A man with diffuse hyperkeratotic papules and plaques

HISTORY: A 47-year-old African American man with no relevant past medical history presented to Dermatology with a rash that began 2-3 years prior with a sudden onset on the arms and knees and has since spread diffusely. He endorses oral involvement. Denies any history of hepatitis C, syphilis, or HIV. No family history of similar condition. EXAMINATION: Diffusely on the body were many hyperkeratotic scaly papules coalescing into plaques with underlying violaceous macules and patches on the arms, legs, buttocks, and hips. Many papules and plaques were in a linear distribution, suggesting possibility of koebnerization. The mouth had hyperkeratotic papules along the oral commissures, cobblestoning of the palate, and reticulated white streaks on the upper and lower mucosal lip and the left buccal mucosa. HISTOPATHOLOGY: Pathology revealed marked verrucous epidermal hyperplasia with overlying parakeratosis and neutrophils in the stratum corneum. A lichenoid infiltrate at dermal-epidermal junction and necrotic keratinocytes were also seen. Negative HPV staining. DIFFERENTIAL DIAGNOSIS: Hypertrophic lichen planus (HLP) vs keratosis lichenoides chronica (KLC) vs less likely extensive verruca. LABORATORY: CBC and CMP within normal limits. Hepatitis C, syphilis, and HIV negative. DIAGNOSIS: The KLC and HLP present similarly histologically with hyperkeratosis and lichenoid infiltrate with interface change. Given clinical similarity, both are high in the differential in this case. KLC was favored due chronicity of individual lesions and due to the confluent parakeratosis and corneal neutrophils seen on pathology which are uncharacteristic of HLP. COURSE AND THERAPY: At time of presentation, he was on a regimen of acitretin 50 mg daily, betamethasone dipropionate ointment to the body, and tacrolimus 0.1% ointment to the face without significant improvement. Patient was continued on topical steroids and acitretin, and was also started on CellCept 500mg BID, later increased to 1000mg BID. DISCUSSION: HLP and KLC can present similarly with erythematous to violaceous hyperkeratotic papules and plaques. These are usually present on the lower extremities but may present more diffusely, including on the trunk and face. KLC is a rarer condition with a chronic course. Lesions can be pruritic and are typically in a reticular or linear pattern as seen in our patient. Oral and nail involvement, as in our patient, have been reported in about 20-30% of patients. KLC also may present with facial eruption similar to seborrheic dermatitis or rosacea. KLC may present at any age and has a slight male predominance. The etiology of this condition is unknown and given its similarity to other keratotic skin diseases as well as its rarity, it has not been well-studied. Although difficult to treat, oral retinoids such as acitretin and phototherapy have had some documented efficacy in treating KLC.HLP is a variant of lichen planus (LP) with a similar presentation of hyperkeratotic papules and plaques and usually a more chronic course. Lesions often are pruritic and koebnerization may play a role, causing more linear formations. Oral involvement, particularly Wickham striae, or nail changes may also be observed. Given longstanding inflammation, hypertrophic LP may develop malignant transformation to squamous cell carcinomas or keratoacanthomas. Treatments for HLP include topical or intralesional corticosteroids, methotrexate, metronidazole, cyclosporine, dapsone, azathioprine, and phototherapy. Acitretin and mycophenolate mofetil (CellCept) have shown efficacy in resistant HLP.https://scholarlycommons.henryford.com/merf2020caserpt/1002/thumbnail.jp

A Pruritic Eruption Following Gastric Bypass Surgery

Introduction: Prurigo pigmentosa is a rare inflammatory dermatosis characterized by pruritic erythematous papules and papulovesicles on the back, neck and chest. The cause is not well elucidated, but it has been associated with ketotic states. We present the second case of prurigo pigmentosa after gastric bypass surgery. Case: A 38 year-old African American female presented for evaluation of a rash on her neck, chest and back that initially began 2 weeks after gastric bypass surgery. It began with pruritus of the palms and small pruritic papules on her lower back. It spread to involve patchy areas of the lower back, chest, lateral neck and behind the ears. New lesions continued to appear every few days and old lesions would resolve with hyperpigmentation. On exam, indurated papules were noted in clusters behind both ears, on her right lateral neck, beneath the breasts, and in a linear band on the midline lower back. A punch biopsy showed superficial and deep lymphocytic inflammation and focal interface dermatitis. Endothelial cells were swollen, there was red cell extravasation and rare eosinophils were noted. She was started on minocycline 100 mg twice daily for two weeks. The eruption resolved and remained quiescent even after discontinuing minocycline, although she had residual hyperpigmentation. Conclusion: Prurigo pigmentosa is a rare inflammatory dermatosis that starts as crops of inflammatory lesions that undergo multiple stages. Lesions involute within a week and leave macular reticulated hyperpigmentation. It occurs more commonly in young adults, especially females. Traditionally, it had been described in the Japanese population, however recently there have been cases reported in the Middle East and Western Countries. The exact cause and pathogenesis is still unclear. However, it has been associated with ketotic states seen in dieting, diabetes mellitus, soft-drink ketosis and religious fasting. Studies have found elevated blood and urine ketones in patients with prurigo pigmentosa and noted clearance of skin lesions when ketosis resolved. There has been one prior report of prurigo pigmentosa following bariatric surgery, and we present the second. The histological features vary depending on the stage of the condition. Prurigo pigmentosa is believed to be mediated by neutrophils and patients respond well to medications that have an anti-neutrophil effect including tetracyclines and dapsone. Recurrence may occur after treatment cessation.https://scholarlycommons.henryford.com/merf2019caserpt/1021/thumbnail.jp

