Background/Objectives: Acral melanoma (AM) is a rare and aggressive melanoma subtype that arises on sun-shielded, non-hair-bearing skin of the palms, soles, and nail beds. Although more common among individuals of non-European descent, AM remains underrecognized and understudied in the Middle East and North Africa (MENA). This study presents the first dedicated AM registry from Lebanon, aiming to characterize clinical, histopathological, and molecular features and evaluate diagnostic, referral, treatment approaches, and clinical outcomes over a 12-year period. Methods: This retrospective cohort study was conducted at the American University of Beirut Medical Center (AUBMC), a major tertiary referral center in the MENA region. All melanoma cases diagnosed between January 2012 and January 2024 were identified through electronic health records. From this cohort, all adult patients (≥18 years) with biopsy-confirmed AM or tumors located on the palms, soles, or under the nails were selected. Results: Our cohort consisted of 26 adult AM patients, identified from a total of 331 melanoma cases during the study period (8%). Median age at diagnosis was 58.5 years; 54% were female; and 96% of Middle Eastern origin. Most tumors were plantar (81%), and over half (53%) were diagnosed at early stages (Stage I–II). Surgery was performed in 92% of patients, yet 55% had positive margins. Sentinel lymph node biopsy was performed in 46%, and 35% received immunotherapy. Only 35% underwent molecular testing, identifying BRAF mutations in 11% of those tested; no patients received circulating tumor DNA analysis. At a median follow-up of 24.5 months, recurrence occurred in 27%, and metastasis developed in 23%. At the last follow-up, 92% were alive. Conclusions: Despite early-stage detection, high rates of positive margins and limited molecular testing reveal care gaps. This first national registry highlights the need to improve surgical management and expand access to precision oncology in the region.

Background: An apparent AB blood group in a neonate born to a group O mother can raise diagnostic, transfusion, and parentage‐sensitive concerns. CisAB alleles are rare ABO variants in which a single inherited allele encodes glycosyltransferase activity producing both A and B antigens. ABO*cisAB.05 is particularly uncommon, and its detection during routine neonatal cord blood testing has not, to our knowledge, been previously reported. Case Report: A term female neonate born to a group O, RhD‐positive mother and a group AB, RhD‐positive father typed as AB, RhD positive on routine cord blood testing. The direct antiglobulin test was negative by gel but weakly positive by tube anti IgG, with anti‐B in an acid eluate, providing serologic evidence of subclinical ABO incompatibility without clinically significant hemolysis. Repeat testing and reference laboratory evaluation reproduced an AB‐like, RhD‐positive phenotype, with 4+ reactivity to anti‐A, anti‐B, and anti‐A,B reagents, anti‐A1 lectin negativity, and anti‐H lectin positivity graded as 2+. Because the result appeared discordant with the maternal group, identity and specimen concordance were evaluated first. Short tandem repeat analysis confirmed maternity and cord blood–buccal swab concordance. ABO exon sequencing identified an ABO*cisAB.05/ABO*O.01.01 genotype, explaining the discrepancy. Conclusion: To our knowledge, this is the first ABO*cisAB.05 case identified through routine neonatal cord blood testing. A stepwise approach beginning with repeat serology and patient/specimen identity confirmation, followed by targeted molecular testing, can resolve the discrepancy while minimizing premature parentage‐related conclusions and guiding safe transfusion planning.

Background/Objectives: Immune checkpoint inhibitors have revolutionized the treatment of advanced melanoma, yet primary and acquired resistance remain major barriers to durable disease control. This narrative review examines the clinical patterns, biological mechanisms, biomarker limitations, and therapeutic implications of immunotherapy failure. Methods: A structured search of PubMed, Web of Science, and ClinicalTrials.gov identified relevant studies published from January 2010 to May 2026, supplemented by landmark earlier reports. Results: Immunotherapy resistance encompasses heterogeneous patterns, including early progression, oligoprogression, dissociated response, brain-dominant progression, relapse after response, and progression after treatment discontinuation. These clinical phenotypes arise from overlapping mechanisms such as loss of antigen presentation, impaired interferon signaling, oncogenic immune exclusion, melanoma dedifferentiation, suppressive myeloid and regulatory T-cell programs, stromal and vascular barriers, metabolic restriction, and deterioration of tumor-reactive T-cell clones. Conventional response criteria and static biomarkers, including PD-L1 expression and tumor mutational burden, do not adequately capture this complexity because resistance varies across lesions and evolves under treatment pressure. Negative trials of IDO1 inhibition, cytokine intensification, vaccines, and intratumoral immune stimulation further show that biological plausibility and early activity do not guarantee clinical benefit when target engagement, patient enrichment, and endpoint selection are inadequate. Conclusions: Immunotherapy resistance in melanoma should be viewed as a variety of biologically distinct clinical states rather than a single endpoint. Future progress will require resistance-matched treatment, longitudinal tissue and circulating tumor DNA assessment, adaptive trial designs, and endpoints aligned with treatment kinetics. This framework may improve salvage selection and interpretation of post-PD-1 studies in clinical practice.