Durable radiologic and molecular complete response following nivolumab in an HNSCC patient with UV signature and HIV.

Cancer patients living with HIV (CPLWH) may experience increased mortality risk. Furthermore, they have been historically excluded from clinical trials due to safety concerns. Our patient with squamous cell carcinoma of the lower lip received radiotherapy and platinum-based chemotherapy but declined by multiple centers due to his accidental HIV status. Genomic profiling revealed CDKN2A/B, PBRM1, TP53, and TERT alterations corresponding to UV signature, and high tumor mutational burden with positive PD-L1 staining. Accordingly, we report a durable radiologic and molecular complete response upon nivolumab plus IVC and antiretroviral therapy (ART). We demonstrated the safety and efficacy of ICIs, and feasibility of managing adverse events caused by antitumor, antiviral, and integrative therapies.

Navigating uncharted territory: a case report and literature review on the remarkable response to personalized crizotinib containing combinational therapy in a pazopanib refractory patient with novel alterations.

This paper presents a patient with a novel Ig-like-III domain fibroblast growth factor receptor (FGFR2) alteration (W290_P307>C) along with CDKN2A/B alterations and a cadherin 1 (CDH1) alteration. Initial responsiveness to pazopanib monotherapy was encouraging, yet progression occurred after 7.5 months. Following progression, the molecular tumor board recommended a combination therapy approach comprising pazopanib, crizotinib, and palbociclib to target all of the changed pathways at the same time. Pazopanib was chosen to specifically target the FGFR2 alteration, while crizotinib was selected due to its potential synthetic lethality with the CDH1 alteration. In addition, the CDK4/6 inhibitor palbociclib was administered to address the CDKN2A/B alterations. The patient exhibited a remarkable and sustained response to this innovative combination. This case not only underscores the potential of tyrosine kinase inhibitors, exemplified by pazopanib, as a viable alternative for patients without access to pan-FGFR inhibitors, but it also emphasizes their efficacy beyond commonly detected point mutations and rearrangements. Notably, the outstanding response to combination therapy, including crizotinib, in a patient with a CDH1 alteration, further substantiates the preclinical evidence of synthetic lethality between crizotinib and CDH1 alterations. To our knowledge, this represents the first clinical evidence demonstrating the efficacy of crizotinib in a patient with a CDH1 alteration. Through careful dosage adjustments and consideration of individualized genomic information, this case exemplifies the power of personalized medicine in achieving favorable treatment outcomes.

PARP inhibitor combinations with high-dose vitamin C in the treatment of Ewing sarcoma: two case reports and mechanistic overview.

Ewing's sarcoma (ES) is a bone and soft tissue tumor that mainly occurs at a young age. The underlying cause of Ewing's sarcoma is the formation of fusion proteins between FET family genes and ETS family genes. Tumors with FET/ETS fusion genes can have defects in the DNA damage response and are sensitive to PARP inhibitors (PARPi). However, several studies have shown that PARPi alone is not sufficient to induce a meaningful antitumor response and that combinations of DNA-damaging agents with PARPi are required to achieve efficacy. Accordingly, preclinical studies have reported dramatic responses to PARPi treatment in combination with DNA-damaging agents such as temozolomide or irinotecan. Similarly, it has been previously reported that by generating reactive oxygen species, high-dose intravenous vitamin C (IVC) can induce DNA damage. This suggests that the combination of IVC with PARPi may increase genotoxic stress and enhance the antitumor response. In addition, unlike chemotherapeutic agents, IVC induces DNA damage selectively in cancer cells, and the side effects are significantly milder than those of chemotherapy. As ETS fusion-positive ES is deficient in faithful DNA repair, partly due to the interaction between ETS fusion products and PARP1, a PARPi plus IVC seems to be a logical and effective combination for the treatment of ETS fusion-positive ES. This paper reports significant responses to IVC (1-1.5 g/kg) in combination with PARPi (olaparib 300 mg BID or talazoparib 1 mg/day) in two patients with metastatic Ewing's sarcoma. The observations highlight an unmet therapeutic need for patients with advanced metastatic ES. The combination of PARPi with a selective DNA-damaging agent was effective in these cases. This case experience suggests that IVC may be incorporated into PARPi-based therapeutic strategies. Further studies are needed to confirm the efficacy of this combination in the treatment of Ewing sarcoma with ETS fusions.

Combining vitamin C with PARP inhibitors for Ewing sarcoma treatment: mechanistic insights and 2 case studies Ewing's sarcoma is a type of bone and soft tissue tumor that commonly affects young people and it is often resistant to conventional therapy. In this study, clinical cancer scientists and oncologists investigated a new approach to treating this cancer by combining high-dose vitamin C with PARP inhibitors. High-dose vitamin C can damage the DNA of cancer cells and PARP inhibitors block the damaged DNA sites so they can't be repaired and eventually this leads to cancer cells dying. The researchers found that when these two treatments were used together, there were significant improvements in two patients with advanced Ewing's sarcoma. Importantly, the combination led to fewer side effects compared to standard chemotherapy, suggesting it might be a more tolerable treatment option. These findings suggest that combining high-dose intravenous vitamin C with PARP inhibitors could be a promising treatment for Ewing's sarcoma. More research is needed to confirm these results, but this approach shows potential for helping patients with advanced forms of this type of cancer. This is the first clinical report demonstrating the benefits of using high-dose vitamin C with PARP inhibitors and the study emphasizes the importance of exploring more treatment options for this aggressive type of cancer and suggests that further investigations into this combined approach could lead to more effective and tolerable treatments for Ewing's sarcoma.