Primary malignant melanoma of the genitourinary tract: case series of a rare form of primary mucosal melanoma.

Primary malignant melanoma of the genitourinary tract is extremely rare. We present two such cases in elderly Caucasian females. An 81-year-old female with urinary retention and polypoid urinary bladder mass and a 72-year-old female with gross hematuria and urethral caruncle. After thorough evaluation, they were both eventually diagnosed with primary urogenital melanoma (SOX10 and MART1-positive in tumor cells). In both cases, the presence of melanoma-in-situ and absence of primary melanoma in other sites were consistent with primary urogenital melanoma. Immunotherapy with PD-1 inhibitors and use of neoadjuvant and adjuvant treatment are promising, as treatment guidelines remain unclear and overall survival is low. Additional clinical reporting of primary urogenital melanomas can help in better understanding and ultimately treating it.

Primary melanomas of the bladder and urinary tract are rare and usually deadly. They represent only 0.2% of all melanomas, including melanomas of skin. They can be difficult to diagnose and treat due to how rare they are and the lack of clear treatment guidelines. We present two cases of elderly Caucasian women who were unexpectedly diagnosed with primary melanoma cancers of the bladder and urinary tract after having surgery and analyzing tissue that was removed. Both tissue samples had features specific to melanoma and there was no cancer in any other organ, thus making them primary melanomas of the bladder and urinary tract. Current treatment approaches with surgery and chemotherapy have not improved the survival outcomes and prognosis associated with this disease, but treatment before and after surgery as well as cancer treatments that harness the person's own immune system are promising. By reporting additional clinical experiences of this often fatal disease, we hope it can be better understood and appropriately managed in the future.

A Curious Case of Gastrointestinal Eosinophilia Induced by Treatment With Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors have revolutionized oncologic treatment. However, they are linked to various side effects,1 a rare one being gastrointestinal eosinophilia. We present a patient with malignant melanoma treated with nivolumab. She underwent upper endoscopy 6 months later which showed a duodenal ulcer and linear furrows of her esophagus. Biopsies of the esophagus, stomach, and duodenum were consistent with eosinophilic infiltration. Repeat endoscopy after nivolumab discontinuation revealed near-complete resolution of eosinophilia in the stomach and duodenum, with lingering eosinophilia in the esophagus. The purpose of this report was to increase awareness of gastrointestinal eosinophilia associated with checkpoint inhibitors.

Factors associated with immune checkpoint inhibitor use among older adults with late-stage melanoma: A population-based study.

ABSTRACT: Improvement in overall survival by immune checkpoint inhibitors (ICI) treatment in clinical trials encourages their use for late-stage melanoma. However, in the real-world, heterogeneity of population, such as older patients with multimorbidity, may lead to a slower diffusion of ICIs. The objective of this study was to examine the association of multimorbidity and other factors to ICI use among older patients with late-stage melanoma using real world data.A retrospective cohort study design with a 12-month baseline and follow-up period was adopted with data from the linked Surveillance, Epidemiology, and End Results cancer registry/Medicare database. Older patients (>65 years) with late-stage (stage III/IV) melanoma diagnosed between 2012 and 2015 were categorized as with or without multimorbidity (presence of 2 or more chronic conditions) and ICI use was identified in the post-index period. Chi-square tests and logistic regression were used to evaluate factors associated with ICI use.In the study cohort, 85% had multimorbidity, 18% received any treatment (chemotherapy, radiation, and/or ICI), and 6% received ICI. Only 5.5% of older patients with multimorbidity and 6% without multimorbidity received ICIs. Younger age, presence of social support, lower economic status, residence in northeastern regions, and recent year of diagnosis were significantly associated with ICI use; however, multimorbidity, sex, and race were not associated with ICI use.In the real-world clinical practice, only 1 in 18 older adults with late stage melanoma received ICI, suggesting slow pace of diffusion of innovation. However, multimorbidity was not a barrier to ICI use.

Prevalence and risk factors for multimorbidity in older US patients with late-stage melanoma.

INTRODUCTION: Presence of multimorbidity can affect prognosis, treatment, and outcomes of individuals with cancer. However, the prevalence and factors associated with multimorbidity among older late-stage melanoma is not well studied. We estimated the prevalence of any type of pre-existing multimorbidity (autoimmune disorder (AD), physical health conditions (PHC), and mental health conditions (MHC)) among older adults with late-stage melanoma in the United States. We further examined the association of patient-level factors to multimorbidity in late-stage melanoma. METHODS: We derived data on older fee-for-service Medicare beneficiaries (age ≥ 66 years) diagnosed with late-stage melanoma between 2011 and 2015 (N = 4,519) from the linked Surveillance, Epidemiology, and End Results cancer registry and Medicare claims. We defined multimorbidity as the prevalence of two or more chronic conditions prior to the diagnosis of melanoma. We used unadjusted and adjusted logistic regressions to examine the association of patient-level factors to multimorbidity. RESULTS: An overwhelming majority (85%) of older patients with late-stage melanoma had multimorbidity. Pre-existing PHC multimorbidity (84%) was the most prevalent, followed by AD (12%), and MHC (6%). Age and region were associated with any and PHC multimorbidity. Sex, marital status, and region were factors associated with pre-existing AD while sex, marital status, and dual eligibility were associated with MHC multimorbidity. CONCLUSIONS: Pre-existing multimorbidity was highly prevalent among older individuals with late-stage melanoma; prevalence rates and factors associated with multimorbidity varied by type of chronic conditions. This highlights the need for developing systematic approaches to optimizing care of older patients with late-stage melanoma and multimorbidity.

Immune checkpoint inhibitor use, multimorbidity and healthcare expenditures among older adults with late-stage melanoma.

Background: The objective of this study is to assess the impact of immune checkpoint inhibitors (ICIs) and multimorbidity on healthcare expenditures among older patients with late-stage melanoma. Materials & methods: A retrospective longitudinal cohort study using Surveillance, Epidemiology and End Results linked with Medicare claims was conducted. Generalized linear mixed models were used to analyze adjusted relationships of ICI, multimorbidity and ICI-multimorbidity interaction on average healthcare expenditures. Results: Patients who received ICI and those who had multimorbidity had significantly higher average total healthcare expenditures compared with ICI nonusers and no multimorbidity. In the fully adjusted model using ICI-multimorbidity interaction, no excess cost was added by multimorbidity. Conclusion: Use of ICIs, regardless of multimorbidity, is associated with increased healthcare expenditures.

Review of Palliative 223Ra in Metastatic Castration-Resistant Prostate Cancer: Experience at West Virginia University Cancer Center.

The ALSYMPCA trial of the α-emitter 223Ra in symptomatic bone-predominant metastatic castration-resistant prostate cancer (mCRPC) reported a median overall survival (OS) of 14.9 mo, versus 11.3 mo for placebo. However, subsequently reported real-world experience with 223Ra in smaller mCRPC patient cohorts has appeared less successful. We performed a retrospective observational study to review our own 223Ra experience at West Virginia University (WVU). Methods: Demographic, clinical, laboratory, and imaging data were reviewed in all bone-predominant mCRPC patients treated with 223Ra at WVU from 2014 to 2019. The number of bone metastases per patient at the start of treatment with 223Ra was quantified via nuclear bone scans (12 scans, 5 of which also included SPECT/CT), body CT scans (8 scans), and PET/CT scans (4 scans). Standard descriptive statistics were used to study institutional review board-exempted, deidentified patient data. Median survival in ALSYMPCA and WVU patients was compared using a 2-sided, 1-sample log-rank test based on the exponential distributions. The primary endpoint was patient OS after initiating 223Ra. Results: Twenty-four patients received 98 infusions of 223Ra; 83% of these patients were referred from outside WVU. Before the first infusion, all 24 had received androgen deprivation therapy. In total, 73 sequential combinations of androgen deprivation therapy were used, 68 of which (93%) preceded the first 223Ra infusion. Also, before 223Ra, 19 (79%) patients had received docetaxel and 19 (79%) had received 33 courses of radiation, 24 of which targeted nonprostatic sites. Eleven patients (46%) completed all 6 planned 223Ra infusions; 13 (54%) stopped early because of clinical deterioration. As of August 2020, only 1 patient remained alive after completing 6 cycles of 223Ra. Median OS from the first 223Ra infusion to the last follow-up or death was 8.3 mo (range, 0-44 mo)-nearly 50% less than the ALSYMPCA median survival of 14.9 mo (P = 0.01). Compared with ALSYMPCA, more WVU patients received bisphosphonates and docetaxel, more had an Eastern Cooperative Oncology Group performance status of at least 2, more used opiates for pain, more had a greater bone metastasis burden by imaging, and more had lower hemoglobin, albumin, alkaline phosphatase, and prostate-specific antigen levels. Conclusion: Although the science supporting the development and clinical use of 223Ra is compelling, optimal clinical benefit will likely require earlier referral for 223Ra, before patients have exhausted most conventional therapies. At WVU, we found that practically all our referred patients had androgen deprivation therapy, radiation, and cytotoxic therapy before starting 223Ra. We continue to offer 223Ra therapy to patients with symptomatic bone-predominant mCRPC but are encouraging earlier patient referral.

Smoking is associated with adrenal adenomas and adrenocortical carcinomas: a nationwide multicenter analysis.

MICROABSTRACT: The effect of smoking on adrenal cancer is poorly understood. A clear association of adrenal adenoma and adrenocortical carcinoma with smoking among the United States population is observed. This association points to the possibility of environmental carcinogenic and/or lifestyle factors contributing to adrenal cancer formation. Our results support the association of tobacco use with adrenal adenomas and adrenal cortical carcinoma. BACKGROUND: Smoking has been suggested as a risk factor for adrenal cortical carcinoma (ACC), but this hypothesis has only been inferred from a single study using all types of adrenal cancers including pheochromocytoma, neuroblastoma, as well as ACC. Given the high rate of tobacco use in West Virginia, we hypothesized that smoking might contribute to increased prevalence of ACC. MATERIALS AND METHODS: De-identified institutional review board-exempted records were analyzed in the Surveillance, Epidemiology, and End Results (SEER) Program from 2001-2016 and in patients from the United States nationwide, multicenter TriNetX database of 41,063,707 patients from 2008-2018. In addition, the state-level ratio of smoking to ACC prevalence was computed in all 50 states using data from SEER and the Center for Disease Control. West Virginia Health System data from 2008-2018 was extracted to confirm population-level findings. Melanoma was used as a cancer control in both databases. RESULTS: 6,946 ACC cases were identified. West Virginia had the highest smoking rate and the second highest rate of ACC. A significant association was found between smoking and ACC (Pearson correlation coefficient r = 0.4887, p=.0004). From 2008 to 2018 using TriNetX, 846 ACC and 36,434 AA were extracted. Both adrenal neoplasm cohorts had increased prevalence of tobacco use compared with melanoma controls, where 23.5% were smokers compared to 36.4% and 33.9% in the ACC and AA groups, respectively (p<0.0001 each). CONCLUSION: To our knowledge, this is the first United States population-based study supporting smoking as a risk factor for adrenal carcinogenesis and ACC.

Hereditary Trichilemmal Cysts are Caused by Two Hits to the Same Copy of the Phospholipase C Delta 1 Gene (PLCD1).

The autosomal dominant presentation of trichilemmal cysts is one of the most common single gene familial diseases in humans. However, the genetic basis for the inheritance and genesis of these lesions has remained unknown. We first studied patients with multiple trichilemmal cysts using exome and Sanger sequencing. Remarkably, 21 of 21 trichilemmal cysts from 16 subjects all harbored a somatic p.S745L (c.2234 G > A) mutation in phospholipase C delta 1 (PLCD1), a proposed tumor suppressor gene. In addition to this specific somatic mutation in their tumors, 16 of the 17 subjects with multiple trichilemmal cysts were also heterozygous for a p.S460L (c.1379 G > A) germline variant in PLCD1 which is normally present in only about 6% of this population. The one patient of 17 that did not show the p.S460L germline variant had a germline p.E455K (c.1363 C > T) mutation in the same exon of PLCD1. Among 15 additional subjects, with a history suggesting a single sporadic trichilemmal cyst, six were likely familial due to the presence of the p.S460L germline variant. Of the remaining truly sporadic trichilemmal cysts that could be sequenced, only half showed the p.S745L somatic mutation in contrast to 100% of the familial cysts. Surprisingly, in contrast to Knudsen's two hit hypothesis, the p.S745L somatic mutation was always on the same chromosome as the p.S460L germline variant. Our results indicate that familial trichilemmal cysts is an autosomal dominant tumor syndrome resulting from two hits to the same allele of PLCD1 tumor suppressor gene. The c.1379 G > A base change and neighboring bases are consistent with a mutation caused by ultraviolet radiation. Our findings also indicate that approximately one-third of apparently sporadic trichilemmal cysts are actually familial with incomplete penetrance. Sequencing data suggests that the remaining, apparently sporadic, trichilemmal cysts are genetically distinct from familial cysts due to a lack of the germline mutations that underlie familial cysts and a decreased prevalence of the p.S745L somatic mutation relative to familial trichilemmal cysts.

Combined treatment of disfiguring facial angiofibromas in tuberous sclerosis complex with surgical debulking and topical sirolimus.

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder that causes the formation of hamartomatous tumors such as facial angiofibromas (FAs). We present a combination of surgical debulking via shave biopsy, curettage, and electrocautery followed by application of sirolimus ointment 1% to the nose to treat FAs in the setting of TSC. This novel approach achieved an optimal therapeutic response in our patient with minimal recurrence of FAs after 1 year of follow-up.

New mechanistic explanation for the localization of ulcers in the rat duodenum: role of iron and selective uptake of cysteamine.

Cysteamine, a coenzyme A metabolite, induces duodenal ulcers in rodents. Our recent studies showed that ulcer formation was aggravated by iron overload and diminished in iron deficiency. We hypothesized that cysteamine is selectively taken up in the duodenal mucosa, where iron absorption primarily occurs, and is transported by a carrier-mediated process. Here we report that cysteamine administration in rats leads to cysteamine accumulation in the proximal duodenum, where the highest concentration of iron in the gastrointestinal tract is found. In vitro, iron loading of intestinal epithelial cells (IEC-6) accelerated reactive oxygen species (ROS) production and increased [(14)C]cysteamine uptake. [(14)C]Cysteamine uptake by isolated gastrointestinal mucosal cells and by IEC-6 was pH-dependent and inhibited by unlabeled cysteamine. The uptake of [(14)C]cysteamine by IEC-6 was Na(+)-independent, saturable, inhibited by structural analogs, H(2)-histamine receptor antagonists, and organic cation transporter (OCT) inhibitors. OCT1 mRNA was markedly expressed in the rat duodenum and in IEC-6, and transfection of IEC-6 with OCT1 siRNA decreased OCT1 mRNA expression and inhibited [(14)C]cysteamine uptake. Cysteamine-induced duodenal ulcers were decreased in OCT1/2 knockout mice. These studies provide new insights into the mechanism of cysteamine absorption and demonstrate that intracellular iron plays a critical role in cysteamine uptake and in experimental duodenal ulcerogenesis.