Combined systemic inflammation score (SIS) correlates with prognosis in patients with advanced pancreatic cancer receiving palliative chemotherapy.

PURPOSE: The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains dismal. New cytotoxic agents such as nab-paclitaxel and liposomal irinotecan (nal-Iri) have extended the armamentarium of therapeutic options in the last years. Nowadays, sequential therapeutic strategies with moderately toxic chemotherapeutic protocols can be administered to the patients. However, prognostic and predictive biomarkers are still missing to identify those patients, which profit most from a "continuum of care" concept rather than receiving intensive first-line protocols such as FOLFIRINOX. To this end, we retrospectively evaluated the impact of the systemic inflammation as one essential hallmark of cancer in patients with advanced PDAC treated with sequential systemic. METHODS: A cohort of 193 PDAC patients treated at our center from January 2005 to August 2011 were retrospectively evaluated for the following systemic inflammatory response (SIR) markers: neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR) C-reactive protein (CRP), and the modified Glasgow Prognostic Score (mGPS). SIR markers were correlated with clinico-pathological findings, response to chemotherapy and overall survival (OS) using Kaplan-Meier curves and Cox proportional models. RESULTS: All evaluated SIR markers were significantly associated with OS in patients with metastatic disease but not in patients with locally advanced PDAC. Interestingly, all SIR markers were only prognostic in patients not receiving antibiotics as surrogate marker for systemic bacterial infections. Based on the evaluated SIR markers, we propose a new Systemic Inflammation Score (SIS), which significantly correlated with reduced OS (HR: 3.418 (1.802-6.488, p < 0.001)) and the likelihood of receiving further-line systemic therapies (p = 0.028). CONCLUSION: Routinely assessed SIR biomarkers have potential to support therapeutic decision making in patients with metastatic PDAC.

[Polyarthritis and papular eruption revealing leprosy]. / Polyarthrite et éruption papuleuse révélant une lèpre.

Leprosy is generally revealed by cutaneous lesions often associated to nerve impairment. Rarely, it may be revealed by polyarthritis. The diagnosis, often delayed in the cutaneous-nevritic form because of the low prevalence of the disease in metropolitan France, is very difficult in case of rheumatic presentation. We report the case of a 28 year-old woman from Mali, who was diagnosed with lepromatous borderline leprosy with reversal reaction occurring in the postpartum as she presented with polyarthritis and skin lesions.

[Cutaneous and epidural Rosai-Dorfman disease]. / Localisation cutanée et épidurale d'une histiocytose de Rosai-Dorfman.

BACKGROUND: Rosai-Dorfman disease, or sinus histiocytosis with massive lymphadenopathy, is a rare benign histiocytic proliferative lymph node disorder. Whereas the association of nodal and extranodal involvement is common, purely extranodal diseases are rare. CASE-REPORT: We report the case of a thirty-year-old man with papulonodular skin lesions of the face and the legs initially followed by onset of hyposensitivity of the lower extremities. Histologic examination of a facial lesion showed a dermal polymorphous infiltrate, chiefly composed of large histiocytes, some of which contained intracytoplasmic lymphocytes and neutrophils, a process referred to as emperipolesis. Immunohistochemistry revealed positive staining of the histiocytes with anti-S100 protein and anti-CD68 antibodies and negative staining with anti-CD1a antibody. Magnetic resonance showed spinal cord compression linked to epidural involvement. We concluded on cutaneous and epidural Rosai-Dorfman disease. Neurological symptoms rapidly and partially resolved after intravenous corticosteroid therapy, which was followed by oral corticosteroid therapy and etoposide chemotherapy leading to the regression of the cutaneous lesions. DISCUSSION: This case report of cutaneous and epidural Rosai-Dorfman disease is interesting because of the lack of lymph node involvement associated with the cutaneous lesions and because of the presence of an epidural site, rarely described in this disease.

Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer.

This comparative phase III trial of mitoxantrone+vinorelbine (MV) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin (FAC/FEC) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy, while resulting in an improved tolerance in relation to alopecia and nausea/vomiting. This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.

Toward a better understanding of texture in vascular CT scan simulated images.

This paper shows the influence of computed tomography slice thickness on textural parameters by simulating realistic images issued from: 1) a 3D model of vascular tree, with structural and functional features and in which angiogenesis is related to the organ growth; 2) a projection/reconstruction process using fast Fourier transform. Texture analysis is performed by means of second-order statistics and gradient based methods.

