Activation of innate immunity by 14-3-3 ε, a new potential alarmin in osteoarthritis.

OBJECTIVE: The innate immune system plays a central role in osteoarthritis (OA). We identified 14-3-3ε as a novel mediator that guides chondrocytes toward an inflammatory phenotype. 14-3-3ε shares common characteristics with alarmins. These endogenous molecules, released into extracellular media, are increasingly incriminated in sustaining OA inflammation. Alarmins bind mainly to toll-like receptor 2 (TLR2) and TLR4 receptors and polarize macrophages in the synovium. We investigated the effects of 14-3-3ε in joint cells and tissues and its interactions with TLRs to define it as a new alarmin involved in OA. DESIGN: Chondrocyte, synoviocyte and macrophage cultures from murine or OA human samples were treated with 14-3-3ε. To inhibit TLR2/4 in chondrocytes, blocking antibodies were used. Moreover, chondrocytes and bone marrow macrophage (BMM) cultures from knockout (KO) TLRs mice were stimulated with 14-3-3ε. Gene expression and release of inflammatory mediators [interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNFα)] were evaluated via reverse transcription quantitative polymerase chain reaction (RT-qPCR) and ELISA. RESULTS: In vitro, 14-3-3ε induced gene expression and release of IL6 and MCP1 in the treated cells. The inflammatory effects of 14-3-3ε were significantly reduced following TLRs inhibition or in TLRs KO chondrocytes and BMM. CONCLUSIONS: 14-3-3ε is able to induce an inflammatory phenotype in synoviocytes, macrophages and chondrocytes in addition to polarizing macrophages. These effects seem to involve TLR2 or TLR4 to trigger innate immunity. Our results designate 14-3-3ε as a novel alarmin in OA and as a new target either for therapeutic and/or prognostic purposes.

Necrotizing fasciitis and septic shock related to the uncommon gram-negative pathogen Sphingobacterium multivorum.

We report the first case of necrotizing fasciitis due to the uncommon Gram-negative pathogen Sphingobacterium multivorum in an immunocompromised patient, who presented with septic shock. This case adds necrotizing fasciitis to the spectrum of S. multivorum-related infections and highlights the emergence of Gram-negative bacteria in severe soft tissue infections.

Use, timing and factors associated with tracheal intubation in septic shock: a prospective multicentric observational study.

BACKGROUND: No recommendation exists about the timing and setting for tracheal intubation and mechanical ventilation in septic shock. PATIENTS AND METHODS: This prospective multicenter observational study was conducted in 30 ICUs in France and Spain. All consecutive patients presenting with septic shock were eligible. The use of tracheal intubation was described across the participating ICUs. A multivariate analysis was performed to identify parameters associated with early intubation (before H8 following vasopressor onset). RESULTS: Eight hundred and fifty-nine patients were enrolled. Two hundred and nine patients were intubated early (24%, range 4.5-47%), across the 18 centers with at least 20 patients included. The cumulative intubation rate during the ICU stay was 324/859 (38%, range 14-65%). In the multivariate analysis, seven parameters were significantly associated with early intubation and ranked as follows by decreasing weight: Glasgow score, center effect, use of accessory respiratory muscles, lactate level, vasopressor dose, pH and inability to clear tracheal secretions. Global R-square of the model was only 60% indicating that 40% of the variability of the intubation process was related to other parameters than those entered in this analysis. CONCLUSION: Neurological, respiratory and hemodynamic parameters only partially explained the use of tracheal intubation in septic shock patients. Center effect was important. Finally, a vast part of the variability of intubation remained unexplained by patient characteristics. Trial registration Clinical trials NCT02780466, registered on May 23, 2016. https://clinicaltrials.gov/ct2/show/NCT02780466?term=intubatic&draw=2&rank=1.

Major traumatic complications after out-of-hospital cardiac arrest: Insights from the Parisian registry.

