases in the Highland cohort mean age was 51.6 and there were 42% African American, 23% Caucasian, 17% Asian, and 15% Hispanic women. 80% of tumors were grade 3 and 36% were estrogen receptor (ER) negative. Comparing grade 3 cases, the Highland cohort had significantly more promacs, with a mean of 38.5 promacs/hpf versus 9.75 promacs/hpf at UCSF (p < 0.0001). Hispanic women had significantly more promacs than Caucasians (51.2/hpf versus 31/hpf, p=0.0317) and had shorter time to recurrence (p=0.0094). Higher numbers of promacs were associated with early recurrence, with 72% of early recurrences having high promacs versus 44% of those without recurrence (p=0.039). Conclusions: A cohort of ethnically diverse breast cancer patients at a county hospital serving patients of low socioeconomic status had elevated promacs in tumor tissue. These findings may provide insight into the biology of high-risk cancers in these populations, potentially implicating altered immune function in their pathogenesis. No significant financial relationships to disclose.
Anastrozole and goserelin combination as first treatment for premenopausal receptor positive advanced or metastatic breast cancer: A phase II trial
Authors: H. H. Roche, D. Thierry, S. Chieze, K. Pierre, C. Veyret, S. Abadie, M. Campone, D. Florence
Journal: Journal of Clinical Oncology (2009)

1079 Background: Aromatase inhibitors (AIs) have shown high activity in postmenopausal women. However, as AIs do not suppress ovarian oestrogen synthesis, they are not effective in premenopausal women. The aim of this trial was to assess the efficacy of the combination of anastrozole and goserelin (LHRH agonist) in premenopausal women with advanced or metastatic hormonal receptor positive breast cancer. Methods: Premenopausal women with advanced estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer were enrolled in this open, multicentre, non-comparative phase II trial and received anastrozole 1mg/day p.o. and gosereline 3.6 mg subcutaneously monthly until progression. The primary endpoint was objective response rate (ORR) assessed according to RECIST criteria. Results: Thirty-three patients (33), with a mean age of 44 (+ 5.9) years, PS 0–2, were enrolled from December 2001 to May 2005. All patients were ER positive and 75.8% PR positive and 6 patients (18.2%) received adjuvant treatment with anti estrogens. There were 4 (12.1%) complete responses (CR), 14 (42.4%) partial responses (PR), and 11 (33.3%) stable diseases (SD), giving an ORR of 54.6% (IC 95% [36.4; 71.9]). Twenty-one (63.6%) patients showed a clinical benefit (CR+PR+SD≥24 weeks) for a median duration of 13.7 (IC 95% [8.74; 22.97]) months. Median time to progression was 13 (6;33) months. The most commun AEs were hot flush in 29 (87.9%), arthralgia in 13 (39.4%) and nausea in 12 (36.4%) patients. Conclusions: The combination of anastrozole and gosereline is well tolerated and appears to be an effective treatment of premenopausal women with advanced breast cancer in this exploratory phase II trial. No significant financial relationships to disclose.
Essential efficacy and safety profiles of everolimus in Japanese patients with metastatic renal cell carcinoma.
Authors: H. Uemura, H. Kanayama, N. Nonomura, T. Miki, K. Nishimura, A. Matsubara, Y. Tomita, M. Kuroda, Y. Katsuoka, M. Fujisawa, S. Takahashi, T. Nakatani, T. Matsuda, I. Hara
Journal: Journal of Clinical Oncology (2011)

