Relationship between circadian rhythm of vinorelbine toxicity and efficacy in P388-bearing mice.

The relevance of chronopharmacology for improving tolerability and antitumor efficacy of the antimitotic drug vinorelbine was investigated in female B6D2F1 mice standardized with 12 h of light and 12 h of darkness. A single i.v. vinorelbine dose (26 mg/kg) was given to 279 mice at 7, 11, 19, or 23 hours after light onset (HALO). Bone marrow necrosis and leukopenia were nearly twice as large in the mice injected at 7 HALO as compared with those treated at 19 HALO (ANOVA: p <.001 and p = 0.004, respectively). The relevance of vinorelbine dosing time for antitumor efficacy was assessed in 672 P388 leukemia-bearing mice. Vinorelbine was injected as a single dose (20, 24, 26, or 30 mg/kg) or weekly (20, 24, 26, or 28 mg/kg/injection x 3) at one of six circadian times, 4 h apart. A significant correlation between single dose and median survival time was limited to vinorelbine administration at 19 or 23 HALO. An increase in the vinorelbine weekly dose shortened median survival time in the mice treated at 7 HALO (20 mg/kg: 29 days; 24 mg/kg: 17 days; and 26 mg/kg: 6 days) but significantly improved it in those treated at 19 HALO (20 mg/kg: 28.5 days; 24 mg/kg: 32 days; and 26 mg/kg: 36 days). The study demonstrates the circadian rhythm dependence of maximum tolerated dose and the need to deliver maximum tolerated dose at the least toxic time to achieve survival improvement through chronotherapy. This may be obtained with an evening administration of vinorelbine in cancer patients.

Modulation of nonprotein sulphydryl compounds rhythm with buthionine sulphoximine: relationship with oxaliplatin toxicity in mice.

The relationship between the rhythm in tissue nonprotein sulphydryl groups (NPSH) and that in 1,2-diamine (trans-I)-cyclohexane oxalatoplatinum (1-OHP) toxicity was investigated in a total of 266 male B6D2F1 mice, using buthionine sulphoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. Mice were synchronized with an alternation of 12 h light (L) and 12 h darkness (D; LD 12:12), and circadian time was expressed in hours after light onset (HALO). NPSH was measured in liver, jejunum and bone marrow at 0, 8 and 16 HALO. Dosing 1-OHP at these times achieved intermediate. high or low toxicity respectively. The physiological circadian rhythm in NPSH content was statistically significant in all tissues studied, with a maximum at the transition from D to L (0 HALO). BSO administration (450 mg/kg i.p., 4 h before sampling) induced a large depletion in liver and jejunum NPSH at their physiological peak (0 HALO), but exerted no significant effect at their trough (8 HALO). As a result, 24 h rhythm was suppressed in liver and jejunum, but remained similar to the physiological one in bone marrow. BSO enhanced 1-OHP-induced mortality and jejunal toxicity, but exerted no significant effect upon bone marrow toxicity. Despite these differences, 1-OHP remained least toxic at 16 HALO, near the middle of the dark span, which corresponds to maximum activity in the circadian rest/activity cycle. Our results show that mean NPSH levels in liver seem to account for the mean level of 1-OHP toxicity, while jejunal NPSH rhythm plays an important role in the intestinal toxicity rhythm of this drug.

Docetaxel chronopharmacology in mice.

Docetaxel tolerance and antitumor efficacy could be enhanced if drug administration was adapted to circadian rhythms. This hypothesis was investigated in seven experiments involving a total of 626 male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (12:12), after i.v. administration of docetaxel. In experiment (Exp) 1, the drug was given once a week (wk) for 6 wks (20 mg/kg/wk) or for 5 wks (30 mg/kg/wk) at one of six circadian times, during light when mice were resting [3, 7, or 11 hours after light onset (HALO)], or during darkness, when mice were active (15, 19, or 23 HALO). Endpoints were survival and body weight change. In Exp 2 and 3, docetaxel (30 mg/kg/wk) was administered twice, 1 wk apart, at one of four circadian stages (7, 11, 19, or 23 HALO). Endpoints were hematological and intestinal toxicities. In Exp 4, circadian changes in cell cycle phase distribution and BCL-2 immunofluorescence were investigated in bone marrow as possible mechanisms of docetaxel tolerability rhythm. In Exp 5 to 7, docetaxel was administered to mice bearing measurable P03 pancreatic adenocarcinoma (270-370 mg), with tumor weight and survival as endpoints. Mice from Exp 5 and 6 received a weekly schedule of docetaxel at one of six circadian stages (20 or 30 mg/kg/wk at 3, 7, 11, 15, 19, or 23 HALO). In Exp 7, docetaxel (30 mg/kg) was given every 2 days (day 1, 3, 5 schedule) at 7, 11, 19, or 23 HALO. Docetaxel dosing in the second half of darkness (19 or 23 HALO) resulted in significantly worse toxicity than its administration during the light span (3, 7, or 11 HALO). The survival rate ranged from 56.3% in the mice treated at 23 HALO to 93.8 or 87.5% in those injected at 3 or 11 HALO, respectively (Exp 1, P < 0.01). Granulocytopenia at nadir was -49 +/- 14% at 7 HALO compared with -84 +/- 3% at 19 HALO (Exp 2 and 3, P < 0.029), and severe jejunal mucosa necrosis occurred in 5 of 8 mice treated at 23 HALO as opposed to 2 of 18 receiving docetaxel at 7, 11, or 19 HALO (Exp 2 and 3, P < 0.02). The time of least docetaxel toxicity corresponded to the circadian nadir in S or G2-M phase and to the circadian maximum in BCL-2 immunofluorescence in bone marrow. Docetaxel increased the median survival of tumor-bearing mice in a dose-dependent manner (controls: 24 days; 20 mg/kg weekly, 33 days; 30 mg/kg weekly or day 1, 3, 5 schedule, 44 or 46 days, respectively; Exp 5-7). Survival curves of treated mice differed significantly according to dosing time for each dose and schedule (P from log rank <0.003 to P < 0.03). In Exp 5 and 6, the percentage of increase in life span was largest if docetaxel was administered weekly at 7 HALO (20 mg/kg, 220%; 30 mg/kg, 372%) and lowest after docetaxel dosing at 19 HALO (80% with 20 mg/kg) or at 15 HALO (78% with 30 mg/kg). In Exp 7, (day 1, 3, 5 schedule), docetaxel was most active at 11 HALO (percentage increase in life span, 390%) and least active at 23 HALO (210%). Docetaxel tolerability and antitumor efficacy were simultaneously enhanced by drug dosing in the light span, when mice were resting. Mechanisms underlying the tolerability rhythm likely involved the circadian organization of cell cycle regulation. Docetaxel therapeutic index may be improved with an administration at night in cancer patients, when fewest bone marrow cells are in S or G2-M phase.

Post-traumatic membranous obstruction of the inferior vena cava associated with a hypercoagulable state.

It has been hypothesized that abdominal trauma may be one of the factors involved in membranous obstruction of the inferior vena cava. We present two cases of membranous obstruction of the inferior vena cava associated with trauma. One asymptomatic case, associated with an occult myeloproliferative disorder, developed within 3 years of a violent abdominal trauma. The other case, associated with familial plasminogen deficiency, was discovered at surgery 3 days after a road accident with obvious abdominal trauma, since superimposed extensive thrombosis of the inferior vena cava caused acute Budd-Chiari syndrome. We conclude that underlying prothrombotic conditions are probably necessary for the development of membranous obstruction of the inferior vena cava and that minor trauma may contribute to the development of thrombosis through indirect mechanisms.

[Predictive risk factors for progression to cirrhosis in early stage alcoholic liver disease]. / Facteurs prédictifs d'évolution vers la cirrhose à un stade précoce de la maladie alcoolique du foie.

OBJECTIVE: To assess the risk factors of cirrhosis in early stage alcoholic liver disease. PATIENTS: We investigated 83 heavy drinkers (60 males and 23 females) in whom the first of two liver biopsies showed normal or pure alcoholic fatty liver. RESULTS: When the six following variables: sex, age, delay between the first and last biopsy, total duration of alcohol consumption before the first biopsy, daily alcohol consumption for the last 5 years before the first biopsy and the extent of fatty liver in the first biopsy, were considered together in stepwise regression analysis, the delay between the first and last biopsy (p < 0.0001), sex (P < 0.004) and the extent of fatty liver in the first biopsy (P < 0.06) significantly improved the prediction of cirrhosis. The odds ratio of cirrhosis for a women was 19.1 (confidence interval 95% [1.85-197]). The odds ratio for cirrhosis for a percentage of fatty liver > or = 5/10 was 7.4 (confidence interval 95% [1-92]). CONCLUSION: With the same delay between two liver biopsies, the female sex and the extent of fatty liver are two independent risk factors for the development of cirrhosis in heavy drinkers.