AIM: Due to collapse and cardiopulmonary resuscitation (CPR) maneuvers, major traumatic injuries may complicate the course of resuscitation for out-of-hospital cardiac arrest patients (OHCA). Our goals were to assess the prevalence of these injuries, to describe their characteristics and to identify predictive factors. METHODS: We conducted an observational study over a 9-year period (2007-2015) in a French cardiac arrest (CA) center. All non-traumatic OHCA patients admitted alive in the ICU were studied. Major injuries identified were ranked using a functional two-level scale of severity (life-threatening or consequential) and were classified as CPR-related injuries or collapse-related injuries, depending of the predominant mechanism. Factors associated with occurrence of a CPR-related injury and ICU survival were identified using multivariable logistic regression. RESULTS: A major traumatic injury following OHCA was observed in 91/1310 patients (6.9%, 95%CI: 5.6, 8.3%), and was classified as a life-threatening injury in 36% of cases. The traumatic injury was considered as contributing to the death in 19 (21%) cases. Injuries were related to CPR maneuvers in 65 patients (5.0%, (95%CI: 3.8, 6.1%)). In multivariable analysis, age [OR 1.02; 95%CI (1.00, 1.04); p = 0.01], male gender [OR 0.53; 95%CI (0.31, 0.91); p = 0.02] and CA occurring at home [OR 0.54; 95%CI (0.31, 0.92); p = 0.02] were significantly associated with the occurrence of a CPR-related injury. CPR-related injuries were not associated with the ICU survival [OR 0.69; 95%CI (0.36, 1.33); p = 0.27]. CONCLUSIONS: Major traumatic injuries are common after cardiopulmonary resuscitation. Further studies are necessary to evaluate the interest of a systematic traumatic check-up in resuscitated OHCA patients in order to detect these injuries.

Severe atypical pneumonia in critically ill patients: a retrospective multicenter study.

BACKGROUND: Chlamydophila pneumoniae (CP) and Mycoplasma pneumoniae (MP) patients could require intensive care unit (ICU) admission for acute respiratory failure. METHODS: Adults admitted between 2000 and 2015 to 20 French ICUs with proven atypical pneumonia were retrospectively described. Patients with MP were compared to Streptococcus pneumoniae (SP) pneumonia patients admitted to ICUs. RESULTS: A total of 104 patients were included, 71 men and 33 women, with a median age of 56 [44-67] years. MP was the causative agent for 76 (73%) patients and CP for 28 (27%) patients. Co-infection was documented for 18 patients (viruses for 8 [47%] patients). Median number of involved quadrants on chest X-ray was 2 [1-4], with alveolar opacities (n = 61, 75%), interstitial opacities (n = 32, 40%). Extra-pulmonary manifestations were present in 34 (33%) patients. Mechanical ventilation was required for 75 (72%) patients and vasopressors for 41 (39%) patients. ICU length of stay was 16.5 [9.5-30.5] days, and 11 (11%) patients died in the ICU. Compared with SP patients, MP patients had more extensive interstitial pneumonia, fewer pleural effusion, and a lower mortality rate [6 (8%) vs. 17 (22%), p = 0.013]. According MCA analysis, some characteristics at admission could discriminate MP and SP. MP was more often associated with hemolytic anemia, abdominal manifestations, and extensive chest radiograph abnormalities. SP-P was associated with shock, confusion, focal crackles, and focal consolidation. CONCLUSION: In this descriptive study of atypical bacterial pneumonia requiring ICU admission, mortality was 11%. The comparison with SP pneumonia identified clinical, laboratory, and radiographic features that may suggest MP or CP pneumonia.

Noninvasive ventilation during acute respiratory distress syndrome in patients with cancer: Trends in use and outcome.

PURPOSE: The objectives of our study were to describe the outcome of patients with malignancies treated for acute respiratory distress syndrome (ARDS) with noninvasive ventilation (NIV) and to evaluate factors associated with NIV failure. METHODS: Post hoc analysis of a multicenter database within 20 years was performed. All patients with malignancies and Berlin ARDS definition were included. Noninvasive ventilation use was defined as NIV lasting more than 1 hour, whereas failure was defined as a subsequent requirement of invasive ventilation. Conditional backward logistic regression analyses were conducted. RESULTS: A total of 1004 met the Berlin definition of ARDS. Noninvasive ventilation was used in 387 patients (38.6%) and NIV failure occurred in 71%, with an in-hospital mortality of 62.7%. Severity of ARDS defined by the partial pressure arterial oxygen and fraction of inspired oxygen ratio (odds ratio [OR], 2.20; 95% confidence interval [CI], 1.15-4.19), pulmonary infection (OR, 1.81; 95% CI, 1.08-3.03), and modified Sequential Organ Failure Assessment (SOFA) score (OR, 1.13; 95% CI, 1.06-1.21) were associated with NIV failure. Factors associated with hospital mortality were NIV failure (OR, 2.52; 95% CI, 1.56-4.07), severe ARDS as compared with mild ARDS (OR, 1.89; 95% CI, 1.05-1.19), and modified SOFA score (OR, 1.12; 95% CI, 1.05-1.19). CONCLUSION: Noninvasive ventilation failure in ARDS patients with malignancies is frequent and related to ARDS severity, SOFA score, and pulmonary infection-related ARDS. Noninvasive ventilation failure is associated with in-hospital mortality.

Changes in aortic blood flow induced by passive leg raising predict fluid responsiveness in critically ill patients.

INTRODUCTION: Esophageal Doppler provides a continuous and non-invasive estimate of descending aortic blood flow (ABF) and corrected left ventricular ejection time (LVETc). Considering passive leg raising (PLR) as a reversible volume expansion (VE), we compared the relative abilities of PLR-induced ABF variations, LVETc and respiratory pulsed pressure variations (DeltaPP) to predict fluid responsiveness. METHODS: We studied 22 critically ill patients in acute circulatory failure in the supine position, during PLR, back to the supine position and after two consecutive VEs of 250 ml of saline. Responders were defined by an increase in ABF induced by 500 ml VE of more than 15%. RESULTS: Ten patients were responders and 12 were non-responders. In responders, the increase in ABF induced by PLR was similar to that induced by a 250 ml VE (16% versus 20%; p = 0.15). A PLR-induced increase in ABF of more than 8% predicted fluid responsiveness with a sensitivity of 90% and a specificity of 83%. Corresponding positive and negative predictive values (PPV and NPV, respectively) were 82% and 91%, respectively. A DeltaPP threshold value of 12% predicted fluid responsiveness with a sensitivity of 70% and a specificity of 92%. Corresponding PPV and NPV were 87% and 78%, respectively. A LVETc of 245 ms or less predicted fluid responsiveness with a sensitivity of 70%, and a specificity of 67%. Corresponding PPV and NPV were 60% and 66%, respectively. CONCLUSION: The PLR-induced increase in ABF and a DeltaPP of more than 12% offer similar predictive values in predicting fluid responsiveness. An isolated basal LVETc value is not a reliable criterion for predicting response to fluid loading.

[Epidermoid carcinomas of anal canal treated with radiation therapy and concomitant chemotherapy (5-fluorouracil and cisplatin)]. / Carcinomes épidermoïdes du canal anal traités par association concomitante de radiothérapie et de chimiothérapie. Evaluation des résultats fonctionnels.

PURPOSE: To evaluate our results after radiation therapy and concomitant chemotherapy in terms of local control, survival and toxicity in patients with anal cancer. METHODS AND PATIENTS: Between November 1990 and January 2002, 60 patients (pts) were treated with radiation therapy and concomitant chemotherapy. The T-stage according to the 2001 UICC classification were: 2 T1, 26 T2, 25 T3, and 7 T4. There were 20 pts with nodal involvement at presentation. The treatment started with external beam RT (median dose: 45 Gy) and concomitant chemotherapy using 5-fluorouracil and cisplatin during the first week and the fifth week of external beam RT (EBRT). After a rest period of 4 to 6 weeks, a boost of 20 Gy was delivered by EBRT in 58 pts and by interstitial (192)Ir brachytherapy in 2 pts. Mean follow-up were 78.5 months. RESULTS: At the end of RT with concomitant chemotherapy local tumor clinical complete response rate was 83%. Out of 10 non responders or local progression, 5 (50%) were salvaged with abdominoperineal resection (APR). Out of 5 local tumor relapses, 3 were salvaged with APR. The overall local tumor control (LC) rate with or without salvage local treatment were 88%. LC rate with a good anal function scoring (score 0 and 1) was 70%. Among 43 pts who preserved their anus, 98% had a good anal function scoring. The 5-year disease-free survival was 75%. After multivariate analysis, 2 independent predicting factors significantly influenced the disease-free survival: HIV-positive pts (negative vs positive, P=0.032) and clinical tumor response after the first course of radiotherapy (<50% vs >or=50%, P=0.00032). Acute grade 2 or 3 toxicities were low: haematological toxicity in 4 pts and intestinal complication corresponding to diarrhea in 10 pts. Late severe complication was observed in 3 pts: 2 pts with painful necrosis of the anus requiring colostomy and 1 pt with grade 3 rectal bleeding. CONCLUSION: We confirm the good results with RT and concomitant chemotherapy. The clinical tumor response after the first course of RT and concomitant chemotherapy is probably the most important predictive factor on the disease-free survival. For patients with T3 or T4 lesion and tumor regression

Hypoxic hepatitis after out-of-hospital cardiac arrest: Incidence, determinants and prognosis.

