Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers.

PURPOSE: Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS: Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS: Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION: In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.

Genomic and transcriptomic analysis of cutaneous squamous cell carcinoma arising in immunocompetent and immunosuppressed patients.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy arising in immunocompromised patients such as solid organ transplant recipients. In addition to an abundance in number, the morbidity and mortality of these tumors in this patient population exceeds that of immune competent individuals. Here, we used whole exome and bulk RNA sequencing to analyze mutation profiles between tumors arising in immunocompetent and immunosuppressed patients. METHODS: DNA and RNA extracted from twenty formalin-fixed, paraffin embedded tumors and adjacent skin was sequenced. Bioinformatic analysis revealed tumor mutational burden, mutational signatures, microsatellite instability, and aberrant signaling pathways. RESULTS: Similar median tumor mutational burden was found in both the tumors from the immunocompetent and the immunosuppressed cohorts. Mutation signature analysis revealed UVR signatures and evidence of azathioprine exposure. 50% of tumors from the immunosuppressed patients have mutations consistent with microsatellite instability, yet mismatch repair protein expression was preserved in the samples analyzed. Additionally, frequently mutated genes in this cohort belong to the extracellular matrix receptor interaction and calcium signaling pathways, suggesting these may be targets for future treatments of this disease. CONCLUSIONS: This study utilizes whole exome and bulk RNA sequencing to identify difference between cSCC arising in immunosuppressed and immunocompetent patients using the patient's photo exposed, but histologically normal appearing skin as the "germline" comparison. We demonstrate an enrichment in microsatellite instability in the tumors from immunosuppressed patients and differences in oxidative phosphorylation and epithelial-mesenchymal transition which may be targets for therapeutic intervention based on identification of mutations.

Predictors of patient satisfaction with Mohs micrographic surgery at time of surgery and 3 months postsurgery: A prospective cohort study.

BACKGROUND: Despite the importance of patient satisfaction in ensuring high-quality care, studies investigating patient satisfaction in Mohs micrographic surgery (MMS) are limited. OBJECTIVE: We investigated the factors associated with patient satisfaction in MMS for nonmelanoma skin cancer and how patient satisfaction changes in the postoperative period. METHODS: In this prospective cohort study including 100 patients, patient satisfaction surveys were administered at the time of surgery and at 3 months postsurgery. Sociodemographic characteristics, medical history, and surgical parameters were collected by chart review. Univariate linear and logistic regression models were created to examine these relationships. RESULTS: Decreased satisfaction was observed in patients requiring 3 or more MMS stages both at the time of surgery (P = .047) and at 3 months post-surgery (P = .0244). Patients with morning procedures ending after 1:00 pm had decreased satisfaction at the time of surgery (P = .019). A decrease in patient satisfaction between the time of surgery and 3 months postsurgery was observed in patients with surgical sites on the extremities (P = .036), larger preoperative lesion sizes (P = .012), and larger defect sizes (P = .033). LIMITATIONS: Single-institution data, self-selection bias, and recall bias. CONCLUSION: Patient satisfaction with MMS is impacted by numerous factors and remains dynamic over time.

Patient Anxiety Related to Patient-Perceived Delays in Surgical Treatment of Skin Cancer.

BACKGROUND: Patients undergoing dermatologic surgery report higher anxiety levels than those undergoing nonsurgical treatments. However, little is known about the association between patient-perceived delays in skin cancer surgery and patient-reported anxiety. OBJECTIVE: To examine the relationship between patient-perceived delays in surgery and patient-reported anxiety. METHODS MATERIALS: Patients undergoing wide local excision or Mohs micrographic surgery were recruited to complete a survey to assess perception of surgical delay and anxiety related to skin cancer surgery using the validated Psychosocial Screen for Cancer-Revised. Demographic and surgical characteristics were collected through chart review. Chi-square and Student t -tests were used to compare demographic and surgical information between patients who did and did not perceive a surgical delay. Differences in anxiety and depression scores for patients who did and did not report a delay were assessed using univariate and multivariate regressions. RESULTS: Twenty-seven percent ( N = 33) of patients perceived a surgical delay. Perception of surgical delay was associated with increased time between biopsy and surgery ( p = .0001) and increased self-reported anxiety scores after controlling for various demographic and surgical factors ( p = .038). CONCLUSION: Patient-perceived delays in dermatologic surgery are associated with increased time to surgery and patient-reported anxiety.

Interventions After First Post-Transplant Cutaneous Squamous Cell Carcinoma: A Proposed Decision Framework.

Cutaneous squamous cell carcinoma (CSCC) is a major cause of morbidity and mortality after organ transplant. Many patients subsequently develop multiple CSCC following a first CSCC, and the risk of metastasis and death is significantly increased compared to the general population. Post-transplant CSCC represents a disease at the interface of dermatology and transplant medicine. Both systemic chemoprevention and modulation of immunosuppression are frequently employed in patients with multiple CSCC, yet there is little consensus on their use after first CSCC to reduce risk of subsequent tumors. While relatively few controlled trials have been undertaken, extrapolation of observational data suggests the most effective interventions may be at the time of first CSCC. We review the need for intervention after a first post-transplant CSCC and evidence for use of various approaches as secondary prevention, before discussing barriers preventing engagement with this approach and finally highlight areas for future research. Close collaboration between specialties to ensure prompt deployment of these interventions after a first CSCC may improve patient outcomes.

