The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial.

BACKGROUND: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. METHODS: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0-1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1-14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m(-2)) was administered on day 1 starting with cycle 2. 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. RESULTS: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing (18)F-FLT-PET scans showed increases (23-92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF(V600E/K) patients had significantly worse PFS than patients without these mutations. CONCLUSIONS: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3'-Deoxy-3'-(18)F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.

Bacillary angiomatosis masquerading as Kaposi's sarcoma in East Africa.

BACKGROUND: Bacillary angiomatosis (BA) is a rare manifestation of infection caused by Bartonella species, which leads to vasoproliferative lesions of skin and other organs. Bacillary angiomatosis affects individuals with advanced HIV disease or other immunocompromised individuals. In sub-Saharan Africa, despite the high prevalence of HIV infection and documentation of the causative Bartonella species in humans, mammalian hosts, and arthropod vectors, BA has only rarely been described. METHODS: Three adult patients from Uganda and Kenya with deep purple dome-shaped papules or nodules of the skin underwent punch biopsies for histopathologic diagnosis. The biopsies of all 3 patients were sent to a local pathologist as well as to a dermatopathologist at the University of California, San Francisco. RESULTS: All 3 patients were clinically suspected to have Kaposi's sarcoma (KS), and local pathologists had interpreted the lesions as KS in 2 of the cases and nonspecific inflammation in the third. Histologic examination by dermatopathologists in the United States revealed nodular dermal proliferations of irregular capillaries lined by spindled to epithelioid endothelial cells. The surrounding stroma contained a mixed inflammatory infiltrate with lymphocytes, eosinophils, and neutrophils. Extracellular deposits of pale amphophilic granular material were noted in the surrounding stroma. A Warthin-Starry stain highlighted clumps of bacilli, confirming the diagnosis of BA. CONCLUSIONS: These 3 cases, to our knowledge, are the first reports of BA in East Africa in the biomedical literature. Each had been originally incorrectly diagnosed as KS. We speculate BA is underdiagnosed and underreported in resource-poor regions, such as sub-Saharan Africa, that have high endemic rates of HIV infection.

Factors associated with pruritic papular eruption of human immunodeficiency virus infection in the antiretroviral therapy era.

BACKGROUND: Pruritic papular eruption (PPE) of HIV is common in HIV-infected populations living in the tropics. Its aetiology has been attributed to insect bite reactions and it is reported to improve with antiretroviral therapy (ART). Its presence after at least 6 months of ART has been proposed as one of several markers of treatment failure. OBJECTIVES: To determine factors associated with PPE in HIV-infected persons receiving ART. METHODS: A case-control study nested within a 500-person cohort from a teaching hospital in Mbarara, Uganda. Forty-five cases and 90 controls were enrolled. Cases had received ART for ≥ 15 months and had an itchy papular rash for at least 1 month with microscopic correlation by skin biopsy. Each case was individually matched with two controls for age, sex and ART duration. RESULTS: Twenty-five of 45 cases (56%) had microscopic findings consistent with PPE. At skin examination and biopsy (study enrolment), a similar proportion of PPE cases and matched controls had plasma HIV RNA < 400 copies mL(-1) (96% vs. 85%, P = 0·31). The odds of having PPE increased fourfold with every log increase in viral load at ART initiation (P = 0·02) but not at study enrolment. CD4 counts at ART initiation and study enrolment, and CD4 gains and CD8(+) T-cell activation measured 6 and 12 months after ART commencement were not associated with PPE. Study participants who reported daily insect bites had greater odds of being cases [odds ratio (OR) 8·3, P < 0·001] or PPE cases (OR 8·6, P = 0·01). CONCLUSIONS: Pruritic papular eruption in HIV-infected persons receiving ART for ≥ 15 months was associated with greater HIV viraemia at ART commencement, independent of CD4 count. Skin biopsies are important to distinguish between PPE and other itchy papular eruptions.

Differential expression of PHLDA1 (TDAG51) in basal cell carcinoma and trichoepithelioma.

