Hydroxyurea potentiation of the antineoplastic activity of cyclophosphamide and 4′-(9-acridinylamino)methanesulfon-M-anisidide (AMSA) in the brown Norway rat myelocytic leukemia model

Summary The activities of hydroxyurea (HU), 4-(9-acridinylamino) methanesulfon-M-anisidide (AMSA) and cyclophosphamide (CY) were examined in the brown Norway rat myelocytic leukemia model in experiments designed to determine the synergy, optimal drug sequencing, and therapeutic index of combinations of these agents. A single dose of CY or four consecutive daily doses of AMSA produced increased survival in leukemic rats, with a positive-slope dose-response curve up to the maximum tolerated dose (MTD). HU at 1/2 MTD produced a minimal antileukemic effect but significantly potentiated the antineoplastic activity of 1/2 MTD of CY or AMSA with no significant toxic death rate. Drug-sequence experiments demonstrated that maximal synergy was achieved when HU was given immediately after CY but immediately before or during AMSA administration. No significant cure rate was seen with any CY/HU or HU/AMSA sequence. The three drugs given in the sequence of CY followed 3 days later by HU and AMSA simultaneously, however, was curative in the majority of rats with advanced leukemia, whereas other sequences were more toxic or less effective. Each of the drugs in these experiments was given at 1/2 of its single-agent MTD. HU significantly potentiates the antineoplastic effect of CY and AMSA in a drug-sequence-dependent manner in this model, apparently with an improved therapeutic index.Supported by the State of Nebraska Cancer and Smoking Disease Research Program Grant #87-10R     

Prognostic and immunohistochemical validation of the capella classification of pancreatic neuroendocrine tumours: an analysis of 82 sporadic cases

AIMS: To study the clinical outcome of 82 cases of pancreatic neuroendocrine tumours classified according to the recent histological and prognostic classification of Capella. METHODS AND RESULTS: Eighty-two surgical cases of pancreatic neuroendocrine tumours were examined histologically with immunohistochemical staining of paraffin sections using streptavidin-biotin complex and application of antibodies against chromogranin A and 10 hormonal peptides. Classification in four groups correlated with long follow-up and outcome of these cases. Histological examination showed 30 group I, four group II, 41 group III and seven group IV tumours. Twenty-one (70%) of group I tumours were insulinomas, whereas 25% of group III tumours were glucagonomas and 25% were unclassified. Most group IV tumours were unclassified, showing no immunohistochemical staining with any of the 10 hormonal peptides tested. Outcome was clearly correlated with tumour group. Among the 14 patients who died of the disease, four had group IV and 10 group III tumours. Thus, unclassified asymptomatic tumours without immunohistochemical staining had a poorer prognosis than asymptomatic tumours with staining. CONCLUSION: This study validates the Capella classification as easy to apply and useful in predicting clinical outcome.     

Increased vaccination efficiency with apoptotic cells by silica-induced, dendritic-like cells

We have demonstrated previously the ability of apoptotic cells to prime a functional immune response using an i.p. vaccination protocol with apoptotic cells and interleukin 2, before injecting a lethal dose of tumor cells into syngeneic rats. This protocol resulted in a survival rate of 33%. To elucidate the nature and the activity of the phagocytes involved in the clearance of apoptotic cells in vivo, we modulated the peritoneal cavity environment by administrating either thioglycollate or silica i.p. before injecting the apoptotic cells. Our results showed that thioglycollate abrogated vaccination efficiency, because none of the rats survived under these conditions. In fact, thioglycollate treatment induced a massive recruitment and activation of inflammatory macrophages that efficiently engulfed apoptotic cells, bypassing induction of specific immune responses. In contrast, silica treatment enhanced the vaccination efficiency of apoptotic cells plus interleukin 2 up to 66%. We distinguished a population of dendrite-like cells among the cells derived from the silica-treated peritoneal cavity both by their phenotype (MHC II(+)/CD80(+)/CD86(+)) and by their ability to induce the proliferation of allogeneic T cells in a mixed leukocyte reaction. Our results demonstrate the different roles of macrophages and dendritic-like cells in the physiological clearance of dead tumor cells and their implication in the design of immunomodulating vaccines.     

Hypopigmented mycosis fungoides

INTRODUCTION: Hypopigmented mycosis fungoides is a rare clinical form of the disease, first described in 1978. Since then, only a hundred odd cases have been documented. CASE REPORT: A young 19 year-old African woman had presented with hypochromatic macules since the age of 9 and for which the diagnostic enquiry had finally concluded in hypopigmented mycosis fungoides. DISCUSSION: The particularities of this form of mycosis fungoides, grade I according to the TNM classification, are principally its onset in black-skinned persons or of Asian origin, and the age of early onset with a predominance of pediatric cases. Its course is indolent for several years and thus source of delayed diagnosis. The differential diagnoses to be evoked are basically vitiligo, achromate eczematides and parapsoriasisis. The post-inflammatory depigmentation, frequent in black-skinned subjects, is only an eliminating diagnosis. Its treatment is that of classical Grade I mycosis fungoides: topical mechlorethamine, phototherapy and topical corticosteroids.     

Cutaneous aseptic abscesses, manifestations of neutrophilic diseases]

BACKGROUND: Neutrophilic skin disease includes several entities: Sweet syndrome, pyoderma gangrenosum, erythema elevatum diutium, Sneddon-Wilkinson sub-keratous pustulosis, and neutrophilic eccrine hidradenitis. We report two cases of aseptic abscesses which correspond to the deepest anatomoclinical form of neutrophilic dermatosis. CASE REPORTS: A 28-year-old man was hospitalized for fever and abdominal pain with bloody diarrhea in relation with Crohn's disease. The patient also presented two skin abscesses on the lower limbs. Bacteriology specimens were negative. The histology specimen of a skin lesion revealed neutrophil infiltration of the hypodermis without granulomatosis. Systemic corticosteroid therapy was given and rapidly led to resolution of the inflammatory bowel disease and the skin lesions. The patient developed inflammatory spondylarthropathy several months later. The second patient was a 36-year-old woman with a history of splenomegaly with asceptic abscesses. She was admitted for abdominal pain with non-bloody diarrhea, fever and multiple joint pain related to spondylarthropathy. She developed several simultaneous abscessed nodules on the legs. Biopsy revealed neutrophil infiltration of the hypodermis. The diagnosis of neutrophilic disease with aseptic cutaneous and visceral abscesses was retained. Nonsteroidal antiinflammatory drugs and dapsone were given leading to regression of the skin lesions and the abdominal and joint pain. DISCUSSION: Aseptic skin abscesses result from a deep localization of neutrophilic disease. They suggest the presence of inflammatory bowel disease, spondylarthropathy or other aseptic visceral localizations.     

Frequency and Risk Factors for Associated Lymphomas in Patients With Lymphomatoid Papulosis

Background.

Lymphomatoid papulosis (LyP) is classified as an indolent cutaneous lymphoma, but outcome dramatically worsens if LyP is associated with lymphoma. The frequency of this association remains unclear in the literature. Here, we assess the frequency and risk factors of association between LyP and another lymphoma in an 11-year retrospective study conducted in 8 dermatology departments belonging to the French Study Group on Cutaneous Lymphoma (FSGCL).

Patients and Methods.

Patients with LyP were identified and data extracted from the FSGCL registry between 1991 and 2006. Patients were followed up to January 2014. Age, sex, number of skin lesions, histologic subtype, and genotype were recorded at baseline. Risk factors were determined using univariate and multivariate analysis. Cumulative probability of association was calculated using the Kaplan-Meier method.

Results.

We observed 52 cases of lymphomas (cutaneous, n = 38; systemic, n = 14) in 44 of 106 patients (41%). Lymphoma diagnosis was concomitant with or prior to LyP diagnosis in 31 cases and occurred during the course of LyP in 21 cases (cutaneous, n = 14; systemic, n = 7; median delay: 5 years; interquartile range: 1.5–7 years). In multivariate analysis, main prognostic factors for association between LyP and another lymphoma were older age (odds ratio [OR]: 1.05 per year; 95% confidence interval [CI]: 1.01–1.08; p = .011) and presence of a T-cell clone in LyP lesions (OR: 7.55; 95% CI: 2.18–26.18; p = .001).

Conclusion.

Older age and presence of a T-cell clone in LyP lesions are risk factors for associated lymphomas in patients with LyP. These findings should help to identify patients who require close management in clinical practice.

Implications for Practice:

The management of lymphomatoid papulosis (LyP) is that of an indolent cutaneous lymphoma, based on its excellent prognosis. However, this good prognosis is altered if LyP is associated with lymphoma. Furthermore, risk factors for and frequency of this association remain unclear in the literature. The results presented here demonstrate a high rate of association between LyP and other lymphomas (41%) as well as a long median delay of occurrence (5 years), which emphasizes the need for prolonged follow-up of patients with LyP. Moreover, two main risk factors (i.e., older age and presence of a T-cell clone in LyP lesions) are highlighted, which should help clinical practitioners to identify patients who require close management.     

Mouth ulcers in patients receiving tacrolimus

INTRODUCTION: The buccal side effects of immunodepressors are well defined with cyclosporine and certain antimitotic agents. We report a case of buccal ulcerations in a patient treated with a new immunosuppressive macrolide: tacrolimus (Prograf). OBSERVATION: A 53 year-old woman presenting a severe cardio-myopathy, underwent heart transplantation in May 1997. Tacrolimus was introduced in October 1997 after 3 episodes of acute reject. Eight months after tacrolimus, painful apthoid buccal ulcerations appeared. Biopsy of the buccal mucosa and other biological examinations revealed no particular etiology. Since tacrolimus could not be stopped, treatment with thalidomide was initiated. It was suspended on two occasions due to adverse events. The buccal ulcerations relapsed rapidly. The intrinsic imputability of tacrolimus in the occurrence of these lesions was noted "l2" ("plausible"). DISCUSSION: Several arguments suggest that these buccal ulcerations may result from the toxicity of tacrolimus: 1) absence of past history of apthae; 2) anatomo-clinical aspect of the lesion differing from that of common apthae, but similar to the ulcerations observed with nicorandil; 3) delay in occurrence of analogous ulcerations compared with that observed with methotrexate or nicorandil; 4) absence of another etiology; 5) relapse of ulcerations on two occasions after suspension of thalidomide, whilst tacrolimus was continued.