Phase II trial of a paclitaxel-carboplatin combination in recurrent squamous cell carcinoma of the head and neck.

OBJECTIVE: Twenty-seven patients with recurrent squamous cell carcinoma of the head and neck were entered in a multicenter study to determine the efficacy of the paclitaxel-carboplatin association. METHODS: Standard eligibility criteria applied, i.e. measurable disease, and chemotherapy given as induction treatment or concomitant chemoradiotherapy was allowed if completed more than 6 months prior to the study. Every 21 days, paclitaxel 175 mg/m(2) and carboplatin AUC 6 were administered. The patient group included 3 females and 24 males with a median age of 61 years (range 39-75 years). RESULTS: All patients were assessable for toxicity and 24 for responses. Main grade 3-4 toxicities were: neutropenia (62.9%), febrile neutropenia (18.5%), anemia (11.1%), thrombocytopenia (14.8%), mucositis (7.4%) and vomiting (7.4%). Among the intent-to-treat population, 29.6% of patients had an objective response, with a median response duration of 4.2 months (range 1-5.7 months). Stable and progressive disease were observed in 11.1 and 48.1% of patients, respectively. The median overall survival was 7.2 months (range 0.5-10.9 months). CONCLUSION: From these data, paclitaxel-carboplatin seems to have an activity in recurrent squamous cell carcinoma of the head and neck, but the high level of toxicity highlights the need to search for a safer chemotherapy combination.

Endotoxemia and cytokine generation in cardiac surgery in relation to flow mode and duration of cardiopulmonary bypass.

We investigated whether pulsatile flow in cardiopulmonary bypass (CPB), which has been shown to improve intestinal perfusion, reduces endotoxin translocation from the gut and, in consequence, decreases cytokine generation. The study population consisted of 48 adult patients who underwent elective CPB surgery. Pulsatile flow was used during aortic cross-clamping in 24 patients and nonpulsatile flow in 24 patients. Plasma endotoxin concentration increased in all patients during CPB. Significantly (P < 0.05) lower peak levels of 8.25 +/- 1.17 (SEM) pg/mL were reached 30 min after CPB in patients with pulsatile flow in contrast to 11.26 +/- 1.42 pg/mL in patients with nonpulsatile flow. The extent of endotoxemia was not related to the duration of CPB. Following the increase of plasma endotoxin, the concentrations of IL-6 and IL-8 increased with delay of approximately 1 h. The peak levels of these cytokines corresponded significantly (P < 0.005 and P < 0.01, respectively) with duration of CPB, but not with flow mode. Thus, in patients with CPB of more than 97 min (median), IL-6 reached a peak of 335.5 +/- 48.87 pg/mL and IL-8 of 64.86 +/- 24.79 pg/mL in contrast to 210.9 +/- 18.45 pg/mL and 21.2 +/- 10.19 pg/mL, respectively, with bypass times of less than 97 min. The degree of endotoxemia in CPB mainly depends on the quality of tissue perfusion. Cytokine generation, however, is not triggered exclusively by endotoxin, but rather by the trauma of CPB and surgery.

Randomized comparison of prophylactic antidiarrheal treatment versus no prophylactic antidiarrheal treatment in patients receiving CPT-11 (irinotecan) for advanced 5-FU-resistant colorectal cancer: an open-label multicenter phase II study.

Delayed diarrhea is the main toxicity of irinotecan at the currently recommended dose of 350 mg/m2 30-minute intravenous infusion, once every 3 weeks. This phase II, multicenter, open-label, randomized study was primarily designed to evaluate the effect of a 15-day Tiorfan (racecadotril) treatment on the incidence and severity of irinotecan-induced delayed diarrhea. One hundred thirty-six patients with metastatic colorectal cancer who failed to respond to a 5-fluorouracil-based treatment received 714 cycles of irinotecan. The patients were randomly allocated either to group A (68 patients) and received Tiorfan (300 mg/day) from D0 to D15 or to group B (68 patients) with no prophylactic treatment. Delayed diarrhea occurred in 197 of 355 cycles (55%) in Group A and 203 of 344 cycles (59%) in Group B. grade III-IV diarrhea was reported in 17 of 40 compliant patients (42%) in group A and 31 of 68 evaluable patients (45%) in group B. No difference was observed between the two groups for delayed diarrhea characteristics, incidence, or severity. The response rate in 99 evaluable patients was 12.1% (6.4%-20.2%). This study has shown that Tiorfan given prophylactically at 300 mg/day has no effect on delayed diarrhea.

