Targeting Isocitrate Dehydrogenase (IDH) in Solid Tumors: Current Evidence and Future Perspectives.

The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included.

The potential roles of antibody-drug conjugates in head and neck squamous cell carcinoma.

PURPOSE OF REVIEW: To summarize the actual antibody-drug conjugates (ADCs) tested for patients with advanced head and neck squamous cell carcinoma (HNSCC), outlining the results of safety and efficacy through published clinical trials. RECENT FINDINGS: ADCs combine the specificity of mAbs with the cytotoxic drug (known as payload) via a chemical linker and it is designed to selectively deliver the ultratoxic payload directly to the target cancer cells. To date, various ADCs have been investigated in multiple solid malignancies and others are in clinical development. In this study, we provide an overview of the structure and biology of ADC and we review recent clinical experience with the ADC in patients with advanced HNSCC, followed by a brief discussion of the evolvement of ADC conception, drug resistance and future perspectives. SUMMARY: ADC strategy is emerging as a potential active treatment in previously treated patients with advanced HNSCC. However, the recent improvement in the bioengineering of ADC and a better comprehension of sequencing and association strategies could provide more benefit to HNSCC patients in need of innovative therapy.

Calcitonin-secreting neuroendocrine tumor of the larynx, a diagnostic challenge of a rare neoplasm: a case report and literature review.

Background: Laryngeal neuroendocrine tumors (NETs) represent less than 1% of all malignancies originating from the larynx and available data are limited on case reports. Calcitonin secreting laryngeal NETs are extremely rare and serial dosing of calcitonin in these patients might reveal early relapse or persistence. Case Description: We report the case of a 71-year-old woman with persistent pharyngodynia who underwent surgery for an initial diagnosis of small cell undifferentiated neuroendocrine carcinoma (SCUNC) of the larynx (on the epiglottis extended to the left glosso-epiglottic vallecula). The immunohistochemical profile showed the presence of synaptophysin, neuron-specific enolase (NSE), chromogranin A, pan-cytokeratin, including cytokeratin AE1-AE2, and focally calcitonin. The circulating NSE was 13.4 microg/L (normal level <12.5 microg/L) and the basal serum level of calcitonin was 237 pg/mL (normal level <11.5 pg/mL). The patient was started on first-line carboplatin-etoposide chemotherapy because of early relapse to an axillary lymph node. After 4 cycles of treatment, a radiological stability and metabolic response were demonstrated together with a drastic decrease of circulating serum level of calcitonin (from 237 to 57.9 pg/mL). During the follow up, locoregional relapse of disease occurred, associated with an increase of serum calcitonin (89.3 pg/mL). Disease further progressed on and rechallenge with platinum-etoposide chemotherapy was administered, during which clinical progression was confirmed. Due to the lack of response, a revision of the histology was performed and concluded for a definitive diagnosis of moderately differentiated G2 NET, with a Ki-67 index of 22.6%. Conclusions: This is the eighth case report of laryngeal NET, highlighting the challenge in pathological differential diagnosis and therapeutic strategies. The association with elevated serum calcitonin and the trend of this parameter during clinical progression suggest a role of this marker in the diagnosis and early identification of recurrent laryngeal NETs.

Hedgehog Inhibitors Beyond Clinical Complete Response in Basal Cell Carcinoma: Should I Stop or Should I Go?

INTRODUCTION: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. MATERIALS AND METHODS: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10). RESULTS: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01). CONCLUSIONS: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC.