Springer Science and Business Media LLC

Although radical cystectomy is considered the gold standard approach for patients with muscle-invasive bladder cancer, tri-modal therapy (TMT) is a well-tolerated and efficacious alternative to radical cystectomy that is underutilized in inoperable patients and rarely offered to cystectomy candidates in the USA. Retrospective data suggest similar outcomes between radical cystectomy and TMT after adjusting for patient selection and other confounding factors. Nearly 70–80% of patients can keep their native bladder with favorable post-treatment quality of life metrics. Current trials are investigating novel combination strategies including immune checkpoint inhibition along with chemoradiation or radiation. Emerging techniques for improved patient selection and risk stratification include incorporating MP-MRI, and novel biomarkers such as inflammatory, stromal, and DNA damage response gene signatures may guide patient selection and expand the landscape of bladder preservation options available to patients in the future.

Genetic assessment is crucial to address the correct treatment for advanced medullary thyroid cancer (MTC). Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and vandetanib are good first line options, even vandetanib prescription is currently limited to RET mutated patients. Selective RET inhibitors such as pralsetinib could be a preferred upfront treatment in case of RET mutated MTC presenting common or gatekeeper RET mutations (e.g. M918T; V804L/M). Selpercatinib, otherwise, can be prescribed as the second line after disease progression to mTKIs. The best option for subsequent lines is to consider inclusion in clinical trials or alternatively other mTKIs such as sunitinib, sorafenib, lenvatinib, or pazopanib could be evaluated. New perspectives include next-generation RET inhibitors able to overcome resistance mechanisms responsible for disease progression to standard mTKIs and RET inhibitors, and immunotherapy for MTC presenting with high tumor mutational burden.

At this time, there are no FDA-approved immune therapies for glioblastoma (GBM) despite many unique therapies currently in clinical trials. GBM is a highly immunosuppressive tumor and there are limitations to a safe immune response in the central nervous system. To date, there have been several failures of phase 3 immune therapy clinical trials in GBM. These trials have targeted single components of an antitumor immune response. Learning from these failures, the future of immunotherapy for GBM appears most hopeful for combination of immune therapies to overcome the profound immunosuppression of this disease. Understanding biomarkers for appropriate patient selection as well as tumor progression are necessary for implementation of immunotherapy for GBM

Gastric cancer is prevalent globally, particularly in Asian countries such as Japan and Korea. While the prevalence of gastric cancer is not nearly as high in the United States (U.S.) as in Asia, the treatment armamentarium differs widely between regions. The role of surgery for gastric cancer in the U.S. has changed drastically over the last decade. While the natural history of gastric cancer seen in the U.S. markedly differs from that seen in Asia, the U.S. experience with endoscopic and minimally invasive techniques is beginning to parallel those seen in Japan and Korea. Minimally invasive surgery has truly come into the forefront of our surgical armamentarium, and its role, along with robotic and endoscopic approaches, remains to be defined as standard of care. At present, minimally invasive approaches appear to offer oncologically equivalent outcomes compared with standard open gastrectomy when performed by experienced surgeons. Extended lymphadenectomy does not appear to offer benefit with improved survival in our patient population, although sufficient lymph node sampling is imperative for adequate staging. Despite aggressive approaches to surgical resection for cure, the U.S. population tends to present with more advanced disease and have a worse prognosis than our Asian counterparts. Palliation with resection and possibly stent placement should be offered for improved quality of life in late-stage disease.

Patients with clinical stage III melanoma, defined as palpable lymph nodes with or without in-transit metastases, have poor prognosis even with recent advances with targeted and checkpoint inhibitor therapy in the adjuvant setting. Neoadjuvant therapy for clinical stage III melanoma is an attractive treatment paradigm as patient outcomes may be improved by earlier introduction to systemic therapy. Additionally, preoperative therapy that shrinks disease has the potential to improve surgical morbidity. Neoadjuvant therapy also provides for pathologic response assessment which can serve as a way to stratify patient outcomes and subsequent disease relapse risk. Early trials of neoadjuvant immunotherapy are yielding promising results, with high rates of pathologic complete response (pCR) and improved relapse-free survival rates. Ipilimumab, nivolumab with or without ipilimumab, and pembrolizumab have been investigated in the neoadjuvant setting. A meta-analysis has shown a 1-year relapse-free survival rate of over 80% with neoadjuvant immunotherapy. Importantly, pooled data also shows that pCR strongly correlates with outcomes. Early phase trials have also highlighted the importance of dosing of neoadjuvant therapy to appropriately balance response and immune related toxicities, which can be severe. The combination of ipilimumab 1 mg/kg and nivolumab 3 mg/kg has been identified as an optimal regimen for further study. Translational studies have highlighted the ability of neoadjuvant immunotherapy to expand tumor-specific T cells in both the tumor microenvironment and peripheral blood. At this time, surgical resection and adjuvant therapy remains standard of care for clinical stage III melanoma; however, appropriate patients should be considered for ongoing neoadjuvant clinical trials.

Juvenile myelomonocytic leukemia is an aggressive neoplasia of early childhood. Only allogeneic stem cell transplantation (SCT) offers a long-term cure. In the absence of an HLA-matched family donor, early SCT from an unrelated donor will be the treatment of choice for most children. With clear evidence of a graft-versus-leukemia effect and a high post-transplant relapse rate, outcome of SCT will depend, in part, on the management of immunosuppression during the procedure. The impact of pretransplant cytoreductive treatment, such as intensive chemotherapy, splenectomy, or 13-cis retinoic acid, is unclear. Hypersensitivity for granulocyte-macrophage colony-stimulating factor and pathologic activation of the Ras/MAPK pathway play an important role in the pathophysiology of juvenile myelomonocytic leukemia and will provide the opportunity for several novel therapy approaches.

The management of thymic tumours is a paradigm of multidisciplinary collaboration. Chemotherapy may be administered part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy, or as an exclusive treatment if local treatment is not achievable. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Given the limited activity of cytotoxic agents in the advanced, refractory setting, novel and innovative agents are needed. The better understanding of thymic carcinogenesis may provide a rationale in this setting. Targeted agents approved for other solid tumors that have shown activity in thymic tumors include mTOR, KIT inhibitors, as well as somatostatin analogues. Anti-angiogenic agent sunitinib may be considered a standard in advanced lines of treatment. Ongoing studies are assessing the opportunity of targeting emerging targets, including PI3K, CDK, and immune checkpoint PD-1/PD-L1.