Slice simulation from a model of the parenchymous vascularization to evaluate texture features: work in progress.

RATIONALE AND OBJECTIVES: To demonstrate the usefulness of a model of the parenchymous vascularization to evaluate texture analysis methods. METHODS: Slices with thickness varying from 1 to 4 mm were reformatted from a 3D vascular model corresponding to either normal tissue perfusion or local hypervascularization. Parameters of statistical methods were measured on 16128x128 regions of interest, and mean values and standard deviation were calculated. For each parameter, the performances (discrimination power and stability) were evaluated. RESULTS: Among 11 calculated statistical parameters, three (homogeneity, entropy, mean of gradients) were found to have a good discriminating power to differentiate normal perfusion from hypervascularization, but only the gradient mean was found to have a good stability with respect to the thickness. Five parameters (run percentage, run length distribution, long run emphasis, contrast, and gray level distribution) were found to have intermediate results. In the remaining three, curtosis and correlation was found to have little discrimination power, skewness none. CONCLUSION: This 3D vascular model, which allows the generation of various examples of vascular textures, is a powerful tool to assess the performance of texture analysis methods. This improves our knowledge of the methods and should contribute to their a priori choice when designing clinical studies.

Modeling of the parenchymous vascularization and perfusion.

RATIONALE AND OBJECTIVES: The authors sought to create a realistic model of the parenchymous vascularization and perfusion. METHODS: A three-dimensional vascular model has been developed that reproduces the growth process of a vascular tree (angiogenesis). This model follows physical laws related to blood flow in vessels (Poiseuille's law), takes into account anatomic constraints, and optimizes a cost function related to the blood volume. RESULTS: Vascular trees, the ramifications of which go from main arteries to small arterioles, were simulated. Vascular structures corresponding to either a normal tissue perfusion or an abnormal perfusion (for example, a local hypervascularization) were presented in three dimensions (volume rendering). Geometric and hemodynamic characteristics computed on these trees were consistent with those of real data found in the literature. The vascular model is also a good tool for studying the propagation of the contrast product in normal and abnormal vessels. CONCLUSIONS: The three-dimensional vascular model presented in this article provides insight into the simulation and the understanding of anatomic or physiologic vascular modifications.

Identification and characterization of a novel delta6/delta5 fatty acid desaturase inhibitor as a potential anti-inflammatory agent.

The anti-inflammatory properties of essential fatty acid deficiency or n-3 polyunsaturated fatty acid supplementation have been attributed to a reduced content of arachidonic acid (AA; 20:4 n-6). An alternative, logical approach to depleting AA would be to decrease endogenous synthesis of AA by selectively inhibiting the delta5 and/or the delta6 fatty acid desaturase. High-throughput radioassays were developed for quantifying delta5, delta6, and delta9 desaturase activities in vitro and in vivo. CP-24879 (p-isopentoxyaniline), an aniline derivative, was identified as a mixed delta5/delta6 desaturase inhibitor during the screening of chemical and natural product libraries. In mouse mastocytoma ABMC-7 cells cultured chronically with CP-24879, there was a concentration-dependent inhibition of desaturase activity that correlated with the degree of depletion of AA and decreased production of leukotriene C4 (LTC4). Production of LTC4 was restored by stimulating the cells in the presence of exogenous AA, indicating that endogenous AA was limiting as substrate. In the livers of mice treated chronically with the maximally tolerated dose of CP-24879 (3 mg/kg, t.i.d.), combined delta5/delta6 desaturase activities were inhibited approximately 80% and AA was depleted nearly 50%. These results suggest that delta5 and/or delta6 desaturase inhibitors have the potential to manifest an anti-inflammatory response by decreasing the level of AA and the ensuing production of eicosanoids.

A double-blind, multicentre comparison of intravenous dolasetron mesilate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy.