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.

Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function.

Duchenne muscular dystrophy in boys progresses rapidly to severe impairment of muscle function and death in the second or third decade of life. Current supportive therapy with corticosteroids results in a modest increase in strength as a consequence of a general reduction in inflammation, albeit with potential untoward long-term side effects and ultimate failure of the agent to maintain strength. Here, we demonstrate that alternative approaches that rescue defective autophagy in mdx mice, a model of Duchenne muscular dystrophy, with the use of rapamycin-loaded nanoparticles induce a reproducible increase in both skeletal muscle strength and cardiac contractile performance that is not achievable with conventional oral rapamycin, even in pharmacological doses. This increase in physical performance occurs in both young and adult mice, and, surprisingly, even in aged wild-type mice, which sets the stage for consideration of systemic therapies to facilitate improved cell function by autophagic disposal of toxic byproducts of cell death and regeneration.

The apical sorting signal for human GLUT9b resides in the N-terminus.

The two splice variants of human glucose transporter 9 (hGLUT9) are targeted to different polarized membranes. hGLUT9a traffics to the basolateral membrane, whereas hGLUT9b traffics to the apical region. This study examines the sorting mechanism of these variants, which differ only in their N-terminal domain. Mutating a di-leucine motif unique to GLUT9a did not affect targeting. Chimeric proteins were made using GLUT1, a basolaterally targeted transporter, and GLUT3, an apically targeted protein whose signal lies in the C-terminus. Overexpression of the chimeric proteins in polarized cells demonstrates that the N-terminus of hGLUT9b contains a signal capable of redirecting GLUT1 to the apical membrane. The N-terminus of hGLUT9a, however, does not contain a basolateral signal sufficient enough to redirect GLUT3. Portions of the GLUT9a N-terminus were substituted with corresponding portions of the GLUT9b N-terminus to determine the motif responsible for apical targeting. The first 16 amino acids were not found to be a sufficient apical signal. The last ten amino acids of the N-termini differ only in amino-acid class at one location. In the B-form, leucine, a hydrophobic residue, is substituted for lysine, a basic residue, found in the A-form. However, mutation of the leucine in hGLUT9b to a lysine resulted in retention of the apical signal. We therefore believe the apical signal exists as an interplay between the final ten amino acids of the N-terminus and another motif within the protein such as the intracellular loop or other motifs within the N-terminus.

Asymmetric syncytial expression of GLUT9 splice variants in human term placenta and alterations in diabetic pregnancies.

Glucose transport from the maternal to fetal side of the placenta is critical for fetal growth and development due to the absence of fetal gluconeogenesis. Human GLUT9, existing as 2 isoforms, is a novel member of the transporter family. This study investigated the localization and relative expression levels of these isoforms in the human term placenta from both control and diabetic patients. Placenta samples were collected from normal pregnancies and those complicated by maternal diabetes (White classifications A1, A2, and B). Antibodies specific for the different isoforms were used to detect expression. Both forms of the protein are expressed in syncytiotrophoblast cells. Subcellular fractionation revealed an asymmetrical expression pattern with GLUT9a on basal membranes, whereas GLUT9b localizes to microvillus membranes. Expression of both isoforms is significantly increased in placental tissue from diabetic pregnancies. Altered expression of GLUT9 in the placenta may play a role in the fetal pathophysiology associated with diabetes-complicated pregnancies.

AMP kinase activation increases glucose uptake, decreases apoptosis, and improves pregnancy outcome in embryos exposed to high IGF-I concentrations.

Women with polycystic ovarian syndrome are at increased risk of miscarriage. Although evidence exists that metformin reduces this risk, the mechanism is unknown. This study tests the hypothesis that AMP kinase (AMPK) activation with metformin directly improves insulin signaling within the blastocyst, leading to improved pregnancy outcomes. Murine embryos were exposed to 200 nmol/l IGF-I, similar to the concentrations that can occur during polycystic ovary syndrome (PCOS). Resulting blastocysts were compared with embryos cocultured with excess IGF-I plus metformin and embryos cultured in control medium for the following: AMPK phosphorylation, insulin-stimulated glucose uptake, and apoptosis. Study and control blastocysts were also transferred into control animals. On embryonic day (E) 14.5, resulting fetuses were examined for size and rates of fetal implantation and resorption. Compared with control blastocysts, blastocysts exposed to high concentrations of IGF-I showed a decrease in AMPK activation and insulin-stimulated glucose uptake and an increase in the number of apoptotic nuclei. Blastocysts cocultured in metformin and excess IGF-I performed as well as controls in all studies. 5-Aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside, another AMPK activator, also prevented the effects of excess IGF-I on blastocysts. Implantation rates and fetal size at day 14.5 were significantly lower among IGF-I-exposed embryos transferred into control mothers compared with control embryos transferred into control mothers. Both of these parameters were reversed by co-incubation with metformin and IGF-I before transfer. Activation of embryonic AMPK may be the mechanism responsible for the improved pregnancy outcomes seen in PCOS patients taking metformin.