BACKGROUND: A recent small series demonstrated perfect sensitivity and specificity utilizing immunostaining for PHLDA1, a marker of follicular stem cells, in the distinction of desmoplastic trichoepithelioma and morphoeiform basal cell carcinoma (BCC) in small biopsy specimens. OBJECTIVES: To assess this result more broadly. METHODS: We performed immunoperoxidase staining of BCCs (superficial n = 16, nodular n = 15, micronodular n = 15, infiltrative n = 17, morphoeiform n = 16, infundibulocystic n = 14) and trichoepitheliomas (conventional n = 19, desmoplastic n = 16) with PHLDA1. RESULTS: Morphoeiform BCCs typically lacked PHLDA1 staining (88% demonstrated no staining and 12% of cases had staining in < 25% of the tumour), while in contrast 74% of classical and 88% of desmoplastic trichoepitheliomas demonstrated strong PHLDA1 staining in over half of the tumour. However, micronodular BCCs demonstrated focal to diffuse positive staining in a third of the cases. CONCLUSIONS: Based upon our staining results, we discuss the biological significance of PHLDA1 expression and the limits in its diagnostic utility.

Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma.

BACKGROUND: Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma. METHODS: Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations. RESULTS: Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response. CONCLUSION: The recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.

Association of Sweet's Syndrome and Systemic Lupus Erythematosus.

Sweet's syndrome is an acute febrile neutrophilic dermatosis which usually presents as an idiopathic disorder but can also be drug induced, associated with hematopoetic malignancies and myelodysplastic disorders, and more, infrequently, observed in autoimmune disorders. Sweet's syndrome has been reported in three cases of neonatal lupus, three cases of hydralazine-induced lupus in adults, and in nine pediatric and adult systemic lupus erythematosus (SLE) patients. We describe three additional adult cases of Sweet's associated with SLE and provide a focused review on nondrug-induced, nonneonatal SLE and Sweet's. In two of three new cases, as in the majority of prior cases, the skin rash of Sweet's paralleled underlying SLE disease activity. The pathogenesis of Sweet's remains elusive, but evidence suggests that cytokine dysregulation may be central to the clinical and pathological changes in this condition, as well as in SLE. Further research is needed to define the exact relationship between the two conditions.

Cryopyrin-associated periodic syndromes and autoinflammation.

Autoinflammatory syndromes are a distinct class of inherited diseases of cytokine dysregulation with important cutaneous features. Several disorders, including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome and neonatal onset multisystem inflammatory disorder (NOMID), are associated with mutations in a common gene, CIAS-1. These disorders are now believed to represent related conditions along a spectrum of disease severity, in which FCAS is the mildest and NOMID is the most severe phenotype. Patients typically present with lifelong atypical urticaria with systemic symptoms, with potential for developing end-organ damage due to chronic inflammation. Advances in the understanding of the genetic basis of these syndromes have also revealed cytokine signalling molecules that are critical to normal regulation of inflammatory pathways. The dramatic response of these syndromes to anakinra, an interleukin (IL)-1 antagonist, highlights the important role of IL-1 cytokine signalling in the pathogenesis of this rare but fascinating class of diseases.

Mixed allogeneic chimerism as a reliable model for composite tissue allograft tolerance induction across major and minor histocompatibility barriers.

BACKGROUND: Although prolonged composite tissue allograft (CTA) survival is achievable in animals using immunosuppressive drugs, long-term immunosuppression of CTAs in the clinical setting may be unacceptable for most patients. The purpose of this study was to develop a model for reliable CTA tolerance induction in the adult rat across a major MHC mismatch without the need for long-term immunosuppression. METHODS: Mixed allogeneic chimeras were prepared by using rat strains with strong MHC incompatibility [WF (RT1Au), ACI (RT1Aa)] WF + ACI-->WF, n=23. The bone marrow (BM) of recipient animals was pretreated with low-dose irradiation (500-700 cGy), followed by reconstitution with a mixture of T cell-depleted syngeneic (WF) and allogeneic (ACI) cells. Additionally, the recipient animals received a single dose of anti-lymphocyte serum (10 mg) 5 days before bone marrow transplantation (BMT) and tacrolimus (1 mg/kg/day) from the day before BMT to 10 days post-BMT. Hindlimb transplants were performed 12 months after BMT. Five animals received a limb allograft irradiated (1000 cGy) just before transplantation. Rat chimeras were characterized (percentage of donor cells present within the bloodstream) by flow cytometry at 3 and 12 months after BM reconstitution and after hindlimb transplantation. RESULTS: Peripheral blood lymphocyte chimerism (WF/ACI) remained stable >12 months after BM reconstitution in 18/23 animals. Multi-lineage chimerism of both lymphoid and myeloid lineages was present, suggesting that engraftment of the pluripotent rat stem cell had occurred. In animals with donor chimerism >60% (n=18) no sign of limb rejection was present for the duration of the study. All animals with chimerism <20% (n=5) developed moderate signs of rejection clinically and histologically. Gross motor and sensory reinnervation (weight bearing, toe spread) developed at >60 days in 14/21 rats. Postoperative flow cytometry studies demonstrated stable chimerism in all animals studied (n=10). Five out of five animals with irradiated limb transplants showed no sign of GVHD at >100 days. CONCLUSIONS: Stable mixed allogeneic chimerism can be achieved in a rat hindlimb model of composite tissue allotransplantation. Hindlimb allografts to mixed allogeneic chimeras exhibit prolonged, rejection-free survival. Partial functional return should be expected. The BM transplanted as part of the hindlimb allograft plays a role in the etiology of GVHD. Manipulating that BM before transplantation may influence the incidence of GVHD. This represents the first reliable rat hindlimb model demonstrating rejection-free CTA survival in an adult animal across a major MHC mismatch without the long-term need for immunosuppressive agents.