The potent serotonin receptor (5-HT3) antagonists are new highly selective agents for the prevention and control of chemotherapy-induced nausea and vomiting that have been shown to be comparable to or more effective than traditional metoclopramide regimens. This study was designed to compare the antiemetic efficacy of dolasetron and metoclopramide in chemotherapy-naive and non-naive cancer patients receiving high-dose cisplatin-containing chemotherapy. This multicentre, double-blind, randomized trial compared the efficacy and safety of single i.v. doses of dolasetron mesilate salt (1.2 or 1.8 mg/kg) and metoclopramide (7 mg/kg) in 226 patients for the prevention of acute emesis and nausea associated with the administration of high-dose (> or = 80 mg/m2) cisplatin. Efficacy and safety were evaluated for 24 h. Complete responses were achieved by 57%, 48%, and 35% of patients given dolasetron mesilate 1.8 mg/kg (P = 0.0009 vs metoclopramide), dolasetron mesilate 1.2 mg/kg (P = 0.0058 vs metoclopramide), and metoclopramide, respectively. Overall, dolasetron was significantly more effective than metoclopramide for time to first emetic episode, nausea, patient satisfaction, and investigator global assessment of efficacy. Males, chemotherapy-naive patients, and alcoholics had higher response rates. Dolasetron was well tolerated, with mild-to-moderate headache most commonly reported. Twelve percent of patients receiving metoclopramide reported extrapyramidal symptoms compared with 0% of patients receiving dolasetron. In conclusion, dolasetron mesilate was effective for the prevention of CINV with high-dose cisplatin. Single i.v. doses of dolasetron mesilate were more effective than 7 mg/kg metoclopramide in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, 1.8 mg/kg dolasetron mesilate consistently produced the highest response rates and appears to be the most effective dose for further clinical development.

Medical staff consolidation issues and concerns.

In the past decade there have been increases in health care consolidations. While the literature on hospital mergers is abundant, there is little on mergers of medical staffs. In this study, we interviewed senior administrators in 22 midwestern medical institutions that had consolidated between 1987 and 1990. Our study is an exploration of topics of concern that administrators have encountered during processes of medical staff consolidation. Administrators stated that the medical staff was most concerned about relationships with nursing and support staff, "turf" issues, and a sense of loss. They recommended that increased attention be paid to specific local issues and that there be active involvement and communication between medical staff and administrators at all phases of the consolidation process.

[Combination of mitoxantrone-vinorelbine as first-line chemotherapy for metastatic breast carcinoma]. / Association mitoxantrone-vinorelbine en première ligne thérapeutique dans le cancer du sein métastatique.

A phase II trial was performed to assess the efficacy and toxicity of the combination mitoxantrone (MXN) and vinorelbine (VNR) as first-line chemotherapy for metastatic breast cancer. Forty-one patients with metastatic disease or local relapse recruited between March 1991 and April 1993 received a first-line chemotherapy treatment consisting in 12 mg/m2 intravenous (IV) bolus of MXN on day 1 followed by a 20-minute perfusion of 25 mg/m2 of VNR on days 1 and 8. Cycles were repeated every 21 days until evidence of disease progression or of severe toxicity. Thirty-seven patients were evaluable for response and all 41 for toxicity. An objective response was observed in 19 patients (51%; 95% confidence interval, 45 to 74%). The response was complete in a further 11 (30%). Median time to treatment failure was 9 months. Median survival was 14 months. There were no treatment-related deaths. Limiting toxicity was myelosuppression. Leukopenia occurred in 29 patients (71%) and was grade 3 or 4 in nine of these (15%). Grade 2 or 3 anemia was encountered in six patients (15%), grade 1 thrombocytopenia in one, neurotoxicity (constipation) in two, and grade 2 or 3 alopecia in 12 (29%). Nausea/vomiting requiring antiemetic treatment was experienced by only two patients (5%). There were two cases of septicemia treated by antibiotic therapy in hospital.

[Analysis of texture in medical imaging. Review of the literature]. / Analyse de texture en imagerie médicale. Revue de la littérature.

This paper presents a review of the applications of texture analysis in medical imaging. Many authors take a great interest in this topic (75 papers have been published since 1984) and try to elaborate automatic methods for tissue characterization. The results are not really convincing and applications are often reduced to feasibility studies. This failure is due to the empirical approach to the problem: the first studies were performed on ultrasound images, in which visual texture is very present, but no data standardization is available with this imaging modality. A more rational approach should provide better results. For each organ or tissue, it is necessary to find the appropriate source and texture analysis method. This difficult task requires reflection concerning the interactions between tissues and imaging sources, to define judicious structuring elements. These structuring elements should facilitate the choice of the best texture analysis method, for the particular application. Considerable methodological progress has yet to be made, after which texture analysis should be a useful and efficient tool for clinical use.