Primary Ewing sarcoma of the larynx with distant metastasis: a case report and review of the literature.

Extraosseous Ewing sarcoma is a rare, poorly differentiated round-cell tumour that is part of the Ewing sarcoma family of tumours. Here, we present an extremely rare case of primary extraosseous Ewing sarcoma arising in the larynx, with distant metastases. A 53-year-old man with a history of Hodgkin lymphoma treated 4 years earlier with 8 cycles of chemotherapy presented to our medical centre with a 2-week history of hoarseness. On physical examination, he was found to have a right supraglottic mass together with a fixed right vocal cord. Computed tomography imaging of the patient's neck showed a heterogeneously enhancing lesion measuring 5.0×3.8×3.8 cm, centred on the right thyroid cartilage and invading the right true vocal cord. Imaging by integrated fluorodeoxyglucose positron-emission tomography and computed tomography showed active subcarinal and axillary lymph nodes, multiple scattered lung nodules, and multiple bony metastases. Needle core biopsy of the laryngeal mass was diagnostic for Ewing sarcoma. The patient received radiation to the laryngeal area and then alternating cycles of vincristine-actinomycin-D-cyclophosphamide and etoposide-ifosfamide. The patient remains in remission 1 year after completing therapy. As demonstrated in the present report, these tumours can behave very aggressively both locally and by metastasizing to distant organs. Our treatment approach provided favourable results for the patient; however, future reports are needed to further elucidate optimal management.

Remote ischemic conditioning in a rat model of testicular torsion: does it offer testicular protection?

BACKGROUND: Testicular torsion is a surgical emergency mainly affecting adolescent boys, with a relatively high rate of missed torsion and testicular loss secondary to delay in prompt diagnosis and surgical intervention. With ischemic reperfusion injury as its underlying culprit, testicular torsion may respond favorably to remote ischemic conditioning (RIC) where a non-privileged site (e.g. limb) is concurrently rendered ischemic to divert the cascade of reperfusion injury from the privileged organ (e.g. testicle), thus offering a protective effect in improving salvage. This mechanism is established for other organs, whereas it has not been evaluated for testis. AIM: It was aimed to evaluate RIC in a rat model of testicular torsion as a proof of principle that, similar to what has been demonstrated in other organs, RIC does offer testicular protection. STUDY DESIGN: This is an animal experimental study. Thirty Sprague-Dawley male rats were divided into control group (n = 15) and experimental group (n = 15). Non-survival surgeries of right-sided spermatic cord torsion (720° counter-clockwise twist) were performed for both the groups (45 min) followed by detorsion and reperfusion (5 min) and then orchiectomy. For the experiment group, an intervention of tail clamping to create RIC was applied 5 min after torsion, then unclamping 5 min before detorsion, followed by detorsion and reperfusion for 5 min and then orchiectomy. The testicles were histologically and immunologically examined using a hypoxia inducible factor (HIF-1α) ELISA Kit. The histological findings on ischemic changes, vascular congestion, and immunohistochemistry were quantified using previously described, validated grading systems. RESULTS: DISCUSSION: This is the first study to demonstrate the concept of RIC in an animal model of testicular torsion. It is limited by the non-availability of similar studies to compare outcomes and by the caution of extrapolating animal studies on humans. It does lay grounds, however, to subsequent studies to further elaborate on this concept and its clinical applicability. CONCLUSION: When RIC is applied in the experimental setting of testicular torsion, there is less evidence of hypoxic injury by histology and immunohistochemistry.

The immune microenvironment in cutaneous leishmaniasis.

BACKGROUND: Cutaneous leishmaniasis is an infection that has spread to non-endemic regions, stimulating recent interest for the enhanced understanding of this disease. Downregulation of the CD1a receptor on Langerhans cells has been described in various cutaneous infections. OBJECTIVE: In this study, the immune response across different Ridley patterns and parasitic indices is outlined in a case series of cutaneous leishmaniasis. METHODS: Skin punch biopsies from the interface of normal and lesional cutaneous leishmaniasis were collected from 33 patients with molecularly confirmed Leishmania tropica or L. major infection. Ridley patterns (2-5) were assessed for various clinicopathological features including age, gender, disease duration, parasitic index and constituents of the inflammatory infiltrate. CD1a, CD68, CD3, CD4, CD8, CD20 and CD138 stains were performed on normal skin tissue, cutaneous leishmaniasis biopsies and cytospin/cell block cytology preparations of cultured leishmania promastigotes. CD1a was quantified per mm2 in the epidermis and dermis. The remaining stains were graded according to a 4-tiered grading system [0 (0-4%); 1 (5-24%); 2 (25-49%); 3 (50-74%) and 4 (75-100%). RESULTS: Total CD1a expression significantly decreased (14-fold) from parasitic indices (0-2) to (5-6); (ρ < 0.001). CD1a expression in the epidermis was at least 5-fold lower than normal skin (58 vs. 400 cells/mm2), inversely correlating with the parasitic index. There was an increase in dermal CD1a Langerhans cells (33 vs. 0 cells/mm² in the dermis). CD1a and CD68 staining of amastigotes was strong and diffuse, whereas promastigotes were negative. The major inflammatory infiltrate, in all Ridley patterns, consisted of macrophages and double-negative CD3(+) CD4(-) CD8(-) T lymphocytes. The double-negative CD3 T cells formed a ring around the parasitic laden macrophages. Apart from CD1a, there was no significant difference in inflammatory markers between the various Ridley patterns and parasitic indices. Disease duration did not correlate with Ridley pattern. CONCLUSION: The significant decrease in CD1a expression is postulated by two mechanisms; either via direct CD1a receptor uptake by leishmania amastigotes and/or negative feedback inhibition of CD1a Langerhans cells by double-negative CD3 T-regulatory cells. Modulation of the immune microenvironment in cutaneous leishmaniasis represents a potential therapeutic and prophylactic target.

BRAF mutation status in primary and metastatic melanomas in two regions with differing potential ultraviolet radiation exposure.

BACKGROUND: Melanoma is seen as a heterogeneous molecular entity, with solar ultraviolet radiation (UVR) and BRAF mutation status being important determinants. AIM: To study primary and metastatic melanomas from two UVR-distinct regions to elucidate correlations between prognostic predictors, UVR and BRAF mutation status. METHODS: Extended BRAF testing for 9 mutations was obtained for 95 primary melanomas [Lebanon (LB) n = 55, Pakistan (PK) n = 40)] and 65 metastatic melanomas (LB n = 36, PK n = 29). Collected data included patient age and sex, melanoma size and anatomical location, prognostic parameters and solar elastosis grade for primary melanomas. For metastatic melanomas, site of metastasis, magnitude of necrosis and degree of pigmentation were assessed. Cumulative 21-year averages of potential UVR exposure for Lebanon (110 kJ/m(2) /year) and Pakistan (128 kJ/m(2) /year) were derived from the National Center for Atmospheric Research databases. RESULTS: BRAF mutation status was obtained for 146/160 cases (91.3%). Overall mutation rate was 24/88 (27.3%) in primary and 25/58 (43.1%) in metastatic melanoma. V600E was the predominant mutation in 21/24 (87.5%) of primary and 23/25 (92%) of metastatic melanomas. A 60% discordant mutation rate was identified; of three patients, two lost the mutation in the metastasis and one gained it. The relative incidence of BRAF mutation with potential UVR exposure showed a similar trend in primary (low vs. high UVR: 32.1% vs. 20.0%) and metastatic (57.1% vs. 21.7%) melanomas (P < 0.05). Predictors of BRAF mutations were trunk location and epithelioid and mixed cytology for primary and subcutaneous metastasis, low UVR exposure and absence of pigmentation for metastatic melanomas (P < 0.05). BRAF-positive status in primary melanomas was predicted by multivariate binary logistic regression with reasonable accuracy (C-statistic = 0.67, 95% CI 0.530-0.81 with one independent predictor, namely, epithelioid cytology (OR = 5.11, 95% CI 1.38-8.88, P = 0.01). In metastatic melanomas, high UVR (OR = 0.21, 95% CI 0.06-0.07; P < 0.01) was an independent negative predictor of BRAF mutation. CONCLUSIONS: We have documented the rate of different BRAF mutation types in a Lebanese and Pakistani cohort, and assessed correlations with prognostic markers and potential UVR exposure.

Primary effusion lymphoma in an elderly patient effectively treated by lenalidomide: case report and review of literature.

Primary effusion lymphoma (PEL) is a rare aggressive subset of non-Hodgkin B-cell lymphoma. It is caused by Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV8). It occurs mainly, but not exclusively, in HIV-positive patients. PEL predominantly develops in serous cavities and occasionally in extracavitary regions. PEL carries a very poor prognosis with a median survival time of <6 months. Indeed, currently used treatment modalities such as CHOP chemotherapy are far from achieving complete and sustainable remission. Therefore, there is no clear standard of care established in the treatment of PEL patients, stressing the need for novel-targeted approaches. Here, we have attempted a comprehensive assessment of the treatment of PEL, discussed avant-garde therapies and updated the state of preclinical research with promising clinical applications in the field. These include inhibitors of viral replication, modulators of cell signaling and inflammation, nuclear factor kappa B (NF-κB) and histone deacetylase inhibitors, and recently the combination of arsenic trioxide and interferon-alpha. Some of these targeted therapies have not yet reached clinical studies, although others were used in a few individual case reports with low numbers of patients. We also describe the first case of a 77-year-old, HIV-negative, HHV8-positive patient diagnosed with PEL limited to the pleural and peritoneal cavities. He received lenalidomide 25 mg/day for 21 days every 28 days. Treatment was well tolerated with no side effects. He rapidly improved after 1 month of treatment and progressively achieved complete remission persistent after 18 months of therapy. We believe that this review will bridge an important gap between classical chemotherapy and modern approaches of targeted therapy. Finally, our findings warrant further evaluation of lenalidomide in future prospective clinical studies.

BRAF mutational epidemiology in dysplastic nevi: does different solar UV radiation exposure matter?

BACKGROUND: Proto-oncogene B-Raf (BRAF) mutation rates have been reported in nevi and melanomas of homogeneous Caucasian cohorts. OBJECTIVE: To study the demographics of BRAF mutations in dysplastic nevi of populations with differing potential solar UV radiation exposure. METHODS: Extended BRAF testing for 9 mutations in 125 dysplastic nevi from 101 patients, derived from populations with differing potential UV radiation exposure rates (Lebanon and Saudi Arabia), was performed. Clinical and microscopic parameters were recorded. RESULTS: BRAF mutation status was carried out for 101/125 (80.8%) cases with an overall mutation rate of 62.4% (63/101). V600E (c.1799T > A) was the predominant mutation, found in 61/63 (96.8%) cases. BRAF mutation rate differed significantly by potential UV radiation exposure (Lebanon: 53.4%, Saudi Arabia: 74.4%, P < 0.05). A 43.8% discordant mutation rate (7/16 patients) was found in patients with multiple nevi, including 2 patients with different BRAF mutations. Microscopic examination subdivided the dysplasia into mild (n = 24), moderate (n = 60) and severe (n = 41) with trunk predominance (72.8%). Higher rates of pigment in the stratum corneum were identified in Saudi Arabia (P < 0.05). No statistical significant increase in BRAF mutation rate was noted with advanced architectural and cytological atypia. Parameters associated with a negative BRAF mutation status included upper extremity location, regression, cohesiveness and presence of suprabasal melanocytes (P < 0.05). Positive BRAF mutation status was reasonably predicted by multivariate binary logistic regression by 2 independent predictors: Geographic location and compound nevus type. CONCLUSIONS: In our Near Eastern cohort, the BRAF mutation rate varied significantly by geographic location. In patients with multiple dysplastic nevi examined, discordant BRAF mutation status potentially negates an underlying constitutional predilection.

Children's reactions to war-related stress. Affective symptoms and behaviour problems.

Questionnaire responses from mothers of 1,039 Lebanese 3-9 yr olds were used to study the effects of children's experiences in war on their emotional and social behaviour. Children who had experienced death of a family member, forced displacement of family, or destruction of home or had witnessed death (30% of sample) were about 1.7 times more likely than those who had not to exhibit nervous, regressive, aggressive and depressive behaviour reactions to a general war stress situation (shelling). Findings are discussed with respect to: (a) research relating stressful life events to onset of psychological disorder and (b) societal implications of youngsters' being repeatedly exposed to models of aggression and the violent resolution of interpersonal disputes.