tbuckley/cabot-search huggingface dataset:
Value of International Prognostic Score (IPS) in predicting need for bone marrow biopsy (BMB) in Hodgkin's lymphoma (HL)
Authors: A. Muslimani, T. Spiro, A. Chaudhry, H. Taylor, I. Jaiyesimi, P. Elson, H. Daw
Journal: Journal of Clinical Oncology (2009)

e19531 Background: BMB is frequently performed during the staging of patients (pts) with HL. Previous data suggested routine use of this procedure may be unnecessary. The Ann Arbor classification is currently used to detect pts requiring BMB. Despite sensitivity (sen) of 100%, specificity (spec) is only 40%. We sought to determine whether IPS [as developed by Hasenclever and Diehl (1998)] would yield greater spec while maintaining good sen. Methods: We retrospectively reviewed charts of 1215 histologically proven HL pts from Jan 2000-Dec 2008 at Cleveland Clinic Taussig and Fairview Moll Cancer Centers. Of 1215 pts, 1089 had BMB (90%). 876 pts were included in our study. 213 were excluded due to un-interpretable BMB or missing data. The IPS is calculated as the number of poor risk features present based on male sex, age ≥45, albumin (alb) &lt;4 g/dL, hemoglobin (hem) &lt;10.5 g/dL, stage IV, white blood cell (WBC) ≥15,000/mm 3 , lymphocyte (lymph) &lt;600/mm 3 and/or &lt;8% of total WBC. Multivariable logistic regression was initially used to assess the association between BMI and each factor in the IPS. All 7 factors were significant (p&lt;.001 for sex, age, albu, hem, stage and lymph; .07 for WBC); and therefore recursive partioning algorithm was used to identify a cutoff for determining bone marrow involvement (BMI). Results: 88 pts (10%) had BMI. Using an IPS of &gt;3 to predict BMI, sen was 97% and spec 87%. BMI by histology was 4% lymphocyte-rich, 5% nodular sclerosis, 20% mixed-cellularity and 21% lymphocyte-depleted. Using the IPS&gt;3 cutoff sen and spec were similar across all types of histologies; ranging from 94–100% and 86–89% respectively. Conclusions: using an IPS of &gt;3 for predicting BMI in HL doubled the spec associated with Ann Arbor classification with little loss of sen. The implementation of IPS is a practical and reliable tool that will allow physicians to predict BMI in HL pts. It may, therefore eliminate painful BMB in many Pts. No significant financial relationships to disclose.
Abstract 18172: FOXO3a Controls Viral Load in Acute Coxsackievirus B3 Myocarditis - Role of NK Cell Function
Authors: Carsten Skurk, Luise Holzhauser, Alexander Jenke, Carmen Scheibenbogen, Madlen Lobel, Sandra Pinkert, Moritz Becher, Heinz-Peter Schultheiss
Journal: Circulation (2012)

Purpose: Coxsackievirus B3 is known to induce myocarditis leading to dilative cardiomyopathy and heart failure. Cardiac injury is mediated by both direct viral damage and the hosts immune response....
Nitric oxide suppresses increases in mesangial cell protein kinase C, transforming growth factor beta, and fibronectin synthesis induced by thromboxane.
Authors: R K Studer, F R DeRubertis, P A Craven
Journal: Journal of the American Society of Nephrology (1996)

Thromboxane (TX) stimulation of fibronectin (FN) synthesis in mesangial cells (MC) is dependent on protein kinase C (PKC)-mediated increases in transforming growth factor beta (TGF beta), and is suppressed by increases in cellular cGMP. The current studies evaluate the role of cGMP-dependent and -independent actions of nitric oxide (NO) in modulating the responses of MC to the TX analogue U46619. TX-stimulated increases in PKC activity, TGF beta, and FN synthesis in MC were suppressed by either 8-Br-PET-cGMP or the NO donor S-nitroso-N-acetylpenicillamine (SNAP). By contrast, NO, but not cGMP, inhibited basal PKC activity, TGF beta bioactivity and FN synthesis. The cGMP-dependent protein kinase 1-alpha inhibitor 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate (Rp) restored the PKC, TGF beta, and the FN synthetic responses to TX when added to MC before exposure of the cells to either cGMP or SNAP. However, neither Rp nor the guanylate cyclase inhibitor Ly83583 significantly altered SNAP inhibition of basal PKC. In addition, Rp failed to alter the decreases in basal TGF beta bioactivity and FN synthesis seen in the presence of SNAP. In contrast to the FN response to U46619, cGMP and SNAP did not affect the stimulation of FN synthesis by exogenous TGF beta. The later findings are consistent with inhibitory actions of NO and cGMP at, or proximal to, U46619-induced increases in TGF beta in the suppression of TX-signaled increases in FN synthesis. Thus, NO depresses basal PKC and TGF beta bioactivity in MC by mechanisms that are largely independent of cGMP, whereas NO inhibition of these MC responses to TX is mediated primarily by increases in cGMP and activation of protein kinase 1-alpha.
Paclitaxel, 5-fluorouracil, and cisplatin (PFC) combination in patients (pts) with localized or advanced gastric-gastroesophageal junction adenocarcinoma (G-GEJA): A monoistitutional experience.
Authors: B. Soini, M. Frisinghelli, G. Ambrosini, O. Caffo, A. Caldara, A. Ferro, V. Murgia, F. Valduga, E. Galligioni
Journal: Journal of Clinical Oncology (2010)

e14678 Background: PFC is effective in G-GEJA, both preoperatively with 20% pCR rates after chemoradiotherapy (Ajani JCO 2005) and in advanced disease, with 34% OR rates (Jin JCO 2007). We report our experience with PFC in patients with locally advanced or metastatic G-GEJA. Methods: Between January 2006 and December 2009 twenty-seven consecutive pts, 16 with operable (Group A) and 11 with metastatic G-GEJA (Group B), were treated with: paclitaxel at 200 mg/sm i.v. on day 1, 5-fluorouracil at 750 mg/sm/d by continuous infusion on day 1 to 5 and cisplatin at 15 mg/sm/d i.v. on days 1 to 5, every 3 weeks for 2 cycles, followed, for patients with operable cancer, by radiotherapy (45 Gy on 25 fractions of 1.8 Gy over 5 weeks) with concomitant 5-FU (250 mg/sm/d continuosus infusion). Prophylactic G-CSFs were administered on days 6 to 16 in all patients. Results: In group A, 14 pts were males and 2 females, with a median age of 60 years (43-74). Ten pts received two cycles of chemotherapy followed by chemo-radiotherapy, while 6 pts received chemotherapy alone: 2 CR (12.5%), 10 PR (62.5%), 2 SD (12.5%) and 1 PD (6.25%) were obtained (1 not evaluable for early death). Nine pts underwent surgery, and 6 (66%) had a R0 resection, however no pathological CR was observed. In group B, 8 pts were males and 3 females, with a median age of 61 years (32-68). Pts received a median of 4 cycles of chemotherapy (range 2-8), obtaining 7 PR (63.6%), 1 SD (9%) and 3 PD (27.2%). In both groups, 92 cycles of chemotherapy were administered, with no WHO grade 4 toxicity or treatment related death. Grade 3 hematologic and non hematologic toxicities included neutropenia (2.1%), mucositis (2.1%), nausea or vomiting (2.1%) or diarrhoea (2.1%). Conclusions: In our experience, a substantial antitumor activity was observed with PFC in localized or advanced G-GEJA, with acceptable/low toxicity, if prophylactic G-CSF are provided. No significant financial relationships to disclose.
Clear cell sarcoma (CCS) or malignant melanoma of soft parts: A retrospective clinicopathologic study of 52 cases
Authors: O. Hocar, A. Le Cesne, P. Terrier, S. Bonvalot, D. Vanel, A. Auperin, C. Le Pechoux, B. N. Bui, J. Coindre, C. Robert
Journal: Journal of Clinical Oncology (2008)

