Long-term follow-up of follicular lymphoma (FL) patients receiving single agent rituximab at two different schedules in trial SAKK 35/98

Background: In FL, Rituximab as a single agent delivered in the standard schedule (4 times weekly) may induce a response rate of 50−70% with an event-free survival (EFS) of 1−3 years according to patients' characteristics. Prolonged Rituximab exposure seems to improve EFS at least in responding patients and to increase the rate of longterm responders. Here we report long-term results of a clinical trial comparing single agent Rituximab delivered in the standard schedule versus prolonged exposure, with focus on the proportion of long-term responders and their characteristics. Material and Methods: Between 1998 and 2002, chemotherapy na¨ıve (n = 64) or pre-treated (n = 138) FL patients received Rituximab in the standard schedule. Those responding or with stable disease were randomized to no further treatment (observation, n = 78) or 4 additional doses of Rituximab given at 2-month intervals (prolonged exposure, n = 73). EFS was calculated from the first dose of standard schedule until progression, relapse, second tumor or death. Results: At a median follow up of 9.4 years and with all living patients having been followed for at least 5 years, the median EFS is 13 months for the observation and 24 months for the prolonged exposure arm (p = 0.0007). In the observation arm 13% had no event at 5-years and only 4% at 8 years, while in the prolonged exposure arm it was 27% at 5 years and remained 21% at 8 years. The only significant prognostic factor for EFS in a multivariate Cox regression was the prolonged Rituximab schedule (hazard ratio 0.58, CI 0.39−0.86, p = 0.007), whereas being chemotherapy na¨ıve, presenting with stage prolonged exposure. 5 patients developed myelodysplastic syndrome; all received previous chemotherapy treatment. Conclusions: Our results confirm that the prolonged exposure to Rituximab significantly improves EFS as compared to the standard schedule. This benefit continues for many years after the end of therapy and the prolonged exposure seems to be the sole factor which may be considered of prognostic value. Patients treated with prolonged schedule (8 doses of Rituximab) may have approximately 25% and 20% chances to be in remission at 5 and 8 years respectively and to avoid subsequent chemotherapy treatment.

Intra-individual variation in body temperature and pectoral muscle size in nestling Alpine swifts Apus melba in response to an episode of inclement weather

The Alpine swift (Apus melba) forages on insects caught exclusively on the wing, implying that dependent nestlings face acute food shortage in periods of cold and rainy weather. Therefore, there should be strong selection on nestling swifts to evolve physiological strategies to cope with periods of undernutrition. We have investigated intra-individual changes in nestling pectoral muscle and body temperature in response to a 1-week period of inclement weather. The pectoral muscle is the largest reserves of proteins, and nestlings have to devote a large amount of energy in the maintenance of body temperature. The results show that nestling pectoral muscle size and body temperature were significantly reduced during the episode of inclement weather. Assuming that these physiological changes are adaptive, our study suggests that nestling swifts spare energy by a pronounced reduction (up to 18 degrees C) in body temperature and use proteins from the pectoral muscle as a source of extra energy to survive prolonged periods of fasting.

Hyperglycemia downregulates Connexin36 in pancreatic islets via the upregulation of ICER-1/ICER-1γ.

Channels formed by the gap junction protein Connexin36 (CX36) contribute to the proper control of insulin secretion. We previously demonstrated that chronic exposure to glucose decreases Cx36 levels in insulin-secreting cells in vitro. Here, we investigated whether hyperglycemia also regulates Cx36 in vivo. Using a model of continuous glucose infusion in adult rats, we showed that prolonged (24-48 h) hyperglycemia reduced the Cx36 gene Gjd2 mRNA levels in pancreatic islets. Accordingly, prolonged exposure to high glucose concentrations also reduced the expression and function of Cx36 in the rat insulin-producing INS-1E cell line. The glucose effect was blocked after inhibition of the cAMP/PKA pathway and was associated with an overexpression of the inducible cAMP early repressor ICER-1/ICER-1γ, which binds to a functional cAMP-response element in the promoter of the Cx36 gene Gjd2. The involvement of this repressor was further demonstrated using an antisense strategy of ICER-1 inhibition, which prevented glucose-induced downregulation of Cx36. The data indicate that chronic exposure to glucose alters the in vivo expression of Cx36 by the insulin-producing β-cells through ICER-1/ICER-1γ overexpression. This mechanism may contribute to the reduced glucose sensitivity and altered insulin secretion, which contribute to the pathophysiology of diabetes.