Cutaneous manifestations of maternal engraftment in patients with severe combined immunodeficiency: a clinicopathologic study.

SCID is a heterogeneous group of disorders characterized by defective T cell and B cell function. Eczematous and morbilliform eruptions are common, and graft-versus-host disease (GVHD) due to maternal engraftment has been documented. We sought to better characterize SCID-related cutaneous disease observed prior to BMT and to compare the eruption to conventional GVHD. Medical records of 51 patients with SCID treated between 1982 and 1999 were reviewed. Ten of 51 (20%) had rash and evidence of maternal engraftment prior to BMT (study group). Eleven of 51 (22%) had no rash or evidence of engraftment pre-BMT but developed GVHD following transplant (control group). Skin biopsies were available for review for 8/10 of the study group and for 8/11 of the control group. Cutaneous findings consisted of a scaling, erythematous maculopapular eruption spread widely over the trunk and extremities, with near-erythroderma in some patients. Microscopically, biopsies from the study group differed significantly from controls. Key differences included parakeratosis (P < or = 0.01), psoriasiform hyperplasia (P < or = 0.04) and spongiosis (P < or = 0.04). The dermatopathologic findings of transplacental GVHD differ from the pattern of post-transplant GVHD. A 'psoriasiform-lichenoid-spongiotic' pattern with necrotic keratinocytes should trigger consideration of SCID and maternal engraftment in the dermatopathologic evaluation of eruptions of infancy.

Rudimentary meningocele: remnant of a neural tube defect?

BACKGROUND: Rudimentary meningocele, a malformation in which meningothelial elements are present in the skin and subcutaneous tissue, has been described in the past under a variety of different terms and has also been referred to as cutaneous meningioma. There has been debate as to whether rudimentary meningocele is an atretic form of meningocele or results from growth of meningeal cells displaced along cutaneous nerves OBJECTIVE: We reviewed the clinical, histological, and immunohistochemical characteristics of rudimentary meningocele in an attempt to assess the most likely pathologic mechanism for it. DESIGN: Retrospective study. SETTING: University hospitals. PATIENTS: Thirteen children with rudimentary meningocele. MAIN OUTCOME MEASURES: Medical records were reviewed and histopathologic examination as well as immunohistochemistry studies were performed for each case. A panel of immunoperoxidase reagents (EMA, CD31, CD34, CD57, S-100, and CAM 5.2) was used to assess lineage and to confirm the meningothelial nature of these lesions. RESULTS: Recent evidence indicating a multisite closure of the neural tube in humans suggests that classic meningocele and rudimentary meningocele are on a continuous spectrum. CONCLUSION: Rudimentary meningocele seems to be a remnant of a neural tube defect in which abnormal attachment of the developing neural tube to skin (comparable to that in classic meningocele) could explain the presence of ectopic meningeal tissue. In the majority of cases, no underlying bony defect or communication to the meninges could be detected. However, in light of the probable pathogenesis, imaging studies to exclude any communication to the central nervous system should precede any invasive evaluation or intervention.

Efficacy of curettage before excision in clearing surgical margins of nonmelanoma skin cancer.

