Predictors of responses to immune checkpoint blockade in advanced melanoma.

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

[Malignant transformation of an eccrine spiradenoma]. / Transformation maligne d'un spiradénome eccrine.

INTRODUCTION: Malignant eccrine spiradenoma is a rare and aggressive tumor, developed on the epithelium of eccrine sweat glands. Typically, it occurs after malignant transformation of benign eccrine spiradenoma, but sometimes it happens de novo. OBSERVATION: We report a case of malignant eccrine spiradenoma in a 62-year-old woman. The patient presented a rapid increase in size of a long-standing tumoral lesion of her forearm. There was no secondary lesion on the chest, abdomen or pelvis at the CT-scanner. Cutaneous biopsy of the lesion was performed and showed a carcinoma with no contact with epidermis. On this biopsy, we could not affirm if the tumor was a metastatic process or a primary tumor of the skin. Histologic examination of the surgical removal of the tumor showed an undifferentiated carcinoma with adjacent nodules of eccrine spiradenoma. Immunohistochemical assessment of Ki67 expression showed a weak expression (5%) in the benign spiradenoma nodules and a high rate expression (80%) in the malignant neoplasm. The final diagnosis was an undifferentiated carcinoma arising from preexisting benign spiradenoma. DISCUSSION: Malignant eccrine spiradenoma is not frequent and is rarely described in the international literature that may lead to diagnostic difficulties.

Pathologies of the male breast.

The majority of breast lesions in men are benign. Gynaecomastia is a very common condition in which hormonal changes cause male breasts to enlarge. Three radiological patterns of gynaecomastia have been described: nodular, dendritic, and diffuse glandular pattern. The main differential diagnosis is lipomastia, which is when adipose tissue deposits are found in the subcutaneous tissue. Male breast cancer is rare. The main risk factors are pathologies that cause hormonal imbalances, a history of chest irradiation, and a family history of breast cancer (particularly in families carrying a mutation of the gene BRCA2). Mammography usually shows a mass with no calcifications. Sonography is useful to investigate local disease spread, and for detecting any enlarged axillary lymph nodes. MRI is not currently indicated to investigate male breast cancer. Very often, the clinical examination alone is enough to distinguish benign lesions from malignant lesions. Imaging must not be automatically carried out, but rather it should be used when the diagnosis is clinically uncertain or when patients present risk factors for breast cancer, as well as for guiding biopsies and for assessing disease spread.

Sentinel lymph node biopsy in melanoma: a micromorphometric study relating to prognosis and completion lymph node dissection.

BACKGROUND: Sentinel lymph node (SLN) positivity has been found to be strongly associated with a poor prognosis in melanoma. OBJECTIVES: This large referral centre study was conducted: (i) to confirm the powerful prognostic value of SLN biopsy (SLNB); (ii) to correlate patient prognosis to the micromorphometric features of SLN metastasis in SLN-positive patients; and (iii) to correlate these micromorphometric features to the likelihood of positive completion lymph node dissection (CLND). PATIENTS AND METHODS: SLNB was performed in 455 cases of primary melanoma between January 1999 and December 2004; for patients with positive SLN, the following micromorphometric features were registered: size of the largest metastasis (two diameters), depth of metastasis, number of millimetric slices involved, maximum number of metastases on a single section, presence of intracapsular lymphatic invasion and extracapsular spread. Kaplan-Meier survival curves were compared with the log-rank test; multivariate analysis was performed using a Cox regression model. Dependence of CLND status on micromorphometric features of SLN was assessed by the chi(2) test and predictive values of the different features were evaluated by multivariate analysis using a logistic regression model. RESULTS: A positive SLN was identified in 98 of our 455 cases. Survival was significantly shorter in SLN-positive patients than in SLN-negative patients. Extracapsular invasion was found to be an independent prognostic factor of disease-free survival; ulceration of the primary and the maximum diameter of the largest metastasis were identified as independent predictive factors of disease-specific survival. Age and the lowest diameter of the largest metastasis were identified as independent predictive criteria of positive CLND, whereas depth of metastasis was not. Positivity of CLND was not significantly associated with a worse prognosis. CONCLUSIONS: Our study confirms the previously demonstrated strong prognostic value of SLNB. It also confirms the relationship between tumour burden in the SLN (evaluated by the maximum diameter of the largest metastasis) and clinical outcome. We point out a new micromorphometric feature of SLN, which seems to be predictive of CLND status: the lowest diameter of the largest metastasis.

[Hepatic portal venous gas]. / L'aéroportie.

STUDY OBJECTIVE: Hepatic portal venous gas is a radiological symptom associated with a poor prognosis (75% to 90% mortality). The aim of this retrospective study was to report 7 cases observed over a 2-year period. PATIENTS AND METHOD: From June 1997 to November 1999, hepatic portal venous gas was diagnosed in 6 patients by CT scan and in one patient by echosonography. It was not detected in any case by plain abdominal X-rays. Three patients had small bowel obstruction with necrosis, three had extensive superior mesenteric infarction and one had preperforative necrosis of the colon. RESULTS: One patient with extensive intestinal infarction and a metastatic head and neck cancer was not operated. Two patients were operated, but the extensive mesenteric infarction was not amenable to surgical management. Three of the 7 patients died, while the other four patients survived after resection of the necrotic small intestine (n = 3) and left colectomy extended to the transverse colon (n = 1). CONCLUSION: Hepatic portal venous gas was associated with intestinal necrosis in the seven cases of this series. The severity of portal venous gas is only correlated with the severity of the disease causing portal venous gas.

Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine and rat pancreatic islets.

Susceptibility of pancreatic islets to oxidant stress may affect islet viability and contribute to primary non function of allo- or xenogenic grafts. We investigated the influence of overexpression of catalase (CAT) on the viability of human, porcine and rat islets, as well as INS-1 beta-cell line. Islets were transfected with a replication-deficient adenovirus vector containing human CAT cDNA under the control of the adenovirus major late promoter (AdCAT) or a vector containing no foreign gene (AdNull) and used as a control. Oxidant stress was induced 48 h later by xanthine oxidase-hypoxanthine (XO 25 mU/ml, HX 0.5 mmol/l) or hydrogen peroxide (100 or 250 micromol/l). Islet cell viability was assessed 72 h after CAT transfer by 4-[3-(4-Idophenyl)-2-(4 nitrophenyl)-2H-5-tetrazolio]-1,2,benzene disulphonate (WST-1) test. Baseline catalase activity was three to fourfold lower in porcine than in human islets. CAT activity was reproducibly increased 2.5- to 7-fold in AdCAT infected islets, at least for 13 days. Overall, AdCAT conferred on human and pig islets a protection of 26.1 +/- 6.1 and 21.2 +/- 9.8% on XOHX injury and 35.4 +/- 4.2 and 57.9 +/- 10.5% on H2O2 stress. Similarly, rat islet cells and INS-1 cells were protected on XOHX stress by 17.8 +/- 2.3 and 30.8 +/- 8.7%, respectively. AdNull had no effect. Basal and stimulated insulin secretion was preserved in AdCAT-transfected human islets despite a XOHX challenge. This study validates adenovirus-mediated catalase gene transfer as a realistic approach to reduce non specific inflammation effects on human or porcine islet grafts. Moreover the relevance of defense mechanisms, previously suggested in human islets, is here illustrated in porcine islets.

[Strangulated urethral prolapse in a young woman: a rare urological emergency]. / Le prolapsus étranglé de l'urètre chez la femme jeune: une urgence urologique rare.

Total prolapse of the urethral mucosa in women is an uncommon lesion, observed at the two extremes of reproductive life. Strangulation of urethral prolapse is a rare complication whose emergency treatment is essentially surgical. The authors report a case of strangulated urethral prolapse in a 43-year-old woman, for which several pathophysiological mechanisms can be proposed: first delivery by forceps, poorly repaired perineal tear, untreated early menopause at the age of 40 years. Urethral prolapse in elderly women has become much less common since the introduction of hormone replacement therapy for menopause. Other physiopathogenic factors may be responsible for this prolapse, such as thrombosis of the juxtameatal submucosal veins, laxity between the mucosa and submucosa or uretrodetrusor dyssynergia. The diagnosis of strangulated urethral prolapse is based on the discovery of a very painful, violaceous, inflammatory circular mucosal tumour surrounding the urethral meatus. If rapid reduction of the prolapse is not obtained with systemic and topical oestrogen therapy, the strangulated mucosal flap must be resected surgically, followed by apposition of the urethral mucosal and submucosal planes. This suture, in tissues which are always inflamed, must be calibrated and the urine must be drained by bladder catheter for about ten days. Meatal stricture is the principal complication of this surgery.(ABSTRACT TRUNCATED AT 250 WORDS)