Gene transfer of interleukin-18-binding protein attenuates cardiac allograft rejection.

Interleukin (IL) 18 is a potent pro-inflammatory Th1 cytokine that exerts pleiotropic effector functions in both innate and acquired immune responses. Increased IL-18 production during acute rejection has been reported in experimental heart transplantation models and in kidney transplant recipients. IL-18-binding protein (IL-18BP) binds IL-18 with high affinity and neutralizes its biologic activity. We have analyzed the efficacy of an adenoviral vector expressing an IL-18BP-Ig fusion protein in a rat model of heart transplantation. IL-18BP-Ig gene transfer into Fisher (F344) rat donor hearts resulted in prolonged graft survival in Lewis recipients (15.8 +/- 1.4 days vs. 10.3 +/- 2.5 and 10.1 +/- 2.1 days with control virus and buffer solution alone, respectively; P < 0.001). Immunohistochemical analysis revealed decreased intra-graft infiltrates of monocytes/macrophages, CD4(+), CD8alpha(+) and T-cell receptor alphabeta(+) cells after IL-18BP-Ig versus mock gene transfer (P < 0.05). Real-time reverse transcriptase polymerase chain reaction analysis showed decreased cytokine transcripts for the RANTES chemokine and transforming growth factor-beta after IL-18BP-Ig gene transfer (P < 0.05). IL-18BP-Ig gene transfer attenuates inflammatory cell infiltrates and prolongs cardiac allograft survival in rats. These results suggest a contributory role for IL-18 in acute rejection. Further studies aiming at defining the therapeutic potential of IL-18BP are warranted.

Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma.

PURPOSE: We conducted an international, randomized, phase III trial to evaluate the efficacy and safety of consolidation with yttrium-90 ((90)Y)-ibritumomab tiuxetan in patients with advanced-stage follicular lymphoma in first remission. PATIENTS AND METHODS: Patients with CD20(+) stage III or IV follicular lymphoma, who achieved a complete response (CR)/unconfirmed CR (CRu) or partial response (PR) after first-line induction treatment, were randomly assigned to receive (90)Y-ibritumomab tiuxetan (rituximab 250 mg/m(2) on day -7 and day 0 followed on day 0 by (90)Y-ibritumomab tiuxetan 14.8 MBq/kg; maximum of 1,184 MBq) or no further treatment (control). The primary end point was progression-free survival (PFS), which was calculated from the time of random assignment. RESULTS: A total of 414 patients (consolidation, n = 208; control, n = 206) were enrolled at 77 centers. (90)Y-ibritumomab tiuxetan consolidation significantly prolonged median PFS (after a median observation time of 3.5 years) in all patients (36.5 v 13.3 months in control arm; hazard ratio [HR] = 0.465; P &lt; .0001) and regardless of whether patients achieved PR (29.3 v 6.2 months in control arm; HR = 0.304; P &lt; .0001) or CR/CRu (53.9 v 29.5 months in control arm; HR = 0.613; P = .0154) after induction treatment. Median PFS with consolidation was prolonged in all Follicular Lymphoma International Prognostic Index risk subgroups. After (90)Y-ibritumomab tiuxetan consolidation, 77% of patients in PR after induction converted to CR/CRu, resulting in a final CR rate of 87%. The most common toxicity with (90)Y-ibritumomab tiuxetan was hematologic, and grade 3 or 4 infections occurred in 8% of patients. CONCLUSION: Consolidation of first remission with (90)Y-ibritumomab tiuxetan in advanced-stage follicular lymphoma is highly effective with no unexpected toxicities, prolonging PFS by 2 years and resulting in high PR-to-CR conversion rates regardless of type of first-line induction treatment.

Bi-ventricular axial micropump: impact on blood cell integrity.

BACKGROUND AND OBJECTIVE: Off-pump coronary artery bypass grafting has stimulated the development of micro-pumps designed to prevent the hemodynamic instability induced by heart luxation for the exposure of target vessels of the posterior wall. Impella (Aachen, Germany) developed micro-pumps with a miniaturized propeller system for both sides of the heart. The aim of this study was to analyze the impact of both pumps working together on blood cell integrity. MATERIALS AND METHODS: Both right and left-sided micro-pumps were implanted in 5 calves (body weight, 72_4 Kg) during 3 h. Blood samples for hematology and hemolysis parameters were drawn hourly. RESULTS: Both pumps performed well with a flow of 3.6 L +/- 0.3 L during the 3 h of the experiment with stable hemodynamic conditions. Mixed venous oxygen saturation was 63.4 +/- 15.2% at baseline and 63.8 +/- 16.3% at the end of the experiment (P = ns). Red cell count, LDH and free plasma hemoglobin were 6.7 +/- 2.1 x 10(12)/L, 1807 +/- 437 IU/L, and 32 +/- 9 mg/L at baseline vs. 6.1 +/- 2.1 x 10(12)/L, 1871 +/- 410 IU/L, and 52 +/- 9 mg/L at the end of the experiment (P = ns for all comparisons). Platelet count exhibited a non-significant drop (872 +/- 126 vs. 715 +/- 22 x 10(9)/L). CONCLUSIONS: This double pump system based on the Archimed screw principle is hematologically well tolerated under conditions of prolonged cardiac assist.

Integrating postoperative value of cardiac Troponin I for a better correlation with in-hospital outcomes after congenital heart surgery.

Objective: Cardiac Troponin-I (cTnI) is a well-recognized early postoperative marker for myocardial damage in adults and children after heart surgery. The present study was undertaken to evaluate whether the integrated value (area under the curve(AUC)) of postoperative cTnI is a better mode to predict long-term outcome than post operative cTnI maximum value, after surgery for congenital heart defects (CHD). Methods: retrospective cohort study. 279 patients (mean age 4.6 years; range 0-17 years-old, 185 males) with congenital heart defect repair on cardiopulmonary by-pass were retrieved from our database including postoperative cTnI values. Maximal post operative cTnI value, post operative cTnI AUC value at 48h and total post operative cTnI AUC value were calculated and then correlated with duration of intubation, duration of ICU stay and mortality. Results: the mean duration of mechanical ventilation was 5.1+/-7.2 days and mean duration of ICU stay was 11.0+/- 13.3 days,11 patients (3.9%) died in post operative period. When comparing survivor and deceased groups, there was a significant difference in the mean value for max cTnI (16.7+/- 21.8 vs 59.2+/-41.4 mcg/l, p+0.0001), 48h AUC cTnI (82.0+/-110.7 vs 268.8+/-497.7 mcg/l, p+0.0001) and total AUC cTnI (623.8+/-1216.7 vs 2564+/-2826.0, p+0.0001). Analyses for duration of mechanical ventilation and duration of ICU stay by linear regression demonstrated a better correlation for 48h AUC cTnI (ventilation time r+0.82, p+0.0001 and ICU stay r+0.74, p+0.0001) then total AUC cTnI (ventilation time r+0.65, p+0.0001 and ICU stay r+0.60, p+0.0001) and max cTnI (ventilation time r+0.64, p+0.0001 and ICU stay r+0.60, p+0.0001). Conclusion: Cardiac Troponin I is a specific and sensitive marker of myocardial injury after congenital heart surgery and it may predict early in-hospital outcomes. Integration of post operative value of cTnI by calculation of AUC improves prediction of early in-hospital outcomes. It probably takes into account, not only the initial surgical procedure, but probably also incorporates the occurrence of hypoxic-ischemic phenomena in the post-operative period.