Pharmacologic modulation of reduced glutathione circadian rhythms with buthionine sulfoximine: relationship with cisplatin toxicity in mice.

The relationship between the rhythm in reduced glutathione (GSH) and that in cisplatin (CDDP) toxicity was investigated in a total of 560 male B6D2F1 mice, using buthionine sulfoximine (BSO). GSH was measured by high-performance liquid chromatography (HPLC) in four tissues, at each of six sampling times, 4 hr apart. A significant 24-hr rhythm was statistically validated in liver, jejunum, and colon, but not in bone marrow. Relative to liver, glutathione content was 56% in colon, 38% in bone marrow, 25% in jejunum, and negligible in kidney, where cysteine, a final product of GSH catabolism, displayed a 12-hr rhythmic variation. This rhythm may reflect that in the activity of GSH-degrading enzymes. BSO (450 mg/kg ip, 4 hr before sampling) reduced liver GSH threefold and kidney cysteine content was halved, but this pretreatment had no significant effect upon GSH content in the other organs. Furthermore, the period of the physiologic liver GSH rhythm changed from 24 hr to a composite (24 + 12 hr) period. This change in the period may result from an unmasking of the 12-hr rhythm in GSH-degrading enzyme activity by GSH synthesis blockade. Maximal values occurred in the mid-rest span and in the mid-active span after BSO administration. In the other tissues, the 24-hr period remained unchanged. BSO injection largely enhanced CDDP toxicity (as assessed by survival, leukopenia, and histologic lesions in kidney and bone marrow) and kidney mean platinum concentration. Furthermore, BSO pretreatment modified the period of CDDP toxicity rhythm: survival followed a significant 12-hr-rhythm, instead of a 24-hr rhythm. The cycling of GSH concentration results from a balance between synthesis and catabolism and likely constitutes one of the main components of the circadian rhythm in CDDP toxicity in mice.

Circadian rhythm in toxic effects of cystemustine in mice: relevance for chronomodulated delivery.

Cystemustine is a new nitrosourea with high anti-tumor activity and a short plasma half-life in mice. The influence of circadian dosing time upon its toxicities was first investigated in a total of 368 synchronized male B6D2F1 mice. Late survival rate varied from 4% in mice receiving a single dose of cystemustine (conventional lethal dose 50%) at 7 hours after light onset (HALO) up to 88% in mice treated at 15 or at 19 HALO. Target organ toxicities (bone marrow, circulating blood cells, spleen, colon and duodenum) were studied following a single slightly lower dose of cystemustine. Leukopenia was the major hematologic effect encountered. Leukocyte count nadir occurred 7 days after injection and was lowest following cystemustine at 7 HALO as compared to 13 or 19 HALO. Recovery was faster after cystemustine at 19 HALO as compared to other dosing times. Bone-marrow necrotic lesions were more pronounced 1 day after cystemustine at 7 HALO than after cystemustine at 19 HALO. Thus, a large-amplitude circadian rhythm characterized the toxicity of this nitrosourea in mice. The lowest cystemustine toxicity was found near the middle of the active span of the rest-activity circadian cycle of mice.

Modulation of cisplatin chronotoxicity related to reduced glutathione in mice.

Intracellular reduced glutathione (GSH) concentrations were measured according to the tissue sampling-time along the 24 h scale in male B6D2F1 mice. A significant circadian rhythm in GSH content was statistically validated in liver, jejunum, colon and bone-marrow (P < or = 0.02) but not in kidney. Tissue GSH concentration increased in the dark-activity span and decreased in the light-rest span of mice. The minimum and maximum of tissue GSH content corresponded respectively to the maximum and minimum of cisplatin (CDDP) toxicity. The role of GSH rhythms with regard to CDDP toxicity was investigated, using a specific inhibitor of GSH biosynthesis, buthionine sulfoximine (BSO). Its effects were assessed on both tissue GSH levels and CDDP toxicity at three circadian times. BSO resulted in a 10-fold decrease of the 24 h-mean GSH in kidney. However a moderate GSH decrease characterized liver (-23%) and jejunum (-30%). BSO pretreatment largely enhanced CDDP toxicity which varied according to a circadian rhythm. Although BSO partly and/or totally abolished the tissue GSH rhythms, it did not modify those in CDDP toxicity. We conclude that GSH have an important influence on CDDP toxicity but not in the circadian mechanism of such platinum chronotoxicity.

Carcinosarcoma of the liver with mesenchymal differentiation: a case report.

Carcinosarcoma of the liver with mesenchymal differentiation are very rare in adult patients. A case is reported with an exhaustive pathologic examination and review of the literature. A 61-year old man presented with general fatigue and dull abdominal pain. Two liver masses were diagnosed and resected by a right hepatectomy. Specimen pathology revealed that the tumor and lymph node consisted of two cancerous components. One carcinomatous component corresponding to a hepatocellular carcinoma and a sarcomatous component characterized by a diffuse proliferation of spindle shaped cells with chondrosarcomatous and osteosarcomatous changes. Patient died 9 months later of a diffusion of the tumor. For the first time, to our knowledge, a mesenchymal differentiation is demonstrated in liver carcinosarcoma.

Cross-reactive immunity against different strains of the hepatitis E virus transferable by simian and human sera.

Monkey infection with the hepatitis E virus induces protection. We confirm the humoral nature of this immunity and show that protection is effective against the homologous strain, as well as against heterologous strains isolated from Asian and African countries. However this immunity is incomplete since only the clinical disease seems to be prevented, while the virus is still excreted in stools and can even appear in blood as well after serotherapy as previous acute or occult infections. We obtained also a preliminary evidence that convalescent human sera are also efficient for the passive protection, indicating that seroprophylaxis of HEV hepatitis in pregnant women (20% of mortality during the 3rd trimester of pregnancy) should be attempted in the case of epidemics.

Nonhereditary colonic angiodysplasias: histomorphometric approach to their pathogenesis.

The pathogenesis of colonic angiodysplasias, more accurately termed vascular ectasias (VE) has not been definitely established. The aim of this study was to assess that the VE of noncirrhotic patients are not associated with diffuse abnormalities of the colonic mucosal microvasculature unlike the VE of cirrhotic patients. Three groups of nine consecutive patients were studied: group I, control patients with an irritable bowel syndrome; group II, noncirrhotic patients with VE; and group III, alcoholic cirrhotics with VE. A histomorphometric analysis of normal-appearing colonic mucosa was achieved from biopsies taken at six predetermined sites. Noncirrhotics with VE had a significantly lower mean number of mucosal capillaries and a significantly lower mean cross-sectional area of mucosal capillaries than alcoholic cirrhotics with VE. Alcoholic cirrhotics with VE had a significant increase of all the vascular parameters compared to the control group. There was no difference between the control patients and the noncirrhotic patients with VE. These results suggest that the VE of noncirrhotic and cirrhotic patients are entities of distinct pathogenesis.

Primary lymphoplasmacytic lymphoma of the liver associated with a serum monoclonal peak of IgG kappa.

We report a case of primary lymphoma of the liver successfully treated by major liver resection. The tumor exhibited the immunohistological features of a B-cell low-grade lymphoma of the lymphoplasmacytic type. Tumoral plasmacytic cells showed cytoplasmic-positive staining for IgG and kappa light chains. In addition, we detected a serum monoclonal peak of IgG kappa, a finding that has not been reported previously. Clinical, pathological, and immunohistochemical data from the literature are reviewed.

Circadian changes in mitoxantrone toxicity in mice: relationship with plasma pharmacokinetics.

Circadian time-dependent differences in clinical toxicity of several anti-cancer agents were predicted from murine studies. Mitoxantrone is an anthracenedion (an anthracycline-related class of compounds) of increased clinical use, which may benefit from selective circadian timing. In 3 consecutive studies, a total of 428 male B6D2F1 mice aged from 8 to 10 weeks were synchronized by an alternation of 12 hr of light and 12 hr of darkness (LD 12:12). They received a single i.v. injection of mitoxantrone at one of 6 or 4 circadian stages differing by 4 or 6 hr. A dose-response relationship characterized body-weight loss and survival rate. Dose-toxicity relationship further closely depended upon circadian dosing time. Thus, a dose of 16 mg/kg killed 100% of the mice injected at 3 hr after light onset (HALO), and none of them at 11 or at 15 HALO (p from chi 2 < 0.001). Body-weight loss varied from 41% at 3 HALO to 32% at 15 HALO (p from ANOVA < 0.0001). Least hematologic toxicity and fastest recovery of a normal circulating leukocyte count corresponded to mitoxantrone injection near the middle of the dark-activity span, at 16 HALO. Similar findings characterized colonic and splenic lesions. Moreover, mitoxantrone was both distributed and eliminated faster after injection at 16 HALO. If such data apply to cancer patients, as was the case for other drugs investigated with this methodology, an afternoon infusion should enable high-dose mitoxantrone to be well tolerated.