AIM: Hypoxic hepatitis (HH) may complicate the course of resuscitated out-of-hospital cardiac arrest (OHCA) patients admitted in intensive care unit (ICU). Aims of this study were to assess the prevalence of HH, and to describe the factors associated with HH occurrence and outcome. METHODS: We conducted an observational study over a 6-year period (2009-2014) in a cardiac arrest center. All non-traumatic OHCA patients admitted in the ICU after return of spontaneous circulation (ROSC) and who survived more than 24h were included. HH was defined as an elevation of alanine aminotransferase over 20 times the upper limit of normal during the first 72h after OHCA. Factors associated with HH and ICU mortality were picked up by multivariate logistic regression. RESULTS: Among the 632 OHCA patients included in the study, HH was observed in 72 patients (11.4% (95% CI: 9.0%, 14.1%)). In multivariate analysis, time from collapse to ROSC [OR 1.02 per additional minute; 95% CI (1.00, 1.04); p=0.01], male gender [OR 0.53; 95% CI (0.29, 0.95); p=0.03] and initial shockable rhythm [OR 0.35; 95% CI (0.19, 0.65); p<0.01] were associated with HH occurrence. After adjustment for confounding factors, HH was associated with ICU mortality [OR 4.39; 95% CI (1.71, 11.26); p<0.01] and this association persisted even if occurrence of a post-CA shock was considered in the statistical model [OR 3.63; 95% CI (1.39, 9.48); p=0.01]. CONCLUSIONS: HH is not a rare complication after OHCA. This complication is mainly triggered by the duration of resuscitation and is associated with increased ICU mortality.

Adrenocorticotropic hormone in the prevention of cisplatin-induced nausea and vomiting.

A double-blind trial to evaluate the antiemetic effects of adrenocorticotropic hormone (ACTH) in patients treated with cisplatin was performed. Thirty-seven adults with advanced cancer who were treated with cisplatin were randomly assigned to receive either synthetic long-acting ACTH (1 mg IM given 24 hours, 12 hours, and immediately preceding the administration of cisplatin) or a placebo given under the same conditions. All of the patients received chlorpromazine (50 mg IM) 30 minutes before cisplatin infusion. Patients receiving ACTH and chlorpromazine had significantly fewer episodes of vomiting (p less than 0.01) and shorter periods of nausea (p less than 0.02) than patients receiving placebo and chlorpromazine. Patients receiving ACTH and chlorpromazine were significantly more comfortable than patients receiving placebo and chlorpromazine. No important side effects were observed. ACTH may be an effective agent in preventing nausea and vomiting induced by cisplatin.

Autologous marrow transplantation for patients with chronic myeloid leukemia in accelerated or blastic phase: report of 14 cases.

Between June 1979 and October 1983, 14 autografts were performed in 13 patients with CML (ten blast crisis, four accelerated phase). Results were disappointing: four patients died during aplasia; seven returned to chronic phase, but three died of hemorrhage, four relapsed, and three did not reverse. The main problem was the very low rate of successful engraftment. Both the collection of bone marrow after treatment with busulfan and a particular sensitivity of CFU-GM to cryoinjury were responsible for the infusion of very low doses of CFU-GM. However, we observed some promising results: In one patient in acute blast crisis, the Ph 1 chromosome disappeared, as well as the cytogenetic marker of transformation; in another patient with acute pure cytogenetic acceleration, the abnormal clone disappeared for 27 months; a third patient was maintained in a second chronic phase for 20 months. Thus we suggest that the results of autografting in chronic myeloid leukemia would be improved by infusing the largest possible dose of stem cells collected before or long after treatment by busulfan, and freezing them following a careful program.

Changes in intensive care for allogeneic hematopoietic stem cell transplant recipients.

Intensive care unit (ICU) admission is associated with high mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Whether mortality has decreased recently is unknown. The 497 adult allogeneic HSCT recipients admitted to three ICUs between 1997 and 2011 were evaluated retrospectively. Two hundred and nine patients admitted between 1997 and 2003 were compared with the 288 patients admitted from 2004 to 2011. Factors associated with 90-day mortality were identified. The recent cohort was characterized by older age, lower conditioning intensity, and greater use of peripheral blood or unrelated-donor graft. In the recent cohort, ICU was used more often for patients in hematological remission (67% vs 44%; P<0.0001) and without GVHD (73% vs 48%; P<0.0001) or invasive fungal infection (85% vs 73%; P=0.0003) despite a stable admission rate (21.7%). These changes were associated with significantly better 90-day survival (49% vs 31%). Independent predictors of hospital mortality were GVHD, mechanical ventilation (MV) and renal replacement therapy (RRT). Among patients who required MV or RRT, survival was 29% and 18%, respectively, but dropped to 18% and 6% in those with GVHD. The use of ICU admission has changed and translated into improved survival, but advanced life support in patients with GVHD usually provides no benefits.

Prognosis of neutropenic patients admitted to the intensive care unit.

PURPOSE: The prognosis of critically ill cancer patients has improved recently. Controversies remain as regard to the specific prognosis impact of neutropenia in critically ill cancer patients. The primary objective of this study was to assess hospital outcome of critically ill neutropenic cancer patients admitted into the ICU. The secondary objective was to assess risk factors for unfavorable outcome in this population of patients and specific impact of neutropenia. METHODS: We performed a post hoc analysis of a prospectively collected database. The study was carried out in 17 university or university-affiliated centers in France and Belgium. Neutropenia was defined as a neutrophil count lower than 500/mm(3). RESULTS: Among the 1,011 patients admitted into the ICU during the study period 289 were neutropenic at the time of admission. Overall, 131 patients died during their hospital stay (hospital mortality 45.3 %). Four variables were associated with a poor outcome, namely allogeneic transplantation (OR 3.83; 95 % CI 1.75-8.35), need for mechanical ventilation (MV) (OR 6.57; 95 % CI 3.51-12.32), microbiological documentation (OR 2.33; CI 1.27-4.26), and need for renal replacement therapy (OR 2.77; 95 % CI 1.34-5.74). Two variables were associated with hospital survival, namely age younger than 70 (OR 0.22; 95 % CI 0.1-0.52) and neutropenic enterocolitis (OR 0.37; 95 % CI 0.15-0.9). A case-control analysis was also performed with patients of the initial database; after adjustment, neutropenia was not associated with hospital mortality (OR 1.27; 95 % CI 0.86-1.89). CONCLUSION: Hospital survival was closely associated with younger age and neutropenic enterocolitis. Conversely, need for conventional MV, for renal replacement therapy, and allogeneic hematopoietic stem cell transplantation (HSCT) were associated with poor outcome.

Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference Center.

BACKGROUND: Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to subclinical injuries. Cardiac troponin-I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value. OBJECTIVES: To assess the predictive value of cTnI in patients with TTP for death or refractoriness. PATIENTS/METHODS: The study involved a prospective cohort of adult TTP patients with acquired severe ADAMTS-13 deficiency (< 10%) and included in the registry of the French Reference Center for Thrombotic Microangiopathies. Centralized cTnI measurements were performed on frozen serum on admission. RESULTS: Between January 2003 and December 2011, 133 patients with TTP (mean age, 48 ± 17 years) had available cTnI measurements on admission. Thirty-two patients (24%) had clinical and/or electrocardiogram features. Nineteen (14.3%) had cardiac symptoms, mainly congestive heart failure and myocardial infarction. Electrocardiogram changes, mainly repolarization disorders, were present in 13 cases. An increased cTnI level (> 0.1 µg L(-1) ) was present in 78 patients (59%), of whom 46 (59%) had no clinical cardiac involvement. The main outcomes were death (25%) and refractoriness (17%). Age (P = 0.02) and cTnI level (P = 0.002) showed the greatest impact on survival. A cTnI level of > 0.25 µg L(-1) was the only independent factor in predicting death (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.13-7.22; P = 0.024) and/or refractoriness (OR 3.03; 95% CI 1.27-7.3; P = 0.01). CONCLUSIONS: A CTnI level of > 0.25 µg L(-1) at presentation in patients with TTP appears to be an independent factor associated with a three-fold increase in the risk of death or refractoriness. Therefore, cTnI level should be considered as a prognostic indicator in patients diagnosed with TTP.

Fractionated or single-dose total body irradiation in 171 acute myeloblastic leukemias in first complete remission: is there a best choice? SFGM. Société Française de Greffe de Moelle.

