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Head and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiationinduced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (gH2AX and 53BP1) and the expression of senescence-associated markers (SA-bgal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation-induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy. Cancer Res; 76(5); 1170-80. Ó2016 AACR.

Dermatophytes are common pathogens of skin but rarely cause invasive disease. We present a case of deep infection by Trichophyton rubrum in an immunocompromised patient. T. rubrum was identified by morphological characteristics and confirmed by PCR. Invasiveness was apparent by histopathology and immunohistochemistry. The patient was treated successfully with itraconazole. CASE REPORTA 56-year-old male was admitted for evaluation of elevated erythrocyte sedimentation rate (ESR), anemia, and multiple subcutaneous nodules on both legs. The patient was under close medical supervision due to an autoimmune disease with liver, cardiac, and lung involvement.His medical history included pericarditis (27 years before admission), and a profound jaundice after a respiratory infection treated with cefuroxime (3 years before admission). Serology was negative for hepatitis viruses and positive for antiparietal, antinuclear, and antineutrophil cytoplasmic antibodies. Liver biopsy revealed a profound destruction of liver architecture, fibrosis, active inflammation, and cholestasis. Treatment with steroids was followed by a good clinical response and normalization of liver enzymes. Attempts to wean the patient from steroids including administration of azathioprine and cyclosporine failed, and during the 2 years prior to admission he received both prednisone and cyclosporine. Several weeks before admission, he was evaluated for a chronic cough. He had undergone a transbronchial biopsy that disclosed chronic inflammation and thickening of the basement membrane, without any specific diagnosis, but responded to an increase of the dose of steroids. A few weeks later, while trying to taper the steroids, he developed multiple, hard cutaneous nodules, distributed mainly on the lower limbs. Some later softened and discharged caseous material spontaneously.Other underlying conditions included glucose-6-phosphate dehydrogenase deficiency, nephrolithiasis, benign prostate hypertrophy, bilateral inguinal hernia repair, and osteoporosis.On admission, medications included prednisone (10 mg once a day [QD]), cyclosporine (100 mg QD), ursodeoxycholic acid (300 mg twice a day), alendronate (10 mg QD), omeprazole (20 mg QD), and calcium (600 mg) and vitamin D (0.25 g) once daily. On physical examination, rhonchi were heard over both lungs. A few hard, mobile subcutaneous nodules were present on both lower limbs, mainly around the knees and thighs (Fig. 1a), and the sacral area. Some of these nodules were purplish and soft. Onychomycosis was present on the feet and both hands (Fig. 1b and c).Laboratory test results were as follows: ESR, 80; hemoglobin level, 10.8 g/dl; leukocyte count, 7,900/l (42% granulocytes); albumin level, 34 g/liter; total protein level, 83 g/liter; liver enzyme levels, normal.Two of the patient's nodules were excised. A granulomatous inflammatory reaction was present in the dermis and hypodermis. It was composed of monocytes, macrophages, multinucleated giant cells, and rare neutrophils (Fig. 2). Septate hyphae were revealed...

Lesions of the caruncle are uncommon. On account of the histological composition of the caruncle, which includes, in addition to conjunctiva, hair follicles, sebaceous glands, sweat glands, and accessory lacrimal tissue, the caruncle may develop lesions that may be similar to those found in the skin, conjunctiva, or lacrimal gland. Clinical preoperative diagnosis is very difficult and reached only in about half of the cases. The vast majority of lesions of the caruncle are benign, mainly nevi. Reported malignant lesions are very rare but can be potentially fatal. Although malignancy is clinically overestimated, any suspected malignant lesion should be excised and examined histopathologically by an experienced pathologist. This study presents the clinical and histological data of 42 consecutive caruncular lesions processed at our laboratory and reviews previously reported cases of caruncular lesions.

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Group A Streptococcus (GAS) causes diverse infections in humans, ranging from mild to life-threatening invasive diseases, such as necrotizing fasciitis (NF), a rapidly progressing deep tissue infection. Despite prompt treatments, NF remains a significant cause of morbidity and mortality, even in previously healthy individuals. The early recruitment of leukocytes is crucial to the outcome of NF; however, although the role of polymorphonuclear neutrophils (PMNs) in host defense against NF is well established, the role of recruited macrophages remains poorly defined. Using a cutaneous murine model mimicking human NF, we found that mice deficient in TNF-α were highly susceptible to s.c. infections with GAS, and a paucity of macrophages, but not PMNs, was demonstrated. To test whether the effects of TNF-α on the outcome of infection are mediated by macrophages/monocytes, we systemically depleted C57BL/6 mice of monocytes by pharmacological and genetic approaches. Systemic monocyte depletion substantially increased bacterial dissemination from soft tissues without affecting the number of recruited PMNs or altering the bacterial loads in soft tissues. Enhanced GAS dissemination could be reverted by either i.v. injection of monocytes or s.c. administration of peritoneal macrophages. These experiments demonstrated that recruited macrophages play a key role in defense against the extracellular pathogen GAS by limiting its spread from soft tissues.

This study analyzes the histopathological findings in H syndrome, a recently recognized autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin in well-defined anatomical areas accompanied by various systemic manifestations. So far, descriptions of the histopathological skin changes in this disorder, as reported in a few small case series, were inconsistent, leading to diverse clinical interpretations. In an attempt to define standardized, diagnostic, morphological criteria that will distinguish this disorder from other fibrosing conditions, we studied skin biopsies from 10 patients with H syndrome. The characteristic morphology included widespread fibrosis (moderate in dermis and severe in subcutis); striking mononuclear infiltrates consisting mainly of monocyte-derived cells (small CD68 histiocytes and CD34 and FXIIIa dendrocytes) and plasma cells; and thickened, fragmented, and partially calcified elastic fibers, admixed with well-formed psammoma bodies, a previously unrecognized feature in nonneoplastic skin and subcutaneous conditions. In addition, the ultrastructure of CD68 small histiocytes exhibited distended endoplasmic reticulum and scarcity of lysosomes, features typical for fibroblasts but unusual for histiocytes. These unusual findings in the histiocytes pose a question as to their possible role in the fibrotic cascade in this disorder. We conclude that the above findings are essential for the diagnosis of H syndrome and that incisional biopsies are mandatory for recognition of the full spectrum of histopathological findings.

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