Spatial learning by rats across visually disconnected environments

Experiments were designed to examine some properties of spatial representations in rats. Adult subjects were trained to escape through a hole at a fixed position in a large circular arena (see Schenk 1989). The experiments were conducted in the dark, with a limited number of controlled visual light cues in order to assess the minimal cue requirement for place learning. Three identical light cues (shape, height and distance from the table) were used. Depending on the condition, they were either permanently on, or alternatively on or off, depending on the position of the rat in the field. Two questions were asked: a) how many identical visual cues were necessary for spatial discrimination in the dark, and b) could rats integrate the relative positions of separate cues, under conditions in which the rat was never allowed to perceive all three cues simultaneously. The results suggest that rats are able to achieve a place discrimination task even if the three cues necessary for efficient orientation can never be seen simultaneously. A dissociation between the discrimination of the spatial position of the goal and the capacity to reach it by a direct path suggests that a reduced number of cues might require prolonged locomotion to allow an accurate orientation in the environment.

The bioavailability of bromazepam, omeprazole and paracetamol given by nasogastric feeding tube.

AIMS: To characterize and compare the pharmacokinetic profiles of bromazepam, omeprazole and paracetamol when administered by the oral and nasogastric routes to the same healthy cohort of volunteers. METHODS: In a prospective, monocentric, randomized crossover study, eight healthy volunteers received the three drugs by the oral (OR) and nasogastric routes (NT). Sequential plasma samples were analyzed by high-performance liquid chromatography-UV, pharmacokinetic parameters (Cmax, AUC(0-infinity), t(1/2), k(e), tmax) were compared statistically, and Cmax, AUC(0-infinity) and t(max) were analyzed for bioequivalence. RESULTS: A statistically significant difference was seen in the AUC(0-infinity) of bromazepam, with nasogastric administration decreasing availability by about 25%: AUC(OR) = 2501 ng mL(-1) h; AUC(NT) = 1855 ng mL(-1) h (p < 0.05); ratio (geometric mean) = 0.74 [90% confidence interval (CI) 0.64-0.87]. However, this does not appear to be clinically relevant given the usual dosage range and the drug's half-life (approx. 30 h). A large interindividual variability in omeprazole parameters prevented any statistical conclusion from being drawn in terms of both modes of administration despite their similar average profile: AUC(OR) = 579 ng mL(-1) h; AUC(NT) = 587 ng mL(-1) h (p > 0.05); ratio (geometric mean) = 1.01 (90% CI 0.64-1.61). An extended study with a larger number of subjects may possibly provide clearer answers. The narrow 90% confidence limits of paracetamol indicate bioequivalence: AUC(OR) = 37 microg mL(-1) h; AUC(NT) = 41 microg mL(-1) h(p > 0.05); ratio (geometric mean) = 1.12 (90% CI 0.98-1.28). CONCLUSION: The results of this study show that the nasogastric route of administration does not appear to cause marked, clinically unsuitable alterations in the bioavailability of the tested drugs.

Nosocomial nontyphoidal salmonellosis after antineoplastic chemotherapy : reactivation of asymptomatic colonization ?

Abstract An increased frequency of nontyphoidal salmonellosis is well established in cancer patients, but it is unclear whether this represents increased susceptibility to exogenous infection or opportunistic, endogenous reactivation of asymptomatic carriage. In a retrospective study, a simple case definition was used to identify the probable presence of reactivation salmonellosis in five cancer patients between 1996 and 2002. Reactivation salmonellosis was defined as the development of nosocomial diarrhea >72 h after admission and following the administration of antineoplastic chemotherapy in an HIV-seronegative cancer patient who was asymptomatic on admission, in the absence of epidemiological evidence of a nosocomial outbreak. Primary salmonellosis associated with unrecognized nosocomial transmission or community acquisition and an unusually prolonged incubation period could not entirely be ruled out. During the same time period, another opportunistic infection, Pneumocystis pneumonia, was diagnosed in six cancer patients. Presumably, asymptomatic intestinal Salmonella colonization was converted to invasive infection by chemotherapy-associated intestinal mucosal damage and altered innate immune mechanisms. According to published guidelines, stool specimens from patients hospitalized for longer than 72 h should be rejected unless the patient is neutropenic or ≥65 years old with significant comorbidity. However, in this study neutropenia was present in only one patient, and four patients were <65 years old. Guidelines should thus be revised in order not to reject stool culture specimens from such patients. In cancer patients, nosocomial salmonellosis can Occur as a chemo-therapy-triggered opportunistic reactivation infection that may be similar in frequency to Pneumocystis pneumonia.