PURPOSE: To evaluate the importance of fractionating total body irradiation (TBI) in patients receiving an allogenic bone marrow transplant (BMT) for an acute myeloblastic leukemia (AML) in first complete remission (CR1). METHODS AND MATERIALS: Between 1983 and 1990, 171 consecutive patients received either single dose TBI (STBI) (n = 65) or fractionated TBI (FTBI) (n = 106) after being conditioned with cyclophosphamide and before receiving a non-T-depleted Human Leucocyte Antigen (HLA)-identical marrow. Both groups were comparable except for date of BMT and diagnosis-to-BMT interval (D-BMT). RESULTS: After 63 months median follow-up, transplant-related mortality (TRM), probability of relapse, and 5-year disease-free survival (DFS) were 0.38 and 0.27 (p = 0.04), 0.29 and 0.26 (p = 0.22), 0.43 and 0.56 (p = 0.06), respectively, for STBI and FTBI. The supposed influence of the schedule of TBI disappeared in the multivariate analysis: TRM was enhanced by severe acute graft vs. host disease (p = 0.0002), early years of transplant (before January 1, 1987) (p = 0.0003), and longer D-BMT intervals (p = 0.038). Relapse was linked to early years of transplant (p < 0.00001), and the absence of chronic GVHD (p = 0.007). Longer DFSs were observed for later years of transplant (after January 1, 1987 and later) (p = 0.001), milder acute GVHD (p = 0.005), and shorter D-BMT intervals (p = 0.045). Important improvements of the results were made during the 7-year observation period: TRM, probability of relapse, and DFS were, respectively, 0.36, 0.28, and 0.46 for patients transplanted before January 1, 1987 vs. 0.21, 0.15, and 0.67 after that date. CONCLUSION: Our data strongly suggest that allogenic BMT is the best postremission treatment for AML in CR1, and the results are better when BMT shortly follows the achievement of remission. The schedule of TBI was of little importance compared with the improvements made in the management of patients undergoing BMT during the 1980s, and, therefore, reports concerning data prior to 1985 should be interpreted cautiously.

A modified 60C teletherapy unit for total body irradiation.

PURPOSE: A modified teletherapy unit to achieve total body irradiation with a vertical beam in a conventional treatment room. METHODS AND MATERIALS: A standard 60C teletherapy unit has been modified to achieve total body irradiation with a vertical beam in a conventional treatment room. Patients are treated in prone and supine positions. Removal of the adjustable collimator assembly of this standard machine provides a circular field of 196 cm in diameter at 167 cm from the source. Second, the machine has been elevated by about 50 cm on a metallic base to enlarge irradiation field to obtain 248 cm in diameter at 210 cm from the source, and to encompass tall patients under better conditions. A special lead conical beam flattening filter, 10-mm thick at the center, was designed to compensate the spatial inhomogeneity of the beam. An instantaneous dose rate of 6.10(-2) Gy/min is attained at the L4 level (midplane) in an average 20-cm thick patient with a source activity of 5099 RHM (air kerma rate of 44.8 Gy.h-1.m2). Between February 2, 1984 and December 27, 1990, 244 total body irradiations were performed either by single dose (n = 69, 10 Gy were given to midplane at L4 level in about 6 to 8 h, 8 Gy to the lungs), or by fractionated dose (n = 175, 12 Gy were given in 6 fractions over 3 consecutive days to midplane at L4 level, 9 Gy to the lungs). RESULTS: The dose distribution is similar than the ones obtained by a linear accelerator with patients lying on their sides. CONCLUSION: Patients were treated in a comfortable and highly reproductible position. Organ shielding was easily achievable. This could be a less expensive and reasonable alternative to linear accelerator.

Epidermoid carcinoma of the anal canal treatment results and prognostic variables in a series of 242 cases.

UNLABELLED: From 1972 to 1985, 260 cases of anal canal epidermoid carcinoma were irradiated. Eighteen cases treated for palliation were excluded from the study; 242 (93%) were treated with curative intent. The sex ratio was 1/5.5; mean age was 66 years. HISTOLOGY: 60.3% were well differentiated epidermoid carcinoma; 31.0% moderately differentiated and 8.7%, cloacogenic cases. Staging: T1: 11.5%; T2: 16.1%; T3a: 17%; T3b: 33.5%; and T4: 21.9%. Abnormal inguinal nodes were present in 15.3% of cases. Crude overall survival (Kaplan-Meier) for the 242 cases is 86.4% at 1 year, 63.9% at 3 years, 51.2% at 5 years, and 30.8% at 10 years. Radiation therapy was the sole treatment for 193 cases. No chemotherapy was given. Patients were irradiated by external beam. They received a first course of X rays (mostly 18 MV, some 6 MV) 40 to 45 Gy (box technique) over 4 to 5 weeks in the pelvis. Age and size of tumor were considered when deciding on the target volume. After a rest period of 4 to 6 weeks, a second course of 15 to 20 Gy in 2 weeks was given through a perineal field by electron-beam of suitable energy. The mean total dose was 60.56 Gy and median was 62.5 Gy; the mean overall treatment duration was 85.3 days (median 82 days) and the mean Time Dose Factor including decay factor was 98.96. In this group, 5-year determinate survival was: T1-T2, 84.5%; T3a, 74.8%; T3b, 64.9%; T4, 58.9%. In 147/193 patients (76.2%) local control was achieved. The overall anal conservation rate was 62.6%. In 106 cases (55%), the anus had maintained normal function. The 5-year survival rate by N was 73.3% in the absence of inguinal nodes (169 cases) and 36.1% if such nodes were present. There was no significant difference in survival rate according to histological type. In the second group, receiving radiation therapy plus surgery, 33/49 cases (T3b-T4) were irradiated before surgery (median dose 40.5 Gy). Post operative radiation therapy was administered in 16 cases (T3b-T4) (median dose 49.6 Gy). The 5-year determinate survival is 53.2% for T3b and 79% for T4. According to the log-rank test, there was no significant difference between survival with radiation therapy alone and radiation therapy plus surgery. Multivariate analysis of the whole group indicated that T stage is the only predictive variable.(ABSTRACT TRUNCATED AT 400 WORDS)

Interstitial pneumonitis following autologous bone-marrow transplantation conditioned with cyclophosphamide and total-body irradiation.

PURPOSE: To assess the influence of different total-body irradiation (TBI) regimens on interstitial pneumonitis (IP), we retrospectively analyzed our clinical data concerning an homogeneous group of patients conditioned with cyclophosphamide (CY) alone and single-dose or fractionated TBI before autologous bone-marrow transplantation (ABMT). METHODS AND MATERIALS: One hundred eighty-six patients with acute nonlymphoblastic leukemia (n = 101), acute lymphoblastic leukemia (n = 62), chronic myeloid leukemia (n = 11), non-Hodgkin's lymphoma (n = 10), and multiple myeloma (n = 2) referred to our department between May 13, 1981 and September 16, 1992, underwent TBI before ABMT. The male-to-female ratio was 123:63 (1.95), and mean and median age was 33 +/- 12 (6-63 years) and 35 years, respectively. Cyclophosphamide alone (60 mg/kg/day on each of 2 successive days) was used as conditioning chemotherapy in all patients. Patients were irradiated according to two techniques: either with single-dose (STBI) (n = 124; 10 Gy administered to the midplane at the level of L4, and 8 Gy to the lungs) or with fractionated (FTBI) (n = 62; 12 Gy in 6 fractions over 3 consecutive days to the midplane at the level of L4, and 9 Gy to the lungs) TBI. The mean instantaneous dose rate was 0.057 +/- 0.0246 Gy/min (0.0264-0.1692 Gy/min). It was < or = 0.048 Gy/min in 48 patients (LOW group), > 0.048 and < or = 0.09 Gy/min in 129 patients (MEDIUM group), and > 0.09 Gy/min in 9 patients (HIGH group). The median follow-up period was 5 years (24-120 months). RESULTS: In January 1994, the 5-year overall (including all causes of death) and disease-free survival (DFS) rates were 50 and 48%, respectively. The 5-year DFS was 47.9% in the STBI group, and 47.8% in the FTBI group (p = 0.77). It was 44% in the HIGH group, 53% in the MEDIUM group, and 34% in the LOW group (LOW vs. MEDIUM, p = 0.009). The 5-year IP incidence was 17% in all patients, 16% in the STBI group and 18% in the FTBI group (p = 0.37), but it was significantly higher in patients receiving high instantaneous dose rate TBI (56% in the HIGH, 13% in the MEDIUM, 20% in the LOW groups; HIGH vs. MEDIUM, p = 0.002). However, sex (p = 0.37), age (18% for > 20 vs. 10% for < or = 20 years, p = 0.37), and body weight (> 60 kg vs. < or = 60 kg, p = 0.09) did not influence the IP incidence in univariate analyses. Multivariate analysis (Cox model) revealed that the instantaneous dose rate (p = 0.05), and the age (p = 0.04) were the two independent factors influencing the incidence of IP. CONCLUSION: This retrospective study including only the patients transplanted with ABMT conditioned with CY alone and STBI or FTBI concluded that instantaneous dose rate and age significantly influenced the incidence of IP, whereas sex, body weight, and fractionation did not.