10576 Background: CCS are aggressive, rare soft tissue tumors and their classification among melanoma or sarcoma is still undetermined due to their clinical, pathologic and molecular properties found in both types of tumors. We report clinical presentation, pathology, molecular biology and outcome profiles of 52 patients (pts) with CCS. Methods: This is a retrospective study of 52 pts with CCS seen between April 1979 and April 2005 in two institutions. Data analyzed included age, gender, anatomic location and size of tumors, local, regional or distant recurrences, treatments and pt status at last follow-up. The EWS-ATF-1 fusion transcript was studied in 30 pts and an activating mutation of the BRAF or NRAS gene was researched in 22 pts. Results: 30 men and 22 women, with a mean age of 33 were studied. 62% of the tumors were located in the lower extremities. Median initial tumor size was 4.8 cm (1 to 15 cm). Necrosis involving more than 50% of the tumor cells was found in 14 cases (27%). High mitotic rate was found in 25 cases (48%). Forty pts had a grade 2 histoprognostic grading (FNCLCC grading). The EWS/ATF-1 translocation was found in 28/30 (93.3%) patients and mutation of BRAF or NRAS were found in only 2/22 patients analyzed cases (9%). Among the tumor-associated parameters, only tumor size (> 5 cm) emerged as a significant prognostic factor. Forty-nine pts had a localized disease at diagnosis (94%) and underwent surgical resection immediately (90%) or after neoadjuvant chemotherapy (CT) (10%). Nineteen pts (36.5%) developed regional lymph node metastases and 30 (57.6%) presented distant metastases that were strongly associated with a poor outcome. Various CT regimen were used in 37 pts (71%) with no significant efficacy. The 5 and 10 year OS rates were 59% and 41%, respectively. Conclusions: Tumor size was the only emerging prognosis factor in our series. Complete surgical resection remains the optimal treatment for this aggressive chemoresistant tumor. No significant financial relationships to disclose.
Treatments of malignant peritoneal mesothelioma: A retrospective study on 47 cases.
Authors: Y. Wang, X. Ning, S. Chen
Journal: Journal of Clinical Oncology (2010)

e14611 Background: Malignant peritoneal mesothelioma (MPM) is a rare disease and prognosis is poor. The optimal treatment is still uncertain. Methods: A retrospective study on 47 patients with MPM treated by cytoreduction surgery (CRS), systemic chemotherapy and intraperitoneal (IP) in our institution from 1985 to 2006 was established. The primary end point was overall survival. The secondary end point was evaluation of prognostic variables for overall survival. Results: Follow-up was complete in all patients. The mean age was 51 years (standard deviation [SD], 12 years). Sixteen patients (34%) had diffused disease without organ involvement. Eleven patients (23%) had organ involvement. Eleven patients (23%) had diaphragm or abdominal wall involvement. Nine patients (19%) had positive lymph nodes. Twenty-one patients (44.7%) received CRS, platinum-based chemotherapy (GC: gemcitabine plus cisplatin; MIC mitomycine, isofomine plus cisplatin; PC: paclitaxel with cisplatin) and IP sequentially. Twenty-six patients(55.3%) treated by chemotherapy and IP sequentially. Nontreatment-related death and toxicity was well telorated. Twenty-six patients received second-line chemotherapy. The average time of overall survival was 18.1 months (95%CI,11.9-24.2) in CRS group and 10.0 months (95%CI, 7.7-12.3) in non CRS group, p = 0.011. Four prognostic factors which related to advance of disease were independently associated with poor survival in the multivariate analysis: organ involvement (p < 0.001), diaphragm or abdominal wall involvement (p < 0 .01), lymph node metastasis (p < 0 .01). Conclusions: The data suggest that CRS combined with systemic chemotherapy and IP which used sequentially achieved prolonged survival in selected patients. Organ involvement, diaphragm or abdominal wall involvement and lymph node metastasis independently correlated with decreased survival following comprehensive treatment. No significant financial relationships to disclose.
Abstract 15905: Vasopressin Infusion during Severe Hemorrhagic Shock Increases Systemic Blood Flow and Markedly Improves Survival in a Swine Model
Authors: Raul J Gazmuri, Kasen Whitehouse, Vesna Borovnik-Lesjak, Alvin Baetiong, Jeejabai Radhakrishnan
Journal: Circulation (2012)
Prognostic implications of YKL-40 overexpression in breast cancer
Authors: S. H. Kim, K. Das, S. Noreen, F. Coffman, M. Hameed
Journal: Journal of Clinical Oncology (2006)

20115 Background: YKL-40 has been implicated as a connective tissue growth factor and a migratory factor for endothelial cells. Elevated serum levels of YKL-40 have been found to correlate with worse survival in a variety of malignancies including breast cancer. We wished to determine if tumor overexpression of this protein also had prognostic implications in breast cancer. Methods: A prospectively collected database of breast cancer patients treated at the University Hospital of Newark was used for analysis. Immunohistochemical analysis was performed on 115 patients for whom full clinical information and follow up was available. Specimens were categorized as lacking immunoreactivity (0), having focal sparse immunoreactivity (1), or strong more diffuse immunoreactivity (2). Results: YKL-40 expression was noted in 38 patients (33%). Of these, 24 demonstrated strong (2) immunoreactivity (21%). Strong (2) YKL-40 immunoreactivity significantly correlated with larger tumor size (p &lt; .05). Tumors expressing any level of YKL-40 were also significantly more likely to be estrogen and/or progesterone receptor negative (p &lt; .01). No significant correlation was demonstrated between YKL-40 status and nodal stage. At a mean follow up of 2.3 years, disease-free survival was significantly worse in the subset of patients whose tumors overexpressed any level of YKL-40 compared to the non-expressors (p &lt; .01). In multivariate analysis, YKL-40 status was independent of T-stage and N-stage in predicting disease recurrence. Conclusions: Immunoreactivity for YKL-40 was a significant predictor of breast cancer relapse in this subset of patients. This was independent of T or N-stage and suggests that tumor immunohistochemistry for this protein may be a valuable prognostic marker in breast cancer. No significant financial relationships to disclose.
STAT3 as a molecular target in pediatric T-cell leukemia.
Authors: J. Ding, A. Batista, A. Turk, S. Rodriguez-Rodriguez, L. Wang, C. Mumaw, N. Carlesso, A. A. Cardoso
Journal: Journal of Clinical Oncology (2010)

9564 Background: Increasing evidence suggest an important role for microenvironmental factors in the biology of pediatric acute leukemias. However, little is known on how oncogenic events and microenvironmental cues are integrated within the leukemia cells. Methods: Molecular studies of STAT3 phosphorylation status and transcriptional activity were performed in primary leukemia T-cells or the IL-7-dependent TAIL7 cells. The effects of STAT3 inhibition were assessed using cell viability, proliferation and apoptosis assays. Results: We observed that primary cells from T-ALL patients exhibit activated STAT3, and that IL-7 engages STAT3 signaling and its transcriptional activity. Using TAIL7 cells, we confirmed that IL-7 triggers STAT3 phosphorylation in a dose-dependent manner, modulating the transcription of STAT3 target genes (c-myc, Bcl-xL and survivin). STAT3 blockade by the specific inhibitors STATTIC or S31-201 abrogated STAT3 phosphorylation, resulting in marked inhibition of leukemia cell proliferation (IC50, 1mM), and massive cell death (>90% at d4). Moreover, lentiviral shRNA effectively silenced STAT3 in leukemia cells, preventing their expansion. Strong anti-leukemia synergism was observed between low doses of STATTIC and the conventional drug dexamethasone, or specific mTOR (rapamycin) or PI3K (LY294002) inhibitors. Also, we observed that STAT3 inactivation markedly reduces the responsiveness of T-cells to IL-7 stimulation, even in the presence of STAT5. Interestingly, ChIP studies showed that STAT3 is part of a molecular complex regulating the transcription of IL-7R, thus modulating the responsiveness of leukemia cells to IL-7. Finally, the pro- apoptotic effect of STAT3 inhibition seems to affect also putative leukemia-initiating cells. Studies are in progress to assess the anti-leukemia efficacy of STAT3 inhibition in a NOD/SCID model of human T-cell leukemia. Conclusions: These studies unveil a novel interplay between STAT3 and IL-7 signaling in T-cell leukemia, and suggest that the targeted disruption of STAT3 may represent a valid therapeutic approach in this cancer. No significant financial relationships to disclose.
Evaluation of the 70-gene prognosis MammaPrint signature for the prediction of prognosis of breast cancer independently from histologic grade.
Authors: M. Knauer, E. J. Rutgers, S. Mook, J. Wesseling, L. J. van 't Veer
Journal: Journal of Clinical Oncology (2010)