TLR 2 modulates inflammation in zymosan-induced arthritis in mice

Résumé L'objectif de cette étude est la compréhension des mécanismes sous-jacents à l'inflammation articulaire dans un modèle murin d'arthrite induite par le zymosan (ZIA). En particulier, la participation du récepteur Toll 2 (TLR2) et du complément C3 a été recherchée. L'inflammation articulaire a été quantifiée par l'accumulation de Technetium (Tc) in vivo, et par histologie des articulations arthritiques. Les réponses humorales et cellulaires induites par le zymosan ont été quantifiées par la prolifération lymphocytaire in vitro et par la mesure de la production d'anticorps dirigés contre le zymosan in vivo. L'inflammation associée à l'arthrite induite au zymosan est, d'après le Tc-uptake, d'aspect biphasique, avec un pic après 1 jour, puis une deuxième phase plus tardive. La deuxième phase persiste jusqu'au 24 ème jour et est associée au développement d'une immunité spécifique contre le zymosan. Les souris déficientes pour TLR-2 présentent une réduction significative de l'inflammation articulaire précoce (jour 1) et tardive (jour 24), ainsi qu'une nette diminution de l'infiltrat inflammatoire dans la membrane synoviale. De plus, la prolifération de cellules du ganglion lymphatique ainsi que le taux d'IgG dirigés contre le zymosan sont diminués de façon significative après 25 jour d'arthrite chez les souris déficientes en TLR2 par rapport aux souris sauvages contrôles. Par contraste, chez les souris déficientes pour C3 on n'observe pas de différence dans l'uptake de Tc ou le scoring histologique par rapport à la lignée sauvage. Ces résultats montrent que l'arthrite induite au zymosan n'est pas seulement un modèle d'inflammation aigue, mais que l'inflammation synoviale persiste même après 25 jours. Ce modèle implique à la fois des mécanismes d'immunité innée et acquise. Le signalling via TLR 2 semble jouer in rôle dans l'immunité au zymosan et pourrait être responsable de la nature biphasique de ce modèle d'arthrite. Abstract The interplay between the innate and acquired immune systems in chronic inflammation is not well documented. We have investigated the mechanisms of inflammation in murine zymosan-induced arthritis (ZIA) in the light of recent data on the roles of Toll-like receptor 2 (TLR2) and Dentin-1 in the activation of monocyte/macrophages by zymosan. The severity of inflammation, joint histology, lymphocyte proliferation and antibody production in response to zymosan were analyzed in mice deficient in TLR2 and complement C3, and the effects of Dentin-1 inhibition by laminarin were studied. In comparison with wild-type animals, TLR2-deficient mice showed a significant decrease in the early (day 1) and late phases (day 24) of joint inflammation. C3-deficient mice showed no differences in technetium uptake or histological scoring. TLR2-deficient mice also showed a significant decrease in lymph node cell proliferation in response to zymosan and a lower IgG antibody response to zymosan at day 25 in comparison with wild-type controls, indicating that TLR2 signalling has a role in the development of acquired immune responses to zymosan. Although laminarin, a soluble β-glucan, was able to significantly inhibit zymosan uptake by macrophages in vitro, it had no effect on ZIA in vivo. These results show that ZIA is more prolonged than was originally described and involves both the innate and acquired immune pathways. C3 does not seem to have a major role in this model of joint inflammation.

Prevention of atelectasis formation during the induction of general anesthesia in morbidly obese patients

Résumé: La formation des atélectasies durant l'induction de l'anesthésie générale est plus importante chez le patient obèse morbide. Nous avons démontré dans des travaux de recherche antérieurs que l'utilisation de la PEEP (Pression Positive en Fin d'Expiration) durant l'induction de l'anesthésie prévient la formation d'atélectasies chez des patients non obèses. Par conséquent, nous voulions étudier l'efficacité de la pression positive en fin d'expiration chez le patient obèse morbide dans la prévention de la formation d'atélectasies. Nous avons fait une étude de 23 patients obèses morbides (BMI > 35 kg / m2) dans 2 groupes. Dans le groupe utilisant la pression positive en fin d'expiration, les patients respiraient 100% d'oxygène pendant 5 minutes par l'intermédiaire d'un masque facial type CPAP avec une pression de 10 cm H20. Après l'induction de l'anesthésie, nous avons ventilé les patients au masque facial avec une PEEP de 10 cm H20. Dans le groupe de contrôle, nous avons procédé au même type d'induction sans utiliser la pression positive en fin d'expiration. La surface de poumon atélectatique a été évaluée par tomographie (CT scann). L'étude des échanges gazeux se faisait à 2 reprises, à partir de gazométries réalisées juste avant l'induction de l'anesthésie puis juste après l'intubation. Après l'induction de l'anesthésie et l'intubation, les patients du groupe de contrôle présentaient une quantité d'atélectasies plus importante que les patients du groupe où la PEEP avait été utilisée (10.4% + 4.8% dans le groupe de contrôle versus 1.3% dans le groupe utilisant la pression positive en fin d'expiration p < 0.001). Après l'intubation, en présence d'une fraction inspirée en oxygène à 100%, la Pa02 était significativement supérieure dans le groupe ayant utilisé la pression positive en fin d'expiration en comparaison avec le groupe de contrôle (respectivement 457 ± 130 mmHg versus 315 ± 100 mmHg). Nous avons conclu que chez le patient obèse morbide, le recours à la pression positive en fin d'expiration lors de l'induction de l'anesthésie permet de prévenir largement la formation d'atélectasies et s'accompagne d'une meilleure oxygénation. Abstract: Atelectasis caused by general anesthesia is increased in morbidly obese patients. We have shown that application of positive end-expiratory pressure (PEEP) during the induction of anesthesia prevents atelectasis formation in nonobese patients. We therefore studied the efficacy of PEEP in morbidly obese patients to prevent atelectasis. Twenty-three adult morbidly obese patients (b ody mass index >35 kg/m2) were randomly assigned to one of two groups. In the PEEP group, patients breathed 100% oxygen (5 min) with a continuous positive airway pressure of 10 cm H20 and, after the induction, mechanical ventilation via a face mask with a PEEP of 10 cm H2O. In the control group, the same induction was applied but without continuous positive airway pressure or PEEP. Atelectasis, determined by computed tomography, and blood gas analysis were measured twice: before the induction and directly after intubation. After endotracheal intubation, patients of the control group showed an increase in the amount of atelectasis, which was much larger than in the PEEP group (10.4% -± 4.8% in control group versus 1.7% ± 1.3% in PEEP group; P <0.001). After in.tubation with a fraction of inspired oxygen of 1.0, Pao, was significantly higher in the PEEP group compared with the control group (457 ±- 130 mm Hg versus 315 ± 100 mm Hg, respectively; P = 0.035) We conclude that in morbidly obese patients, atelectasis formation is largely prevented by PEEP applied during the anesthetic induction and is associated with a better oxygenation.

Plastic and evolutionary responses of cell size and number to larval malnutrition in Drosophila melanogaster.

Both development and evolution under chronic malnutrition lead to reduced adult size in Drosophila. We studied the contribution of changes in size vs. number of epidermal cells to plastic and evolutionary reduction of wing size in response to poor larval food. We used flies from six populations selected for tolerance to larval malnutrition and from six unselected control populations, raised either under standard conditions or under larval malnutrition. In the control populations, phenotypic plasticity of wing size was mediated by both cell size and cell number. In contrast, evolutionary change in wing size, which was only observed as a correlated response expressed on standard food, was mediated entirely by reduction in cell number. Plasticity of cell number had been lost in the selected populations, and cell number did not differ between the sexes despite males having smaller wings. Results of this and other experimental evolution studies are consistent with the hypothesis that alleles which increase body size through prolonged growth affect wing size mostly via cell number, whereas alleles which increase size through higher growth rate do so via cell size.

Irinotecan loaded in eluting beads: preclinical assessment in a rabbit VX2 liver tumor model.