Metastatic squamous cell carcinoma in a RDEB patient treated with pembrolizumab

A case of metastatic squamous cell carcinoma in a patient with recessive dystrophic epidermolysis bullosa that was responsive to pembrolizumab, a programmed cell death protein 1 inhibitor. Purpose: Cutaneous squamous cell carcinomas (SCCs) are the leading cause of death in patients with recessive dystrophic epidermolysis bullosa (RDEB). Management of SCCs in these patients is challenging with higher rates of recurrence and lymph nodes metastases. Although surgery is the first-line treatment in the majority of cases, certain clinical situations, such as local recurrence, or regional or distant metastasis, may call for nonsurgical treatment such as chemotherapy. We report the complex management of SCCs in a young female patient with RDEB whose nodal disease responded successfully to programmed cell death protein 1 (PD-1) inhibitor, pembrolizumab. Design: Patient is a 29-year-old female with a long-standing history of RDEB that has been complicated by multifocal and recurrent SCC of the skin. She initially presented in 2015, at the age of 24, for SCC of the skin that was treated with a combination of Mohs micrographic surgery (MMS), wide local excision, and laser-assisted topical delivery of aminolevulinic acid. Over the following 6 months she developed several additional invasive SCCs. Surgical resection was again attempted, however, pathology revealed positive deep and lateral margins at 2 excision sites. Computed tomography (CT) scan at this time revealed bilateral pulmonary nodules and axillary nodes concerning for early metastatic disease. Left axillary node biopsy performed however, was negative for metastatic disease and these were thought to be consistent with a reactive process. Oncology recommended off-label palliative use of cetuximab given her multifocal disease and higher risk of metastasis in RDEB patients. She completed 4 cycles of cetuximab complicated by sepsis due to group G streptococcus, likely from a cutaneous source, as well as a grade 2 EGFR-associated acneiform eruption. After 4 cycles, her CT remained stable and there was no evidence of cutaneous recurrence, so the decision was made to discontinue cetuximab at this time. However, two years following the cessation of cetuximab she developed multiple cutaneous recurrences and a surveillance CT scan showed enlargement of her left axillary lymph nodes to a mass of 3.7 x 4.0 cm in size. Nodal biopsy revealed metastatic SCC and molecular testing performed showed that 100% of tumor cells (tumor proportion score) were positive for PD-L1 staining. The decision was made to start pembrolizumab as off label therapy with plans to pursue axillary node excision after she completed treatment. At the completion of 4 cycles of pembrolizumab, a repeat CT scan showed improvement in the enlarged nodes with reduction to 2.2 x 1.4 cm in size and regional lymph node resection was successfully performed. Summary: Pembrolizumab was the first PD-1 inhibitor approved by the FDA for metastatic melanoma. Recently in clinical trials, a new PD-1 inhibitor cemiplimab showed a 50% response rate in the treatment of cutaneous SCC and became the first systemic drug in it’s class to be approved for the treatment of locally advanced or metastatic cutaneous SCC. We report the first case of metastatic SCC in a RDEB patient that responded to treatment with PD-1 inhibitor, pembrolizumab. Conclusion: Immunotherapy with PD-1 inhibitors, such as pembrolizumab may be an alternative treatment modality for SCC in RDEB patients with late stage or metastatic disease. Further larger scale studies are warranted to determine the utility of PD-1 inhibitors in the multimodal management of these high-risk patients.https://scholarlycommons.henryford.com/merf2020caserpt/1006/thumbnail.jp

A Case of Metastatic Squamous Cell Carcinoma in a Patient with Recessive Dystrophic Epidermolysis Bullosa that was Responsive to Pembrolizumab, a Programmed Cell Death Protein 1 Inhibitor

A case of metastatic squamous cell carcinoma in a patient with recessive dystrophic epidermolysis bullosa that was responsive to pembrolizumab, a programmed cell death protein 1 inhibitor. Purpose: Cutaneous squamous cell carcinomas (SCCs) are the leading cause of death in patients with recessive dystrophic epidermolysis bullosa (RDEB). Management of SCCs in these patients is challenging with higher rates of recurrence and lymph nodes metastases. Although surgery is the first-line treatment in the majority of cases, certain clinical situations, such as local recurrence, or regional or distant metastasis, may call for nonsurgical treatment such as chemotherapy. We report the complex management of SCCs in a young female patient with RDEB whose nodal disease responded successfully to programmed cell death protein 1 (PD-1) inhibitor, pembrolizumab. Design: Patient is a 29-year-old female with a long-standing history of RDEB that has been complicated by multifocal and recurrent SCC of the skin. She initially presented in 2015, at the age of 24, for SCC of the skin that was treated with a combination of Mohs micrographic surgery (MMS), wide local excision, and laser-assisted topical delivery of aminolevulinic acid. Over the following 6 months she developed several additional invasive SCCs. Surgical resection was again attempted, however, pathology revealed positive deep and lateral margins at 2 excision sites. Computed tomography (CT) scan at this time revealed bilateral pulmonary nodules and axillary nodes concerning for early metastatic disease. Left axillary node biopsy performed however, was negative for metastatic disease and these were thought to be consistent with a reactive process. Oncology recommended off-label palliative use of cetuximab given her multifocal disease and higher risk of metastasis in RDEB patients. She completed 4 cycles of cetuximab complicated by sepsis due to group G streptococcus, likely from a cutaneous source, as well as a grade 2 EGFR-associated acneiform eruption. After 4 cycles, her CT remained stable and there was no evidence of cutaneous recurrence, so the decision was made to discontinue cetuximab at this time. However, two years following the cessation of cetuximab she developed multiple cutaneous recurrences and a surveillance CT scan showed enlargement of her left axillary lymph nodes to a mass of 3.7 x 4.0 cm in size. Nodal biospy revealed metastatic SCC and molecular testing performed showed that 100% of tumor cells (tumor proportion score) were positive for PD-L1 staining. The decision was made to start pembrolizumab as off label therapy with plans to pursue axillary node excision after she completed treatment. At the completion of 4 cycles of pembrolizumab, a repeat CT scan showed improvement in the enlarged nodes with reduction to 2.2 x 1.4 cm in size and regional lymph node resection was successfully performed. Summary: Pembrolizumab was the first PD-1 inhibitor approved by the FDA for metastatic melanoma. Recently in clinical trials, a new PD-1 inhibitor cemiplimab showed a 50% response rate in the treatment of cutaneous SCC and became the first systemic drug in it’s class to be approved for the treatment of locally advanced or metastatic cutaneous SCC. We report the first case of metastatic SCC in a RDEB patient that responded to treatment with PD-1 inhibitor, pembrolizumab. Conclusion: Immunotherapy with PD-1 inhibitors, such as pembrolizumab may be an alternative treatment modality for SCC in RDEB patients with late stage or metastatic disease. Further larger scale studies are warranted to determine the utility of PD-1 inhibitors in the multimodal management of these high-risk patients.https://scholarlycommons.henryford.com/merf2020caserpt/1131/thumbnail.jp

Superoxide Production by a Manganese-Oxidizing Bacterium Facilitates Iodide Oxidation

The release of radioactive iodine (i.e., iodine-129 and iodine-131) from nuclear reprocessing facilities is a potential threat to human health. The fate and transport of iodine are determined primarily by its redox status, but processes that affect iodine oxidation states in the environment are poorly characterized. Given the difficulty in removing electrons from iodide (I(−)), naturally occurring iodide oxidation processes require strong oxidants, such as Mn oxides or microbial enzymes. In this study, we examine iodide oxidation by a marine bacterium, Roseobacter sp. AzwK-3b, which promotes Mn(II) oxidation by catalyzing the production of extracellular superoxide (O(2)(−)). In the absence of Mn(2+), Roseobacter sp. AzwK-3b cultures oxidized ∼90% of the provided iodide (10 μM) within 6 days, whereas in the presence of Mn(II), iodide oxidation occurred only after Mn(IV) formation ceased. Iodide oxidation was not observed during incubations in spent medium or with whole cells under anaerobic conditions or following heat treatment (boiling). Furthermore, iodide oxidation was significantly inhibited in the presence of superoxide dismutase and diphenylene iodonium (a general inhibitor of NADH oxidoreductases). In contrast, the addition of exogenous NADH enhanced iodide oxidation. Taken together, the results indicate that iodide oxidation was mediated primarily by extracellular superoxide generated by Roseobacter sp. AzwK-3b and not by the Mn oxides formed by this organism. Considering that extracellular superoxide formation is a widespread phenomenon among marine and terrestrial bacteria, this could represent an important pathway for iodide oxidation in some environments

Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.

BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead