Cancer Screening for Dermatomyositis: A Survey of Indirect Costs, Burden, and Patient Willingness to Pay.

Dermatomyositis (DM) is a rare idiopathic inflammatory myopathy (IIM) associated with an increased risk for malignancy. Although cancer screening is recommended, no consensus guidelines currently exist. Whole-body positron emission tomography/ computed tomography (PET/CT) has similar cost and efficacy to a more traditional conventional cancer screening panel (CSP). Our study sought to characterize patients' perspective of cancer screening and the indirect costs to patients. We conducted a survey of patients recently diagnosed with DM who were undergoing or had recently undergone a CSP. Patient values and indirect costs need to be considered in choosing a screening modality. This study contributes to a greater understanding of patients' experience of cancer screening in DM, which should be taken into consideration when developing consensus guidelines for cancer screening.

Paraneoplastic pemphigus associated with Castleman disease: A multicenter case series.

INTRODUCTION: Paraneoplastic pemphigus (PNP) is a rare, often fatal, autoimmune blistering disease of the skin and mucous membranes. In children, PNP is frequently associated with Castleman disease (CD). This series describes five cases of PNP associated with CD. METHODS: Data were collected retrospectively from the medical records of patients with a diagnosis of PNP and CD from January 2013 to June 2022. Patients ≤22 years old with clinical and immunopathologic evidence of PNP were included; CD was diagnosed histopathologically. RESULTS: Two children, two adolescents, and one young adult (two males, three females) were included. The average age at disease presentation was 11.8 years (range: 7-22 years). Oral (n = 5) and anogenital (n = 3) mucositis were common. Four patients had "unicentric" CD (UCD); one patient had "multicentric" CD (MCD). Castleman tumors were in the retroperitoneum (n = 4) or axilla (n = 1). One patient had myasthenia gravis without thymoma. Three patients had bronchiolitis obliterans (BO). Three patients had complete resection of their CD; two had partial resection. Three patients remain alive with a median follow-up of 13 months (range: 12 months to 13 years); two are clinically stable with resolution of mucocutaneous lesions; one has persistent BO requiring ongoing ventilatory support. Patients who remain alive had UCD with complete resection; all deceased patients had partial resection and BO. CONCLUSION: Most patients had UCD, and the retroperitoneum was the most common location. Patients with MCD, incomplete resection, and BO died; patients with UCD and complete resection remain alive, even in the setting of BO. Consideration of PNP is critical when pediatric patients present with mucositis as PNP may be clinically indistinguishable from more common causes of mucositis.

Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents.

The aldehyde dehydrogenases (ALDHs) are a family of detoxifying enzymes that are overexpressed in various cancers. Increased expression of ALDH is associated with poor prognosis, stemness, and drug resistance. Because of the critical role of ALDH in cancer stem cells, several ALDH inhibitors have been developed. Nonetheless, all these inhibitors either lack efficacy or are too toxic or have not been tested extensively. Thus, the continued development of ALDH inhibitors is warranted. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin backbone. The early molecular docking studies and enzymatic tests revealed that 3(a-l) and 4(a-l) are the potent ALDH1A1, ALDHA2, and ALDH3A1 inhibitors. ALDH inhibitory IC50s of 3(a-l) and 4(a-l) were 230 nM to >10,000 nM for ALDH1A1, 939 nM to >10,000 nM for ALDH2 and 193 nM to >10,000 nM for ALDH3A1. The most potent compounds 3(h-l) had IC50s for killing melanoma cells ranged from 2.1 to 5.7 µM, while for colon cancer cells, it ranged from 2.5 to 5.8 µM and for multiple myeloma cells ranging from 0.3 to 4.7 µM. Toxicity studies of 3(h-l) revealed that 3h to be the least toxic multi-ALDH isoform inhibitor. Mechanistically, 3(h-l) caused increased ROS activity, lipid peroxidation, and toxic aldehyde accumulation, secondary to potent multi-ALDH isoform inhibition leading to increased apoptosis and G2/M cell cycle arrest. Together, the study details the design, synthesis, and evaluation of potent, multi-isoform ALDH inhibitors to treat cancers.

Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent.

The aldehyde dehydrogenases (ALDH) are a major family of detoxifying enzymes that contribute to cancer progression and therapy resistance. ALDH overexpression is associated with a poor prognosis in many cancer types. The use of multi-ALDH isoform or isoform-specific ALDH inhibitors as anticancer agents is currently hindered by the lack of viable candidates. Most multi-ALDH isoform inhibitors lack bioavailability and are nonspecific or toxic, whereas most isoform-specific inhibitors are not effective as monotherapy due to the overlapping functions of ALDH family members. The present study details the development of a novel, potent, multi-isoform ALDH inhibitor, called KS100. The rationale for drug development was that inhibition of multiple ALDH isoforms might be more efficacious for cancer compared with isoform-specific inhibition. Enzymatic IC50s of KS100 were 207, 1,410, and 240 nmol/L toward ALDH1A1, 2, and 3A1, respectively. Toxicity of KS100 was mitigated by development of a nanoliposomal formulation, called NanoKS100. NanoKS100 had a loading efficiency of approximately 69% and was stable long-term. NanoKS100 was 5-fold more selective for killing melanoma cells compared with normal human fibroblasts. NanoKS100 administered intravenously at a submaximal dose (3-fold lower) was effective at inhibiting xenografted melanoma tumor growth by approximately 65% without organ-related toxicity. Mechanistically, inhibition by KS100 significantly reduced total cellular ALDH activity to increase reactive oxygen species generation, lipid peroxidation, and accumulation of toxic aldehydes leading to apoptosis and autophagy. Collectively, these data suggest the successful preclinical development of a nontoxic, bioavailable, nanoliposomal formulation containing a novel multi-ALDH isoform inhibitor effective in the treatment of cancer.

Aldehyde Dehydrogenase Inhibitors for Cancer Therapeutics.

Aldehyde dehydrogenases (ALDHs) are highly expressed in the chemotherapy- and radiotherapy-resistant cell subpopulations of many different cancer types. Accordingly, the development of ALDH inhibitors may be the most direct approach to target these cell populations. However, inhibiting multiple ALDH family members can be toxic and isoform-specific inhibition is often ineffective. This review discusses the role of ALDH in cancer and therapy resistance, and then overviews the various available ALDH inhibitors with a focus on the clinical potential and limitations of these agents as cancer therapeutics. Finally, challenges and future research directions to effectively target ALDH in the management of cancer therapy resistance are discussed.

Aldehyde dehydrogenase in regulatory T-cell development, immunity and cancer.

The role of aldehyde dehydrogenase (ALDH) in carcinogenesis and resistance to cancer therapies is well known. Mounting evidence also suggests a potentially important role for ALDH in the induction and function of regulatory T (Treg) cells. Treg cells are important cells of the immune system involved in promoting immune tolerance and preventing aberrant immune responses to beneficial or non-harmful antigens. However, Treg cells also impair tumor immunity, leading to the progression of various carcinomas. ALDH expression and the subsequent production of retinoic acid by numerous cells, including dendritic cells, macrophages, eosinophils and epithelial cells, seems important in Treg induction and function in multiple organ systems. This is particularly evident in the gastrointestinal tract, pulmonary tract and skin, which are exposed to a myriad of environmental antigens and represent interfaces between the human body and the outside world. Expression of ALDH in Treg cells themselves may also be involved in the proliferation of these cells and resistance to certain cytotoxic therapies. Hence, inhibition of ALDH expression may be useful to treat cancer. Besides the direct effect of ALDH inhibition on carcinogenesis and resistance to cancer therapies, inhibition of ALDH could potentially augment the immune response to tumor antigens by inhibiting Treg induction, function and ability to promote immune tolerance to tumor cells in multiple cancer types.

The value of full-body skin examination: Poland syndrome diagnosed as an incidental finding.

Poland syndrome is a rare congenital disorder characterized by agenesis of the pectoralis major muscle. It is generally unilateral, right-sided, and can be associated with a myriad of thoracic and upper limb defects. Knowledge of this disorder can lead the astute clinician to prompt diagnosis and referral to surgical specialists for further workup. Surgery is often performed for either esthetic or functional concerns.