PURPOSE: The purpose of this study was to study the pharmacokinetics of irinotecan injected intravenously, intra-arterially, or loaded onto a delivery platform. MATERIAL AND METHODS: Fifty-four New Zealand White rabbits with VX2 liver tumor, divided in 3 groups of 17 rabbits, each received irinotecan either by intravenous (IV) route, intra-arterial hepatic (IA) route, or loaded on drug-eluting beads (DEBIRI). Animals were killed at 1, 6, and 24 h. Irinotecan and SN-38 concentrations were measured at different time points in serum, tumor, and normal liver. RESULTS: Twelve milligrams of irinotecan were injected IV and IA, whereas 6-16.5 mg were injected loaded onto DEBIRI. Normalized serum irinotecan reached a peak of 333 ng/ml (range 198.8-502.5) for IV, 327.1 ng/ml (range 277.1-495.6) for IA, and 189.7 ng/ml (range 111.1-261.9) for DEBIRI (P < 0.001) delivery. The area-under-the-curve value from 10 to 60 min of serum irinotecan concentration was significantly lower for DEBIRI (P = 0.0009). Tumor irinotecan levels for IV, IA, and DEBIRI (in ng/200 mg of tissue followed by ranges in parentheses) were, respectively, 23.6 (0.3-24.9), 36.5 (7.7-1914.1), and 20.2 (2.9-319) at 1 h; 4.2 (1-27.9), 99.3 (46.6-159.5), and 42.1 (11.3-189) at 6 h; and 2.7 (2.5-6.9), 18.3 (1.5-369.1), and 174.4 (3.4-5147.3) at 24 h (P = 0.02). At 24 h, tumor necrosis was 25% (10-30), 60% (40-91.25), and 95% (76.25-95) for IV, IA, and DEBIRI, respectively (P = 0.03). CONCLUSION: Compared with IV or IA, DEBIRI induces lower early serum levels of irinotecan, a high and prolonged intratumoral level of irinotecan, and a greater rate of tumor necrosis at 24 h. Further evaluation of the clinical benefit of DEBIRI is warranted.

Boerhaave Syndrom: an unusual complication of acute vomiting in a child

Introduction: Boerhaave syndrome (BS) is a spontaneous esophageal perforation, described in aged, alcoholic males, secondary to forceful vomiting. BS has rarely been described in children. Case presentation: The patient is a 7-year-old Nigerian girl. She has a past history of clinical gastro-esophageal reflux (treated conservatively with prokinetics and good evolution), malaria at the age of 3 months and an episode of acute pancreatitis at 5 years. One week prior admission, she had stopped atovaquone-proguanil (AP) prophylaxis after a trip in an endemic area. Two days prior admission, she presented several bouts of isolated acute vomiting, without fever or diarrhea. On admission, she complained of chest pain. Cardiac auscultation revealed crepitus. No subcutaneous emphysema nor respiratory distress was present. Chest radiography and CT-scan confirmed a pneumomediastinum extending to the neck. Esophageal perforation was suspected. An upper gastrointestinal endoscopy was performed and showed a small esophageal tear, grade II-III esophagitis and a single gastric ulcer without any sign of H. Pylori infection. Enteral feeds were stopped and a nasogastric sucking tube inserted. The patient made a full recovery on intravenous antibiotics and conservative treatment. Of note a second episode of subclinical acute pancreatitis, treated conservatively, probably drug-induced. Discussion: BS is a complete rupture of all layers of the esophagus, secondary to an increased intra-abdominal pressure due to incomplete opening of the cricophayngeal sphincter occurring during vomiting or cough. Rarer causes include eosinophilic or Barrett's esophagitis, HIV and caustic ingestion. Esophageal perforation in children is rare, most of time secondary to necrotizing esophagitis in the newborn, medical intervention (endoscopy, sucking, or intubation) or trauma in the older child. Our patient had none of those risk factors and it is still unclear what predisposed her to this complication. However, we believe that preceding forceful vomiting with increased abdominal pressure acting on a weakened oesophagus due to esophagitis might be responsible. We could not find any association in the literature between AP and BS nor between BS and acute pancreatitis. The origin of her recurrent pancreatitis remains unclear, reason for which genetic testing for mutations in the trypsinogen, trypsin inhibitor and CFTR genes will be performed in case of a third episode.