OBJECTIVE: To determine whether curettage before excision of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) improves margin clearance rates. DESIGN: A retrospective, nonrandomized, case-control series of nonmelanoma skin cancers treated with preexcisional curettage followed by simple excision was identified using a computerized search of the database of a dermatopathology service. A validation cohort was established by manually identifying nonmelanoma skin cancers treated with wide excision on a given day. SETTING: All analyzed specimens were derived from the Dermatopathology Service at the University of California, San Francisco, a university-based laboratory that provides interpretation of skin biopsy specimens received directly from community (90%) and academic (10%) practices. PATIENTS: Our retrospective cohort consisted of all nonrecurrent nonmelanoma skin cancers diagnosed by biopsy and treated by simple excision between April 1, 1997, and April 30, 1999. There were 1983 BCCs and 849 SCCs included in our study. The validation cohort included skin cancers diagnosed by biopsy treated with simple excision on the 16th day of each month during the same period. INTERVENTION: Preexcisional curettage. MAIN OUTCOME MEASURE: We compared the frequency of tumor margin involvement of curetted vs noncuretted lesions. Margin involvement was considered surgical failure. RESULTS: Forty-two pecent of BCCs and 34% of SCCs were curetted before excision. In BCC, risks for surgical failure included head and neck lesions (P<.001), lesions treated by physicians performing fewer than 51 procedures (P<.001), and invasive subtypes (P<.01). Factors associated with surgical failure in SCC included in situ disease (P=.01) and an older (77 vs 74 years) patient population (P=.05). In univariate analysis, curettage before excision decreased the surgical failure rate for BCC by 24% (P=.03) but did not decrease the rate for SCC (P=.8). In multivariate analysis, curettage of BCC reduced surgical failure rates by 26% when the physician performed 50 skin cancer excisions or less during the study (odds ratio, 0.74; 95% confidence interval, 0.57-0.95;P=.02). CONCLUSION: Preoperative curettage decreases the frequency of positive margins in the management of BCC but not of SCC.

Microcystic adnexal carcinoma: forty-eight cases, their treatment, and their outcome.

BACKGROUND: Microcystic adnexal carcinoma, or sclerosing sweat duct carcinoma, is an uncommon cutaneous neoplasm associated with extensive local invasion. The standard of care with regard to the best excisional method in treating microcystic adnexal carcinoma has not been established. OBJECTIVES: To perform a retrospective study comparing patients treated by Mohs micrographic surgery with those treated by wide excision and to elucidate the epidemiological features of microcystic adnexal carcinoma. PATIENTS AND METHODS: A retrospective analysis of a case series involving 48 primary and referral patients diagnosed as having microcystic adnexal carcinoma using standardized criteria. All cases were reviewed by the same dermatopathologists. RESULTS: Microcystic adnexal carcinoma predominantly affects the left side of the face of middle-aged women. Microcystic adnexal carcinoma is misdiagnosed 30% of the time. The recurrence rate is 1.98% per patient-year. Mohs micrographic surgery and simple excision show comparable complication rates. Clear margins were obtained in fewer procedures and, therefore, fewer office visits when the lesions were treated with micrographic surgery. The defect surface area after full extirpation following Mohs micrographic surgery was a mean of 4 times that of the clinically apparent size. The wide range of difference between the pre- and the post-Mohs micrographic surgery surface area noted in our data indicates that a margin cannot be safely predicted. CONCLUSIONS: Microcystic adnexal carcinoma is a predominantly left-sided, locally aggressive facial tumor, which results in significant morbidity. Our data do not support the use of standardized predictable margins. Mohs micrographic surgery is a reasonable initial treatment, as it accomplishes cure in fewer office visits and does not rely on predicted margins.

Photosensitivity in HIV-infected individuals.

