Advanced basal cell carcinoma: What dermatologists need to know about diagnosis.

Basal cell carcinoma (BCC) is the most common human cancer, with approximately 3.6 million cases diagnosed each year. About 2000 deaths annually in the United States are attributed to basal and squamous cell skin cancers. There is a direct link between ultraviolet exposure and the development of BCC, as UV exposure damages DNA and induces mutations in tumor suppressor genes. Aberrations in the hedgehog pathway can also result in BCC, highlighted by the fact that most cases of sporadic BCCs have been found to have mutations in different genes involved in the hedgehog pathway. There are several genetic syndromes that are associated with BCCs, including basal cell nevus syndrome, xeroderma pigmentosum, Bazex-Dupré-Christol syndrome, Rombo syndrome, and Oley syndrome. Other risk factors include age, male gender, occupational hazards, radiation, and immunosuppression. BCCs are not typically staged but are instead stratified by their risk of recurring or metastasizing. Locally advanced BCCs are those tumors that are not amenable to surgery or radiation therapy.

Advanced basal cell carcinoma: What dermatologists need to know about treatment.

The treatment of advanced basal cell carcinoma (BCC) often requires therapies beyond local surgical excision or radiation due to the invasiveness of the tumor. Historically, cytotoxic chemotherapy was used to treat advanced BCC, but with limited data, no standard regimens were established. The discovery of cyclopamine, a natural inhibitor in the Hedgehog pathway, led to the development of the 2 currently approved Hedgehog inhibitors, vismodegib and sonidegib. Both agents are indicated for locally advanced BCC, while vismodegib is also indicated for metastatic BCC. In patients who progress on hedgehog inhibitors or cannot tolerate hedgehog inhibitors, the programmed cell death protein 1 inhibitor cemiplimab can be used to treat locally advanced or metastatic disease. Complex cases of locally advanced or metastatic BCC may be best discussed through a multidisciplinary approach in order to determine the optimal treatment approach for the individual patient.

The impact of corticosteroid use during anti-PD1 treatment.

BACKGROUND: The advent of anti-PD1 therapy for cancer treatment has led to improvements in response rates and overall survival. However, anti-PD1 therapy has the potential to cause immune-related adverse events (irAEs), which can be treated with corticosteroids if severe. The clinical implications of concomitant immunotherapy and systemic steroids remain unclear, as short courses of steroids do not significantly suppress T-cell function. The primary objective of this study is to determine if the use of concomitant steroids impacts the efficacy of anti-PD1 therapy. METHODS: This retrospective, single-center study reviewed adult patients who received at least four cycles of nivolumab or pembrolizumab for the treatment of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma from November 2014 to February 2016. Patients who received steroids (prednisone equivalent >10 mg) during anti-PD1 therapy were divided into two main cohorts based on the duration of steroid administration of ≤2 weeks or >2 weeks. Time to disease progression, overall response, and overall survival were assessed. RESULTS: Twenty-seven of 55 patients (13 melanoma, 11 NSCLC, 3 renal cell carcinoma) required steroids during anti-PD1 therapy. In patients who received steroids, median time to disease progression was 5.6 months for melanoma, 5.8 for NSCLC, and 2.0 for renal cell carcinoma. The overall response rate (ORR) was 3/13 (23%) for melanoma, 6/11 (54%) for NSCLC, and 1/3 (33%) for renal cell carcinoma. Median overall survival was 11.9 months for melanoma, 9.9 for NSCLC, and not reached for renal cell carcinoma. Thirteen patients who had received steroids expired; 11 of these patients had received prednisone >10 mg/day for >2 weeks. CONCLUSION: High-dose steroids for long durations during anti-PD1 therapy may be associated with poorer survival outcomes.

Outcomes of combination therapy with tyrosine kinase inhibitors and immune checkpoint inhibitors in metastatic renal cell carcinoma - A retrospective study.