e15140 Background: Although the efficacy of sorafenib and sunitinib was similar in Asian and non-Asian patients with metastatic renal cell carcinoma (mRCC), large differences have been shown in the incidence of adverse events (AEs) in these populations. Due to limited data obtained from the RECORD-1 global study thus far (only 15 patients enrolled in the everolimus group), there is no strong evidence to support the efficacy and safety of everolimus in Japanese patients. Moreover, the incidence of interstitial lung diseases (ILD) in the temsirolimus Asian phase-II study was significantly higher as compared to Western phase-III data. Therefore, it is very important to establish the AE profile of everolimus in the Japanese population. Methods: The target patient population consisted of patients with advanced renal cell carcinoma who had been treated with everolimus since January 2010. Data on efficacy, PFS and response rate and safety were collected and demographic factors that could be correlated with efficacy and safety were carefully investigated. Data will be up-dated until May 2011, when the final data from approximately 150 cases will be shown. Results: Demographic data from 87 evaluable patients is as follows: mean age of 62 years; male to female ratio of 78:22; PS of 0 in 73%, 1 in 14%, 2-4 in 13%; histological diagnosis of clear cell carcinoma in 79%. Prior treatments were cytokines in 52%, sunitinib in 72%, and sorafenib in 60%. The reasons for discontinuation of prior therapy were progression (73%), adverse events (25%), and others (2%). Efficacy was demonstrated with a median PFS of 2.8 months and RR of PR7%/SD47%/PD20%. The incidence of adverse events (all grades) was 85% and discontinuation due to AEs was 30 %. Major AEs were stomatitis (45%), thrombocytopenia (25%), and anemia (24%).Serious adverse events (Grades 3-4) were anemia (9%), thrombocytopenia (6%), hyperglycemia (5%), and ILD (5%). Onset of adverse events was less than 28 days after starting the administration of everolimus. Conclusions: These findings suggest that everolimus was shown to be associated with relatively serious adverse events in Japanese patients and further up-date is necessary to provide an Asian AE profile of everolimus.
Prediction of outcome using positron emission tomography (PET) compared to standard response criteria and potential role in treatment decisions in diffuse large B-cell lymphoma (DLBCL) patients
Authors: M. Trneny, U. Jaeger, O. Belohlavek, C. Skrabs, J. Koren, A. Hanswirth, R. Pytlik, P. Klener
Journal: Journal of Clinical Oncology (2006)

7565 Background: PET has been demonstrated to give valid information about viable tumor residua. There are however only limited data regarding the combination of classical response criteria with PET and there is a lack of information on the impact of additional therapy (add-Th) on the outcome of PET neg. or PET pos. pts. Methods: One hundred thirty-nine pts (median age 50y) with newly diagnosed DLBCL who were examined by PET during (after 2–4 cycles CHT - ‘early PET’) or/and at the end of therapy (‘end PET’) were analyzed retrospectively. IPI risk distribution were as follows: L 28%, LI 24%, IH 33% and H 15% pts. All pts were treated with anthracyclin based CHT. “Early PET” was performed in 84 pts. and “end PET” in 103 pts before add-Th, PET at both time points was performed in 48 pts. Add-Th (HDT with ASCT or/and radiotherapy), was given as planned or as a result of response evaluation (conventional methods - CT, trephine biopsy). No treatment modification was made on PET result only, except for 2 cases when planned RT was skipped because of PET neg. RT was performed in 59 pts (42.4%) and HDT with ASCT as consolidation in 54 pts (38.8%). Median follow up was 30 m. Results: CR or CRu was achieved after CHT in 102 (74%) pts, PR in 24 (17%) pts, stable or progress dis. in 13 (9%). ‘Early PET’ was neg. in 60% pts and ‘end PET’ was neg in 67% pts. PET neg. was achieved at least once in 97 (70%) pts, and PET pos. at least once was found in 50 pts (36%). The PFS at 30 m according to the combination of conventional and PET response was as follows: for CR PET-neg. pts 89%, for PR PET-neg. pts 90%, for CR PET-pos. pts 45% and for PR PET-pos. pts 64% (p=0.0001). OS was 93%, 63%, 90% and 83%, respect.(p=0.004). The analysis of impact of add-Th showed PFS at 30 m: for PET-neg pts with Add-Th 96%, for PET-neg. pts without Add-Th 82%. PET-pos. pts without Add-Th had a PFS of only 10% and PET-pos. pts with add-Th had PFS 58% (p=0.0001). The OS was 92%, 98%, 38% and 74% respect. (p=0.0001). Conclusions: Our data demonstrate that PET give more powerful information than standard response criteria. The second analysis support the the idea that pts with DLBCL in CR who remain PET pos. should undergo the additional therapy. Partial support: Grant MSM 0021620808 No significant financial relationships to disclose.
Nonmyeloablative conditioning with mesenchymal stem cell transplantation for type 1 diabetis mellitus.
Authors: C. Haritha, V. Shankar, H. L. Trivedi, A. Vanikar
Journal: Journal of Clinical Oncology (2010)

e13087 Background: The use of human adipose-tissue-derived insulin-producing mesenchymal stem cells (h-AD-MSC) transfused with unfractionated cultured bone marrow (CBM) in management of type 1 diabetis mellitus (T1DM) patients. Methods: 19 consecutive insulinopenic T1DM patients (M:F-14:5) of 0.6 to 10 yrs duration, age 14-28 yrs under treatment with human insulin (14-70 U/d) showing postprandial blood sugar between 156 to 470 mg%, glycated hemoglobin (HbA1C) 6.8% to 9.9% and c-peptide levels of 0.02 to 0.2 ng/mL were enrolled into this prospective phase I study, since October 2007. Healthy, willing nondiabetic donors of matching blood group from the family of recipients provided consent for the extraction of adipose tissue from anterior abdominal wall (D -14) and bone marrow aspiration following G-CSF stimulation (D -10 and -9). All recipients underwent: (a) nonmyeloablative low-intensity conditioning (D -8 to -1), which included (1) fractionated total lymphoid irradiation-1000cgy/5# delivered by 3- DCRT technique by 6MV/15MV photons to cervical, mediastinal, paraortic, and iliac regions (D -8 to -3); (2) anti-T cell antibody (D -2) and anti-B-cell antibody (D -1) and (b) intraportal infusion of xenogeneic-free h-AD-MSC and hematopoitic stem cell (HSC) (D - 0). Fasting and PP blood sugar levels, C peptide (CP) levels were checked weekly for 1 month and monthly thereupon. Insulin requirement was made on sliding scale as per patient requirements. Key endpoints of study are morbidity/mortality/side effects from MSC+HSC transplantation and temporal changes in exogenous insulin requirements. Secondary endpoints were C-peptide levels and Hb A1c following MSCT. Results: With a mean follow-up of 12 months, all patients were successfully infused h- AD-MSC plus CBM without any untoward effects (infective episodes or GVHD) and heavy immunosupression. There was a statistically significant (p=0.0001) decrease in the insulin requirements(30%-50%), increase in CP levels (4-26fold), and decrease in HbA1C. Conclusions: This report, the first of its kind on human subjects, describes safe and cost-effective treatment of insulinopenic diabetics using insulin-producing h-AD-MSC plus CBM without xenogeneic materials. No significant financial relationships to disclose.
Effect of selinexor (KPT-330), a novel oral selective inhibitor of nuclear export (SINE), on tumor suppressors and cell cycle proteins in prostate cancer cells and regression of castration-resistant patient-derived xenograft tumor growth.
Authors: Sankar N. Maity, Guanglin Wu, Jing-Fang Lu, Anh Hoang, Yosef Landesman, Dilara McCauley, Robert Carlson, Tami Rashal, Sharon Shacham, Bradley McIntosh Broom, Keith A. Baggerly, Ana Aparicio, Eleni Efstathiou, John C. Araujo, Christopher Logothetis
Journal: Journal of Clinical Oncology (2015)

277 Background: Androgen deprivation, anti-androgen and androgen biosynthesis inhibitor treatment can initially control the metastatic prostate cancer (PCa), but treatment-refractory progression frequently follows, with the loss of tumor suppressors (TSPs) and increased expression of cell cycle proteins. Inhibition of the nuclear export protein, Exportin 1 (XPO1) leads to nuclear accumulation of cargo proteins such as TSPs &amp; cell-cycle regulators implicated in castration-resistant PCa (CRPC) progression. XPO1 and specific cargo genes are overexpressed in metastatic CRPC relative to benign &amp; primary prostate tumors, implicating XPO1 activity as playing a role in disease progression. Selinexor (KPT-330), a novel, oral SINE currently in Phase 1/2 for both hematological and solid tumors, has potent activity against CRPC. We hypothesized this activity is due selinexor induced nuclear expression of TSPs. Methods: To test this hypothesis, we treated selected PCa cell lines and patient-derived xenografts (PDXs, two adenocarcinomas and one small cell carcinonoma) with selinexor to determine the effect on survival and cargo protein localization. Results: Treatment with selinexor markedly inhibited PCa cell proliferation in vitro, activated the tumor suppressor TP53 &amp; inhibited cell-cycle regulators. Also, treatment of the PDXs with selinexor for at least 3 weeks significantly inhibited tumor growth &amp; reduced the prostate-specific antigen level in the adenocarcinomas. Selinexor increased cell death in all three PDX tumors and reduced cell proliferation in the adenocarcinomas, but not in the small-cell tumor. Expression analyses demonstrated that selinexor induced nuclear accumulation of different cargo proteins unique to the PCa model, accounting for PDX-specific regression. Conclusions: These results point to an anti-tumorigenic effect of selinexor treatment across a spectrum of hormone-refractory PCa that may provide insight into the drivers of PCa treatment resistance and heterogeneity.
Combination chemotherapies in advanced gastric cancer: An updated systematic review and meta-analysis
Authors: A. D. Wagner, W. Grothe, J. Haerting, G. Kleber, A. Grothey, W. E. Fleig
Journal: Journal of Clinical Oncology (2007)

4555 Background: Combination chemotherapy is widely accepted for patients with advanced gastric cancer, but uncertainty remains regarding the choice of the regimen. Methods: Our objectives were to assess the effect of: 1) 5-FU/cisplatin combinations with versus without anthracyclines; 2) 5-FU/anthracycline combinations with versus without cisplatin; 3) Irinotecan versus non-irinotecan containing combination chemotherapies; 4) Docetaxel versus non-docetaxel containing combinations; on overall survival and toxicity. Search strategy: We searched: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, proceedings from DDW, ECCO, ESMO, ASCO until october 2006. Selection criteria: Randomised controlled trials on different combination chemotherapies as above in advanced gastric cancer. Results: 13 trials including in total 2,184 patients (pts) are included in this meta-analysis. Comparison 1) including 501 pts (HR 0.77; 95% CI 0.62–0.95); and 2) including 1,147 pts (HR 0.83; 95%CI 0.76–0.91) both demonstrate a significant survival benefit for three-drug regimens including 5-FU, anthracyclines and cisplatin. Among these, the rate of treatment-related deaths was higher when 5-FU was administered as bolus compared to infusional 5-FU (exact Mantel-Haenszel OR 2.33, p=0.285). Comparison 3) including 536 pts results in a HR of 0.88; 95% CI 0.73- 1.06. The rate of treatment related deaths was 0.7% versus 2.6% in the irinotecan versus non-irinotecan-containing arms (exact Mantel-Haenszel OR 0.275, p=0.166). Comparison 4) 4 relevant trials were identified. A meta-analysis will be performed as soon as the final results of at least 3 trials are available. Conclusions: Three-drug regimens containing 5-FU, anthracyclines and cisplatin achieve superior survival results compared to cisplatin/5-FU or antracycline/5-FU combinations. Among these, ECF (epirubicin, cisplatin and 5-FU) is tolerated best. Combinations including irinotecan demonstrate a non-significant trend towards better survival in this meta-analysis, but have never been compared against three-drug regimens containing 5-FU/cisplatin and an anthracycline. Supported by: KKS Halle, grant number [BMBF/FKZ 01GH01GH0105]. No significant financial relationships to disclose.
The therapeutic potential of artesunate in hepatocellular carcinoma
Authors: Yves-Paul Vandewynckel, Debby Laukens, Anja Geerts, Isabelle Colle, Louis Libbrecht, Eliene Bogaerts, Lindsey Devisscher, Annelies Paridaens, Xavier Verhelst, Christian Vanhove, Benedicte Descamps, Sophie Janssens, Bart Lambrecht, Christophe Van Steenkiste, Hans Van Vlierberghe
Journal: Hepatology (2013)
Lung allograft loss: naming helps seeing… and <i>vice versa</i>!
Authors: Peter Dorfmüller, Tom Kotsimbos
Journal: European Respiratory Journal (2015)

The loss of allograft function in the long term (whatever its pattern over time) not only remains the single major cause of death following lung transplantation but has continued largely unabated since the beginning of the modern era in the 1980s [1–3]. As obliterative bronchiolitis (OB) was the most common histopathological finding on biopsy of the failing lung allograft, this feature became the unequivocal manifestation of chronic rejection in the lung allograft [3]. The logistical difficulties of obtaining frequent and numerous sampling biopsies to reliably and easily detect OB, however, led to another leap of faith where a syndromic definition (bronchiolitis obliterans syndrome; BOS) became the "working definition" of chronic rejection in the lung allograft [4]. BOS had both defining features that had to be present (irreversible loss in forced expiratory volume in 1 s (FEV1) as a percentage of the best achieved post-transplant) and exclusionary ones (the irreversible loss in FEV1 was "otherwise unexplained"; e.g. clinically relevant airways infection and aspiration had to be absent) [4, 5]. However, although the concept of BOS greatly increased the ease with which "chronic rejection" could be diagnosed after lung transplant, it also railroaded thinking for many years. In particular, a protocolised definition of chronic rejection through the diagnostic label of BOS hindered thoughts that infection (key non-alloimmune factor)- and alloreactivity-associated obliterative bronchiolitis may not necessarily be independent events [6, 7] and that chronic rejection could either have a reversible component or manifest as a restrictive pattern of lung allograft loss [8]. The many forest fires of chronic lung allograft dysfunction: where are they, when were they lit and how do they burn? <http://ow.ly/Sob6f>