OBJECTIVE: To characterize photosensitivity in HIV-infected individuals using minimal erythema dosage (MED) UVA (ultraviolet A light) and UVB (ultraviolet B light) photoprovocation light testing. DESIGN: Prospective, controlled analytical study. SETTING: University of California, San Francisco, between March 1995 and January 1997. PATIENTS: 13 HIV-seropositive patients with clinical and pathological features consistent with photodermatitis, 13 HIV-seropositive patients with biopsy-proven eosinophilic foliculitis (EF), and 10 HIV-seropositive patients with CD4 (T helper cell) count below 200 cells/uL and no history of photosensitivity or EF. INTERVENTION: Each patient underwent MED testing for UVB. All 13 patients with suspected photodermatitis underwent full photochallenge testing with UVA and UVB for up to 10 consecutive week days. RESULTS: Mean MED to UVB in patients with clinical photosensitivity and EF was lower (p = 0.004 and p = 0.022 respectively) than that of patients without a clinical history of photodermatitis. There were no significant differences in mean CD4 count or Fitzpatrick skin type. Positive photochallenge tests (papular changes at site of provocative light testing) to UVB (9 of 13 patients) were much more common than reactions to UVA (3 of 13 patients) in the photodermatitis group. All patients with clinically active photodermatitis developed papular changes at the site of UVB photochallenge testing, but only 1 of 5 patients with photodermatitis in remission developed papular changes with UVB photochallenge testing. Seven of the 13 patients with photodermatitis had Native American ancestry. Photosensitive patients were commonly taking trimethoprim-sulfamethoxazole (TMP-SMX), but no more commonly than EF or control patients. CONCLUSIONS: Photosensitivity in HIV-infected individuals appears to be a manifestation of advanced disease. Most patients are sensitive to UVB. The most severely affected individuals are both UVB and UVA sensitive, and may show reactions to visible light. A significant Native American ancestry may be a risk factor for development of photodermatitis in patients with advanced HIV disease. Finally, patients with eosinophilic folliculitis may be subclinically photosensitive.

Cutaneous melanoma with myxoid features: twelve cases with differential diagnosis.

Substantial myxoid change can occur in malignant melanoma, but its importance in primary disease has not been systematically evaluated. This report describes the clinical, microscopic, histochemical, and immunohistochemical findings in 12 patients with primary cutaneous malignant melanoma with myxoid features. The tumors presented as solitary lesions situated on the limbs (six lesions), trunk (four lesions), and head and neck (two lesions). The patients included six women and six men, whose ages ranged from 26 to 95 years, with a mean of 63 years. Breslow thickness varied from 0.48 mm to more than 12 mm, with a mean of more than 3.2 mm. Clinical follow-up for an average of 22 months showed one local recurrence, but no evidence of metastases yet. In all cases, there was a combination of myxoid and nonmyxoid areas. A minimum of 15% myxoid cross-sectional area was required for inclusion in the study, and up to 80% was observed. The pale blue mucin identified on hematoxylin and eosin staining was sensitive to hyaluronidase and positive for alcian blue in the 10 cases stained. Immunohistochemical staining was positive for S-100 in all 9 cases stained, positive for HMB-45 in 9 (90%) of 10, and negative for cytokeratin in all 9 cases in which myxoid melanoma remained in the block after previous sections. The presence of myxoid stroma did not define a biologically significant subgroup of melanoma. Only in cases with extensive (>50%) myxoid stromal effacement of the melanoma was there a major diagnostic hurdle. The diagnosis of primary cutaneous melanoma with myxoid features was seldom as problematic as metastatic myxoid melanoma. Positive S-100 stains, negative cytokeratin immunohistochemical stains, and hyaluronidase-sensitive alcian blue staining assisted in the diagnosis of this entity.

Imipramine-induced hyperpigmentation: four cases and a review of the literature.

BACKGROUND: Hyperpigmentation is a side effect of several medications, including amiodarone, bleomycin, chlorpromazine, and minocycline. OBJECTIVE: The purpose of this study is to describe the clinical and light microscopic findings in 4 patients with imipramine-induced hyperpigmentation and to better understand its origin. METHODS: All 4 patients underwent a skin biopsy for light microscopy. In 1 patient, a biopsy specimen was obtained for electron microscopy. Tissue from patient 1 was analyzed with a mass spectrophotometer, and energy-dispersive x-ray analysis was performed on tissue from patients 1 and 2. RESULTS: All 4 women had been taking imipramine for at least 2 years. Hyperpigmentation occurred in a photodistribution on the face, arms, and backs of the hands. Light microscopy in all cases demonstrated golden-brown granules in the superficial dermis, which were strongly positive for Fontana-Masson stain. Electron microscopy demonstrated areas of electron-dense inclusion bodies within macrophages, which were distinct from melanosomes. Mass spectrophotometric and energy-dispersive x-ray analysis of the electron-dense bodies showed the presence of sulfur atoms, and no peak corresponding to that expected for imipramine was found. A peak closely corresponding to phaeomelanin, a sulfur-containing compound, was found. CONCLUSION: Hyperpigmentation is a side effect of long-term imipramine use. It may result from the deposition of melanin in an unusual form. The melanin pigment is possibly complexed with a metabolite of imipramine, and does not represent the deposition of imipramine in its native form.