INTRODUCTION: Renal cell carcinoma (RCC) is a highly vascularized and immunogenic tumor. At the time of this study, there was limited published data on the combination of tyrosine kinase inhibitors and immune checkpoint inhibitors in patients who were heavily pretreated. At our institution, providers have used these combinations in heavily pretreated patients. METHODS: We conducted a retrospective review of patients receiving this combination with the primary objectives of assessing duration of therapy and toxicities and a secondary objective of disease progression at six months. We included adult patients with confirmed mRCC receiving combination therapy (immune checkpoint inhibitors/tyrosine kinase inhibitors) any time after January 2015. Electronic medical records were reviewed for pertinent data and follow-up descriptive statistics were performed. RESULTS: Fifteen patients were on combination immune checkpoint inhibitors/tyrosine kinase inhibitors, with a median of three lines of previous therapy. The median duration of combination therapy was 7.2 months (range: 0.2 to 39.8) with 126 incidences of toxicities. The most frequent toxicity was fatigue (n = 15), followed by diarrhea (n = 8), anorexia (n = 7) and palmar-plantar erythrodysesthesia (n = 7). Overall, 9 (60%) patients experienced at least one grade 3 or 4 toxicity. Eight of 15 (53%) patients remained on therapy at the six-month mark and did not have progression confirmed by an oncologist. Of the 15 patients, 10 discontinued therapy due to progression, 2 due to intolerable side effects, 2 transitioned to end of life care, and 1 patient was still ongoing at the time of data collection. CONCLUSION: Based on this review, it appears that combination tyrosine kinase inhibitors/immune checkpoint inhibitors therapy in pre-treated patients with mRCC is tolerable and beneficial.

A targeted proteomics toolkit for high-throughput absolute quantification of Escherichia coli proteins.

Transformation of engineered Escherichia coli into a robust microbial factory is contingent on precise control of metabolism. Yet, the throughput of omics technologies used to characterize cell components has lagged far behind our ability to engineer novel strains. To expand the utility of quantitative proteomics for metabolic engineering, we validated and optimized targeted proteomics methods for over 400 proteins from more than 20 major pathways in E. coli metabolism. Complementing these methods, we constructed a series of synthetic genes to produce concatenated peptides (QconCAT) for absolute quantification of the proteins and made them available through the Addgene plasmid repository (www.addgene.org). To facilitate high sample throughput, we developed a fast, analytical-flow chromatography method using a 5.5-min gradient (10 min total run time). Overall this toolkit provides an invaluable resource for metabolic engineering by increasing sample throughput, minimizing development time and providing peptide standards for absolute quantification of E. coli proteins.

The effects of green tea polyphenols on drug metabolism.

INTRODUCTION: Tea, made from the dried leaves of the plant Camellia sinensis Theaceae, is a very popular beverage consumed worldwide. Recently, green tea extract-based dietary supplements have also been widely consumed for the acclaimed beneficial health effects, such as weight reduction. Although tea consumption is considered to be innocuous, the potential interactions between tea polyphenols and drugs have been demonstrated in studies in vitro and in vivo. AREAS COVERED: This article reviews the current literature on the chemistry and biotransformation of tea constituents, mainly catechins from green tea. The article also provides a review of their effects on the absorption, efflux, metabolism and elimination of different drugs. EXPERT OPINION: Tea catechins may bind to certain drugs to affect their absorption and bioactivities. Tea catechins may inhibit the activities of drug-metabolizing enzymes and drug transporters or affect the expression of these proteins, either upregulation or downregulation. Although these effects have been demonstrated in studies in vitro and in animal models, such effects have only been observed in limited cases in humans at common doses of human tea consumption. The ingestion of tea catechins from dietary supplements, which could be in large bullet doses, may produce more profound effects on drug metabolism, and such effects with drugs need to be further investigated.

Coexistencia anatómica estricta de vitíligo y psoriasis / Strict anatomical coexistence of vitiligo and psoriasis

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