Pancreatic lesions in HIV-infected patients.

The pancreas is frequently involved during HIV infection, especially by disseminated infections or neoplasms. These lesions are generally asymptomatic and are discovered at autopsy. However, hypoglycaemia secondary to massive pancreatic infiltration by a tumour or tuberculous necrosis may occur. The most important cause of pancreatic dysfunction in HIV-infected patients is a drug toxic effect (intravenous pentamidine, didanosine, zalcitabine). Hypoglycaemia, which may or may not be followed by diabetes, can develop during intravenous pentamidine therapy. In cases with increased serum amylase and/or lipase levels, potentially toxic drugs must be promptly discontinued to avoid major pancreatic involvement.

[Neurogenic appendicitis. A case]. / Appendicite neurogène. Une observation.

Laparoscopic procedures have changed the indications for appendectomy. Routine exeresis should not be performed if a normal organ is observed during an exploratory procedure, but should be in cases with clinical manifestations of right flank pain since neurogenic appendicitis is not rare. We report a recent case observed in a 76-year-old woman. The patient was initially hospitalized for right flank pain with nausea and irregular episodes of diarrhoea. Clinical examination and complementary exploration led to cholecystectomy via subcostal access. On per-operative cholangiography the common bile duct appeared normal. Immediate follow-up was uneventful and the patient was discharged. Twelve days later, the patient complained of the same type of abdominal pain and was hospitalized with a fever at 38 degrees C and shivers. The right flank was very painful at palpation. Echography and computed tomography eliminated a subphrenic abscess or secondary pancreatitis. Pain localized at MacBurney's point 8 days later. Barium study showed a normal colon with the exception of uncomplicated diverticulosis. Subjective pain persisted and appendectomy was decided. Pathological examination revealed neurogenic appendicitis. First described in 1924, neurogenic appendicitis is relatively frequent. Macroscopically, a sclerous fibromyxomatous nodule obliterates the lumen. Microscopically, the central obliterating lesion is composed of hyperplastic nervous tissue in a fibromyxoid matrix, particularly important at the point of the appendix. Clinically neurogenic appendicitis is usually chronic and the appendix appears healthy in situ. Cure is always achieved with resection. Laparoscopic procedures can identify para-appendicular causes of painful abdominal syndromes and sclero-atrophic appendicitis, but in the absence of another explanation exeresis appears to be justified due to the possibility of neurogenic appendicitis.

[Giant cell chondroma of soft tissues. Apropos of a case and review of the literature]. / Chondrome à cellules géantes des tissus mous. A propos d'un cas avec revue de la littérature.

Soft tissue chondroma is a benign cartilaginous tumour most often located at the extremity of the upper limbs. We report a very unusual case of soft tissue chondroma due to its location in the sole of the foot resulting in delayed diagnosis. Diagnosis of soft tissue chondroma was confirmed by microscopic examination and by immunohistochemistry showing S 100 protein in the cells of mature and immature areas. The presence of numerous giant cells is exceptional. Labelling of the giant cells by KP 1 protein in the present case suggest that they are derived from macrophages.

Transforming growth factor beta 1: in situ expression in the liver of patients with chronic hepatitis C treated with alpha interferon.

In a semiquantitative assessment of the expression of transforming growth factor (TGF) beta 1 in liver biopsy specimens from patients with chronic hepatitis C, treatment with interferon alfa-2b (3 million units (MU) three times weekly) decreased the expression of TGF beta 1 in six of seven patients. The reduction in TGF beta 1 correlated significantly with the scores for inflammation (p < 0.05) and necrosis (p < 0.05), but not with the alanine aminotransferase activities (p = 0.36) or the score for fibrosis (p = 0.86).