Total body irradiation prior to bone marrow transplantation: efficacy and safety of granisetron in the prophylaxis and control of radiation-induced emesis.

PURPOSE: Radiation-induced emesis is one of the most disturbing side effects of total body irradiation (TBI). To evaluate the efficacy and to determine the best schedule of granisetron (a selective 5-hydroxytryptamine3 serotonin receptor antagonist) administration in the prevention of radiation-induced nausea and vomiting, we conducted a trial involving patients receiving single-dose TBI before bone marrow transplantation (BMT). METHODS AND MATERIALS: Thirty-six patients with non-Hodgkin's lymphoma (n = 12), multiple myeloma (n = 8), acute lymphoblastic leukemia (n = 7), acute nonlymphoblastic leukemia (n = 6), and chronic myeloid leukemia (n = 3) referred to our department between March 1992 and February 1994 were enrolled in this study to assess the efficacy of granisetron during single-dose TBI before autologous BMT (n = 26), allogeneic BMT (n = 8), or syngeneic BMT (n = 2). The male-to-female ratio was 22:14 (1.57), and the mean age was 41 +/- 11 years (range 16-58). Before TBI, conditioning chemotherapy consisted of cyclophosphamide (CY) alone (60 mg/kg per day on 2 successive days) in 24 patients, CY combined with other drugs in 6, and combinations without CY in 6. All patients received single-dose TBI (10 Gy administered to the midplane at L4, and 8 Gy to the lungs). The mean instantaneous and average dose rates were 0.039 +/- 0.012 Gy/min (range 0.031-0.058), and 0.025-0.006 Gy/min (range 2.08-3.96), respectively. Granisetron was administered 30-45 min before TBI according to two different modalities: a total dose of 3 mg as a 5-min intravenous (i.v.) infusion (Treatment A, n = 15; 42%) or the same treatment plus 3 mg of granisetron as a 24-h continuous i.v. infusion (total dose: 6 mg, Treatment B, n = 21; 58%). Depending on the BMT teams, hyperdiuresis was continued (n = 19, 53%) or suspended (n = 17, 47%) during TBI. Nausea and vomiting were assessed during the TBI session and the following 12 h, and were scored as follows: S1 = no nausea or vomiting; S2 = moderate nausea; S3 = severe nausea and/or single episode of vomiting; and S4 = multiple episodes of vomiting. RESULTS: During TBI, 18 (50%) patients were scored as complete responders (S1), 1 (3%) as a major responder (S2), 9 (25%) as minor responders (S3), and 8 (22%) as nonresponders (S4). During the following 12 h, 28 (78%) patients were free of severe nausea and vomiting (S1 or S2), whereas 8 (22%) vomited (S3 or S4). In univariate analyses, the 12-h probability of emesis was significantly higher in patients undergoing hyperdiuresis (63% vs. 30%; p = 0.05), and in patients older than 45 years (65% for age > 45 vs. 33% for age < or = 45; p = 0.05). The probability of S3 or S4 emesis was 50% with Treatment A and 47% with Treatment B (p = 0.86). Sex, body weight, and type of conditioning chemotherapy did not influence the 12-h probability of emesis. Multivariate analysis revealed that hyperdiuresis (p = 0.02) and Treatment A (p = 0.04) were independently associated with radiation-induced emesis, whereas sex (p = 0.85), body weight (p = 0.13), age (p = 0.12), and type of conditioning chemotherapy (p = 0.92) were not. No early toxicity related to granisetron was observed. CONCLUSION: Granisetron is a well-tolerated and effective antiemetic agent that can be used as monotherapy during single-dose TBI. Good control of nausea and vomiting is obtained with this antiemetic drug, and its effect is increased when hyperdiuresis is suspended during TBI.