561 Background: Histologic grade is one of the strongest prognostic factors for breast cancer patients. In this study we assessed the prognostic value of the 70-gene prognosis signature (MammaPrint), validated for node-negative and -positive patients, for grade (G) 1-3 breast cancer. Methods: 1630 tumor samples of pT1-3 N0-1 breast cancer patients from 7 previously reported studies were analyzed and classified by MammaPrint as low or high risk. 10-year breast cancer-specific survival (BCSS) and distant disease-free survival (DDFS) was analyzed using Kaplan-Meier survival curves and multivariate Cox regression analyses. Results: Of 1,630 patients 392 (24%) were classified as G1 (21% 70-gene high risk), 646 (40%) as G2 (42% high risk) and 592 (36%) as G3 (86% high risk), respectively. At 10 years of follow-up, the 70-gene signature accurately distinguished low-risk from high-risk tumors for all histologic grades: within G1 tumors, absolute BCSS was 91% for 70-gene low risk and 82% for 70-gene high risk patients, HR 2.6 (95%CI 1.1-5.7), p = 0.02. Within G2 survival was 88% (low risk) and 68% (high risk), HR 3.3 (2.1-5.3), p < 0.01 and within G3 survival was 86% (low risk) and 64% (high risk), HR 3.4 (1.6- 7.2), p < 0.01. For DDFS: G1 HR 2.8 (1.5-5.4), p < 0.01), G2 HR 2.2 (1.5-3.2), p < 0.01 and G3 HR 2.4 (1.3-4.5), p < 0.01. Multivariate analysis with known prognostic factors and adjuvant therapy including histologic grade and the signature confirmed MammaPrint as strongest independent prognostic factor for 10-year survival (HR BCSS 2.8 [1.8-4.3], p < 0.01) and DDFS HR 2.2 [1.5-3.2], p < 0.01). Limited to chemotherapy-untreated patients only, results were similar (multivariate HR BCSS 2.3 [1.5-3.8], p < 0.01 and DDFS HR 1.9 [1.3-2.8], p < 0.01). Conclusions: The 70-gene MammaPrint signature provides independent prognostic information for all histological grades. Of note, “G1/70-gene high-risk” patients had a relatively poor 10-year BCSS of 82%, and therefore may be treated aggressively. In contrast, “G3/70-gene low-risk” patients achieved a 10-year BCSS of 86%, where adjuvant chemotherapy might be of limited benefit. This study confirms the clinical value of the 70-gene signature for all histological grades. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Agendia Agendia
Mucinous histology in advanced colorectal cancer patients treated with first-line irinotecan- and/or oxaliplatin-based chemotherapy
Authors: V. Catalano, S. D’Emidio, F. Loupakis, F. Graziano, U. Torresi, D. Mari, R. Bisonni, P. Giordani, L. Giustini, A. Falcone, R. R. Silva
Journal: Journal of Clinical Oncology (2008)

4120 Background: Recently, patients with advanced mucinous colorectal cancer (MCRC) were found to have a poorer response to fluorouracil-based first-line chemotherapy and reduced survival compared with patients with non-mucinous colorectal cancer (NMCRC) (Ann Oncol 2005; 16:1305–10). Todate, regimens containing fluoropyrimidines and irinotecan (IRI) or oxaliplatin (OXA) are considered standard for the first line chemotherapy of advanced colorectal cancer. The aim of this study was to investigate the efficacy of IRI and/or OXA in combination with fluoropyrimidines as first-line chemotherapy in patients with advanced MCRC. Methods: The study population consisted of patients with advanced/metastatic colorectal cancer followed at 5 oncology centers (years 2001–2006). Prognostic factors associated with overall response rate (ORR) and overall survival (OS) were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. Results: The study included 255 patients, M/F 153/102, median age 67 years (range, 43–89), locally advanced/metastatic 11/244, 49 MCRC and 206 NMCRC. First-line chemotherapy included IRI-based (MCRC/NMCRC 9/56), OXA-based (MCRC/NMCRC 34/135), and OXA/IRI-based (MCRC/NMCRC 6/15) regimens. The ORRs for MCRC and NMCRC were 18.4% (95% CI, 7.5% to 29.2%) and 49% (95% CI, 47.2% to 55.8%), respectively (chi-test, p<0.001). With a median follow-up of 45 months, median OS for the MCRC patients was 14.1 months compared with 23.4 months in the NMCRC group (hazard ratio, HR=1.74; CI 95%, 1.27–3.31; p=0.003). After correcting for significant prognostic factors by multivariate Cox regression analysis, mucinous histology was associated with poorer OS (HR=1.59, 95% CI, 1.057–2.401; p=0.026) together with number of metastatic sites (2–4 versus 0–1; HR=1.47; 95% CI, 1.04–2.08), peritoneal disease (present versus absent; HR=1.58; 95% CI, 1.01–2.49), and performance status (2 versus 0–1; HR=3.52; 95% CI, 2.07–5.99). Conclusion: Patients with MCRC have poor responsiveness and survival to IRI and/or OXA-based first-line chemotherapy compared with NMCRC patients. No significant financial relationships to disclose.
Diagnostics and therapy of Merkel cell carcinoma (MCC) in Germany— Guidelines and reality
Authors: J. C. Becker
Journal: Journal of Clinical Oncology (2006)

18564 Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy of the elderly. Due to its low incidence, current guidelines for diagnostic and therapeutic interventions are based on low levels of evidence. Moreover, it is unclear how strictly these guidelines are followed in the management of MCC patients. Methods: A review of MCC patients treated in 15 selected centres of the Dermatologic Cooperative Oncology Group between 1998 and 2004, i.e. when the initial version of national guidelines were valid, identified 150 patients of whom tumor- and treatment-related factors were analyzed for association with recurrence. Results: Initial tumour staging was completed in about 1/3 rd of MCC patients in accordance with the guidelines (i.e. ultrasound of the abdomen and the regional lymph nodes, chest X-ray), in 1/3 rd using an intensified regimen, and in the remaining patients was incomplete. Staging revealed that 82.5% of the patients were in stage I, 16.1% in stage II and 1.4% in stage III at the time of primary diagnosis of MCC. With respect to initial therapy, the mean surgical excision margin was 1.86 cm (instead of 3 cm) and adjuvant radiation was applied in 40% of the patients. Pathologic staging of the draining nodal basin was performed in 37 patients (24.6%), and 24.2% of these had node-positive disease. 56 patients (37.3%) recurred and the median time to recurrence was 10 months. Local and/or loco-regional recurrence developed in 29 and 33 patients, respectively; in 22 patients distant metastases occurred. While age, gender, tumour diameter and histological type were not significantly correlated with recurrence, therapeutic measures were, i.e. lower surgical margins and lack of adjuvant radiation were associated with an increased recurrence rate. Conclusions: Our study demonstrates that the current guidelines were only partially implemented in the clinical routine. This is particularly worrisome as our data indicate that MCC treatment in accordance to the guidelines results in an improved control of the disease. No significant financial relationships to disclose.