Faculty Bibliography

BACKGROUND:For primary triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), higher pretreatment tumor-infiltrating lymphocytes (TILs) correlates with increased pathologic complete response (pCR) rates, and improved survival. We evaluated the added prognostic value of residual disease (RD) TILs to residual cancer burden (RCB) in predicting survival post-NAC. PATIENTS AND METHODS:We combined four TNBC NAC patient cohorts who did not achieve pCR. RD TILs were investigated for associations with recurrence-free survival (RFS), and overall survival (OS) using Cox models with stromal TILs as a continuous variable (per 10% increment). The likelihood ratio test was used to evaluate added prognostic value of RD TILs. RESULTS:A total of 375 RD TNBC samples were evaluable for TILs and RCB. The median age was 50 years, with 62% receiving anthracycline/taxane chemotherapy. The RCB class after NAC was 11%, 50%, and 39% for I, II, and III, respectively. The median RD TIL level was 20% (IQR 10-40). There was a positive correlation between RD TIL levels and CD8+ T-cell density (ρ = 0.41). TIL levels were significantly lower with increasing post-NAC tumor (P = 0.005), nodal stage (P = 0.032), but did not differ by RCB class (P = 0.84). Higher RD TILs were significantly associated with improved RFS (HR: 0.86; 95% CI 0.79-0.92; P < 0.001), and improved OS (HR: 0.87; 95% CI 0.80-0.94; P < 0.001), and remained significant predictors in multivariate analysis (RFS P = 0.032; OS P = 0.038 for OS). RD TILs added significant prognostic value to multivariate models including RCB class (P < 0.001 for RFS; P = 0.021 for OS). The positive prognostic effect of RD TILs significantly differed by RCB class for RFS (PInt=0.003) and OS (PInt=0.008) with a greater magnitude of positive effect observed for RCB class II than class III. CONCLUSIONS:TIL levels in TNBC RD are significantly associated with improved RFS and OS and add further prognostic information to RCB class, particularly in RCB class II.

BACKGROUND:Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)-uninfected adults for safety, immunogenicity, and 6-month durability of immune responses. METHODS:A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections. RESULTS:At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4(+) T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8(+) T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4(+) and CD8(+) T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold. CONCLUSIONS:DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses.

BACKGROUND: Women with HIV and prior exposure to combination antiretroviral therapy (cART) solely for prevention of mother-to-child transmission (pMTCT) need to know whether they can later be treated successfully with a commonly used regimen of efavirenz (EFV) and coformulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). METHODS: Nonpregnant women with plasma HIV-1 RNA of >/=500 copies per milliliter, previously cART exposed for pMTCT only, were eligible if they were off ART for >/=24 weeks before entry, were without evidence of drug resistance on standard genotyping, and were ready to start EFV plus FTC/TDF. The primary endpoint was virologic response (defined as plasma HIV RNA <400 copies/mL) at 24 weeks. RESULTS: Fifty-four women were enrolled between October 2007 and December 2009; 52 of 54 completed 24 weeks of follow-up. Median baseline CD4 T-cell count was 265/mm and baseline plasma HIV-1 RNA was 4.6 log10 copies per milliliter. Median prior cART duration was 14 weeks, and median time elapsed from the last pMTCT dose to entry was 22 months. Virologic response at 24 weeks was observed in 42 of 52 women or 81% (exact 95% confidence interval: 68% to 90%). There were no differences in response by country, by number, or class of prior pMTCT exposures. Although confirmed virologic failure occurred in 8 women, no virologic failures were observed in women reporting perfect early adherence. CONCLUSIONS: In this first prospective clinical trial studying combination antiretroviral retreatment in women with a history of pregnancy-limited cART, the observed virologic response to TDF/FTC and EFV at 24 weeks was 81%. Virologic failures occurred and correlated with self-reported nonadherence.

BACKGROUND: Melanocytic nevi are well-known, important precursors of melanoma among children and adults. The adolescence period is an important period for nevi formation and evolution. This study provides data of a longitudinal study of nevi in a Hispanic adolescent population. MATERIALS AND METHODS: A cross-sectional survey and 1-year prospective follow-up study was performed on Hispanic students from grades 6 and 7 at a school in Caguas, Puerto Rico (n = 90). The survey was completed by the students and one of their parents. The backs of the children were clinically examined for melanocytic nevi using digital photography and dermoscopy. Follow-up was conducted one year later. RESULTS: The study cohort consisted of 53 (59%) boys and 37 (41%) girls, with an average age of 11.9 years (range 11-13 years). At the beginning of the study, 85% (n = 71/90) of the students presented with melanocytic nevi on their backs. After one year, new nevi were identified in 62% (n = 44/71), and there was a mean increase in nevus count of 1.8 (P < 0.001). A trend toward increased nevus count in lighter skin types was observed (P < 0.001). The predominant dermoscopic pattern was reticular (44%). The globular pattern was found most commonly in children with skin-type II (100%), while the reticular pattern was the most common among skin-types III (32%), IV (56%), and V (45%). CONCLUSIONS: This study supports the utility of digital photography and dermoscopy for the evaluation of melanocytic nevi, providing evidence of the interrelationship between nevus count, dermoscopic pattern, and skin phenotype.

It has been proposed by many authors that follicular mucinosis is directly associated with mycosis fungoides (MF). Follicular mucinosis may be classified into 3 main clinical variants: a benign idiopathic form in children and young adults, which includes an acneiform presentation; an idiopathic form in older patients with a benign course; and a third variant that occurs in adults and is associated with MF. Our goal was to study the relationship between the acneiform variant of follicular mucinosis and MF. Eight patients previously diagnosed with the acneiform variant of follicular mucinosis were identified. Biopsy specimens were reviewed to evaluate the histopathologic attributes that characterize the disease and the infiltrate's immunohistochemistry. Also, patient follow-up was assessed to evaluate the clinical course of the disease. Median age of onset of disease was 29.5 years; 95% of lesions were located in the head and neck region. Biopsy specimens showed a moderate to dense perivascular, perifollicular, and interstitial infiltrate of lymphocytes with mucinous deposits within the follicular epithelium. On immunohistochemistry, the infiltrate showed prominent leukocyte common antigen (LCA) positivity and a CD3-positive and CD4-positive infiltrate with rare CD20-positive cells. None of the study patients showed evidence of MF after a mean follow-up of 3 years. The benign course of disease demonstrated in the study patients suggests that the acneiform variant of follicular mucinosis probably represents a subpopulation of the benign idiopathic form of the disease. However, given that histopathologically this variant cannot be distinguished from the lymphoma-associated variant of follicular mucinosis, longitudinal evaluation is still warranted in these patients.

Primary cutaneous neoplasms of histiocytes and dendritic cells are rare. Langerhans cells are a subset of antigen-presenting dendritic cells. Neoplasms of Langerhans cells are classified into cytologically benign Langerhans cell histiocytosis and cytologically malignant Langerhans cell sarcoma. Langerhans cell sarcoma is a rare entity characterized by multiorgan involvement and an aggressive clinical course. To date, only 30 cases of Langerhans cell sarcoma, including the present case, have been reported. We report a new case of Langerhans cell sarcoma that presented with multifocal cutaneous involvement. Diagnosis was done based on histopathological, immunohistochemical evaluation, as well as ultrastructural analysis identifying the presence of Birbeck granules. Our case represents a new case of this extremely rare, overtly aggressive neoplasm of Langerhans cells. Within 2 years of diagnosis, the patient developed metastatic disease and consequently died. Early recognition is important because of the tendency of Langerhans cell sarcoma to recur and metastasize. Therefore, ancillary techniques such as immunohistochemical and ultrastructural studies to confirm the diagnosis are very advantageous.

BACKGROUND: There are few published guidelines that describe the forethought and logistical considerations needed to create a dermatology-specific medical mission. OBJECTIVE: To report the experience of planning and executing a successful medical mission to an underserved community in Puerto Rico. METHODS: We identified an area of need and projected the volume of patients and diseases to be treated. After recruiting medical staff, pharmaceutical and surgical supplies were collected. Important concerns included establishing the scope of medical and educational services to be rendered, advertising the clinic, arranging for biopsy processing, ensuring follow-up, and selecting a method for medical documentation. We tracked the number of patients seen, diagnoses made, and materials used to prepare for future missions. RESULTS: We recruited 12 physicians and 25 ancillary (i.e. nonlicensed physician) staff members, including: six dermatologists, four internists, one pathologist, one psychiatrist, 23 medical students, and two medical assistants. We secured 12 examination rooms in an existing medical facility. Two pharmaceutical companies and two pathology companies provided the medications and surgical supplies with the remainder coming from the volunteer physicians' offices. Three thousand dollars were raised and used toward purchasing additional supplies. Advertising via public announcements resulted in the attendance of 166 patients during the 1-day clinic. A total of 41 procedures were performed, including 14 biopsies, five excisions, three incisions and drainage, and 19 electrodessications and curettage. CONCLUSION: Proper planning is critical in creating a successful dermatology mission. Documenting the care given and supplies used helps to identify needs and optimize limited resources for future missions. The goal of a self-sustaining public health service starts with patient education and coordination with the local healthcare providers.

BACKGROUND: Fox-Fordyce disease is a rare chronic papular condition with a very characteristic clinical presentation but a nonspecific histopathology. Its traditionally described histopathologic features have been criticized as variable and indistinct. Recently, a perifollicular infiltrate of histiocytes with foamy cytoplasm has been described as a consistent and reliable diagnostic finding. METHODS: To evaluate the traditional and most recently described histopathologic and immunohistochemical attributes of Fox-Fordyce disease, we performed a computerized search of specimens in two dermatopathologic databases in Puerto Rico from the years 2000-2010. An additional specimen was donated by a dermatopathologist from an outside institution. Three cases were evaluated using hematoxylin-eosin-stained sections. The tip of an axillary lipoma excision specimen was used as the control tissue. Periodic acid-Schiff, colloidal iron, and immunoperoxidase staining for CD68 and c-kit (CD117) were performed in all specimens. RESULTS: We were able to verify traditionally described histological features such as infundibulum dilation, hyperkeratosis, plugging, acanthosis, and lymphohistiocytic infiltrate. Infundibular spongiosis was also common. A perifollicular foam cell infiltrate was the most distinct pathologic feature among our cases. The periodic acid-Schiff staining patterns suggested that the foam cell cytoplasm material might be similar in nature to the apocrine gland secretion content. CONCLUSIONS: Our results confirmed that a perifollicular foam cell infiltrate is the most distinct histopathologic feature. In addition, findings suggest that the intracytoplasmic foam cell material may be similar in nature to the apocrine gland secretion.

An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = -0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF(114-121)) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ~35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies.