Immune-Checkpoint Induced Skin Toxicity Masked as Squamous Cell Carcinoma: Case Report on Mimickers of Dermatological Toxicity with PD-1 Inhibition.

BACKGROUND: Immune checkpoint inhibitors (ICI) are increasingly the mainstay of oncology treatment. Immune-related adverse events (irAEs) from ICI therapy differ from cytotoxic adverse events. Cutaneous irAEs are one of the most common irAEs and require careful attention to optimize the quality of life for oncology patients. PATIENT AND METHODS: These are two cases of patients with advanced solid-tumour malignancies treated with PD-1 inhibitor therapy. RESULTS: Both patients developed multiple pruritic hyperkeratotic lesions, which were initially diagnosed as squamous cell carcinoma from skin biopsies. The presentation as squamous cell carcinoma was atypical and, upon further pathology review, the lesions were more in keeping with a lichenoid immune reaction stemming from the immune checkpoint blockade. With the use of oral or topical steroids and immunomodulators, the lesions resolved. CONCLUSIONS: These cases emphasize that patients on PD-1 inhibitor therapy who develop lesions resembling squamous cell carcinoma on initial pathology may require an additional pathology review to assess for immune-mediated reactions, allowing appropriate immunosuppressive therapy to be initiated.

Second-Line Treatment of Non-Small Cell Lung Cancer: New Developments for Tumours Not Harbouring Targetable Oncogenic Driver Mutations.

Platinum-based doublet chemotherapy with or without bevacizumab is the standard of care for the initial management of advanced and metastatic non-small cell lung cancer (NSCLC) without a targetable molecular abnormality. However, the majority of patients with NSCLC will ultimately develop resistance to initial platinum-based chemotherapy, and many remain candidates for subsequent lines of therapy. Randomised trials over the past 10-15 years have established pemetrexed (non-squamous histology), docetaxel, erlotinib and gefitinib as approved second-line agents in NSCLC without targetable driver mutations or rearrangements. Trials comparing these agents with other chemotherapy, evaluating the addition of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to chemotherapy or the addition of another targeted agent to erlotinib or gefitinib have all failed to demonstrate an improvement in overall survival for patients with NSCLC. In contrast, recent data comparing therapy with novel monoclonal antibodies against programmed cell death 1 (PD-1) or PD ligand (PD-L1) pathway versus standard chemotherapy following platinum failure have demonstrated significant improvements in overall survival. Therapy with nivolumab or pembrolizumab would now be considered standard second-line therapy in patients without contraindication to immune checkpoint inhibitors. Atezolizumab also appears promising in this setting.

The effects of gender on adolescent suicide in ontario, Canada.

OBJECTIVE: Identify patterns of suicide amongst male and female adolescents aged 11-18 years in Ontario. METHOD: All 370 adolescent suicides in Ontario between January 2000 and November 2006 were analyzed. Previous attempts, history of psychiatric treatment, location committed and method of suicide were assessed. Data was analyzed using 2-tailed t-tests and chi-square without Yates' correction. RESULTS: Male adolescent suicide was twice as common as female suicide. Males were more likely to use violent methods (p=0.0352) and females were more likely to have a history of a previous suicide attempt (p=0.0001). CONCLUSIONS: While most of the data agree with previous studies in adult populations, the ratio of male to female suicides was much lower in our adolescent population.

Epidermal hyperplasia and expansion of the interfollicular stem cell compartment in mutant mice with a C-terminal truncation of Patched1.

Hedgehog (Hh) signaling is conserved from flies to humans and is indispensable in embryogenesis and adulthood. Patched (Ptc) encodes a receptor for Hh ligands and functions as a tumor suppressor. PTCH1 mutations in humans are found in basal cell carcinoma (BCC) and irradiated Ptc1(+/-) mice recapitulate this phenotype. However, due to embryonic lethality associated with the Ptc1 null mutation, its normal function in embryonic and adult skin remains unknown. Here we describe the epidermal phenotypes of a spontaneous and viable allele of Ptc1, Ptc1(mes), in which the C-terminal domain (CTD) is truncated. Ptc1(mes/mes) embryos display normal epidermal and hair follicle development. Postnatal Ptc1(mes/mes) skin displays severe basal cell layer hyperplasia and increased proliferation, while stratification of the suprabasal layers is mostly normal. Interestingly, truncation of the Ptc1 CTD did not result in skin tumors. However, long term labeling studies revealed a greater than three-fold increase in label-retaining cells in the interfollicular epidermis of Ptc1(mes/mes) adults, indicating possible expansion of the epidermal stem cell compartment. Increased expression of regulators of epidermal homeostasis, c-Myc and p63, was also observed in Ptc1(mes/mes) adult skin. These results suggest that the CTD of Ptc1 is involved in regulating epidermal homeostasis in mature skin.

Mice with a targeted mutation of patched2 are viable but develop alopecia and epidermal hyperplasia.

Hedgehog (Hh) signaling plays pivotal roles in tissue patterning and development in Drosophila melanogaster and vertebrates. The Patched1 (Ptc1) gene, encoding the Hh receptor, is mutated in nevoid basal cell carcinoma syndrome, a human genetic disorder associated with developmental abnormalities and increased incidences of basal cell carcinoma (BCC) and medulloblastoma (MB). Ptc1 mutations also occur in sporadic forms of BCC and MB. Mutational studies with mice have verified that Ptc1 is a tumor suppressor. We previously identified a second mammalian Patched gene, Ptc2, and demonstrated its distinct expression pattern during embryogenesis, suggesting a unique role in development. Most notably, Ptc2 is expressed in an overlapping pattern with Shh in the epidermal compartment of developing hair follicles and is highly expressed in the developing limb bud, cerebellum, and testis. Here, we describe the generation and phenotypic analysis of Ptc2(tm1/tm1) mice. Our molecular analysis suggests that Ptc2(tm1) likely represents a hypomorphic allele. Despite the dynamic expression of Ptc2 during embryogenesis, Ptc2(tm1/tm1) mice are viable, fertile, and apparently normal. Interestingly, adult Ptc2(tm1/tm1) male animals develop skin lesions consisting of alopecia, ulceration, and epidermal hyperplasia. While functional compensation by Ptc1 might account for the lack of a strong mutant phenotype in Ptc2-deficient mice, our results suggest that normal Ptc2 function is required for adult skin homeostasis.

Negative regulation of Gli1 and Gli2 activator function by Suppressor of fused through multiple mechanisms.

During animal development, the Hedgehog (Hh) signal transduction pathway plays critical roles in cell fate determination and tissue patterning. In humans, aberrant Hh signaling has been linked to several genetic disorders and cancers. Binding of Hh to its receptor initiates a signaling cascade, which ultimately results in the activation of the Gli/Ci transcription factors. Suppressor of fused (Su(fu)) is a Gli/Ci-interacting protein, which acts as a negative regulator of Hh signaling in Drosophila and vertebrates. Su(fu) is also implicated as a tumor suppressor as its mutations have been found in medulloblastoma and prostate cancer. Su(fu) is thought to act by preventing the nuclear accumulation of Gli/Ci, however, mechanistic insight into its mode of action has remained elusive. We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms. While Su(fu) itself is not subject to CRM1-dependent regulation, Su(fu) sequesters Gli1 in the cytoplasm mostly through a mechanism that depends on the activity of the nuclear export protein CRM1. In contrast, CRM1-mediated export is not required for Su(fu) to sequester Gli2. Furthermore, we show that the N-terminus of Su(fu) is sufficient for Gli inactivation in the absence of cytoplasmic sequestration. Together, these observations reveal that Su(fu) regulates the activity of Gli1 and Gli2 through distinct cytoplasmic and nuclear mechanisms.