Neuroendocrine neoplasms are a diverse group of neoplasms that can occur in various areas throughout the body. Well-differentiated neuroendocrine tumors (NETs) most often arise in the gastrointestinal tract, termed gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Although GEP-NETs are still uncommon, their incidence and prevalence have been steadily increasing over the past decades. The primary treatment for GEP-NETs is surgery, which offers the best chance for a cure. However, because GEP-NETs are often slow-growing and do not cause symptoms until they have spread widely, curative surgery is not always an option. Significant advances have been made in systemic and locoregional treatment options in recent years, including peptide-receptor radionuclide therapy with α and β emitters, somatostatin analogs, chemotherapy, and targeted molecular therapies.

Brain tumors are the second most common malignancy in childhood. Around 15-20% of pediatric brain tumors occur in the brainstem. The most common type of brainstem tumor are diffuse tumors in the ventral pons, whereas focal tumors tend to arise from the midbrain, medulla, and dorsal pons. Glioma is the most common pathological entity. Contemporary management consists of surgery, radiotherapy, chemotherapy, and other adjuvant treatment. Surgical options range from biopsy to radical excision. Biopsy can be performed for diagnostic and prognostic purposes, or in the setting of clinical trials, mainly for diffuse intrinsic pontine gliomas. For focal tumors, surgeons need to carefully balance clinical outcomes against possible neurological sequelae in order to achieve maximal safe resection. Radiotherapy is essential for control of high-grade tumors and may be applied to residual or recurrent low-grade tumors. Proton therapy may provide similar efficacy and less neurotoxicity in comparison to conventional photon therapy. Oncological treatment continues to evolve from conventional chemotherapy to targeted therapy, immunotherapy, and other novel treatment methods and holds great potential as adjuvant therapy for pediatric brainstem tumors.

Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals. FGFR2 amplification is associated with poor prognosis in G/GEJ cancer, and immunohistochemistry of the FGFR2b protein isoform has proved effective for the detection of such FGFR2-dependent tumors. Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%. Challenges to EGFR- and MET-targeted therapies are being tackled with antibody-drug conjugates (ADCs) and bispecific antibodies. CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials. Antibody-drug conjugates and ADCs that target CLDN18.2 are also being pursued for treatment of such patients. Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities for precision oncology in patients with rare cancers. Therefore, we aimed to explore the factors associated with CGP testing utility in rare cancers and identify barriers to implementing precision oncology. Patients who underwent CGP testing at our institution between September 2019 and June 2021 were enrolled in this retrospective study. Based on their results, the patients received molecularly targeted drugs or immune checkpoint inhibitors. Univariate and multivariate analyses evaluated the association between patient characteristics and the proportion of patients receiving molecularly targeted drugs. Overall, 790 patients underwent CGP testing. Among them, 333 patients with rare cancers were identified, of whom 278 (83.5%) had actionable genomic alterations, 127 (38.1%) had druggable genomic alterations, and 25 (7.5%) received genomically matched therapy. The proportion of patients receiving molecularly targeted drugs was significantly higher among those with treatment options with evidence levels A-D (8.7%) than those without treatment options with evidence levels A-D (2.9%). A potential barrier to CGP testing utility in rare cancers is the limited number of molecularly targeted drugs with clinical evidence. We propose that CGP testing be performed in patients with rare cancers who have treatment options with evidence levels A-D to maximize CGP testing utility in real-world practice.

Breast cancer is the most frequent malignancy in women. However, in the middle and late stages, some people develop distant metastases, which considerably lower the quality of life and life expectancy. The brain is one of the sites where metastasis frequently happens. According to epidemiological research, brain metastases occur at a late stage in 30-50% of patients with HER2-positive breast cancer, resulting in a poor prognosis. Additionally, few treatments are available for HER2-positive brain metastatic breast cancer, and the mortality rate is remarkable owing to the complexity of the brain\'s anatomical structure and physiological function. In this review, we described the stages of the brain metastasis of breast cancer, the relationship between the microenvironment and metastatic cancer cells, and the unique molecular and cellular mechanisms. It involves cancer cells migrating, invading, and adhering to the brain; penetrating the blood-brain barrier; interacting with brain cells; and activating signal pathways once inside the brain. Finally, we reviewed current clinically used treatment approaches for brain metastasis in HER2-positive breast cancer; summarized the traditional treatment, targeted treatment, immunotherapy, and other treatment modalities; compared the benefits and drawbacks of each approach; discussed treatment challenges; and emphasized the importance of identifying potential targets to improve patient survival rates and comprehend brain metastasis in breast cancer.

Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non-small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow-on next-generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing.
Patients with untreated advanced (Stage IIIB-IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single-plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes.
Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre-defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0-41.1, p < 0.001 [one-sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5-17 days).
Rapid follow-on comprehensive testing of ctDNA should be considered prior to first-line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single-plex tissue testing.

Several novel agents (e.g., molecularly targeted drug, bispecific antibody, antibody-drug conjugate, chimeric antigen receptor T-cell therapy) have successively emerged in clinical practice and are occasionally used in allogeneic hematopoietic cell transplantation (allo-HCT) settings. These drugs are expected to reduce pretransplant tumors, lower the risk of relapse with posttransplant maintenance therapy, and consequently improve transplant outcomes. Additionally, some molecularly targeted drugs could be adapted to treat steroid-refractory acute and/or chronic graft-versus-host disease (GVHD), which remained the leading cause of nonrelapse mortality after allo-HCT. However, these agents develop an excessive immune reaction, including GVHD, or presented an increased risk of sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) as their \"off-target\" effects. Thus, this review aimed to summarize the risk assessment and management of post-posttransplant complications, focusing on GVHD and SOS/VOD, in the era of molecularly targeted therapy. Moreover, recent advances in GVHD or SOS/VOD prophylaxis and treatment using novel agents/devices are also discussed.

The management of advanced renal cell carcinoma has advanced tremendously over the past decade, but most patients still do not receive durable clinical benefit from current therapies. Renal cellcarcinoma is an immunogenic tumor, historically with conventional cytokine therapies, such as interleukin-2 and interferon-α, and contemporarily with the introduction of immune checkpoint inhibitors. Now the central therapeutic strategy in renal cell carcinoma is combination therapies including immunecheckpoint inhibitors. In this Review, we look back on the historical changes in systemic therapy for advanced renal cell carcinoma, and focus on the latest developments and prospects in this field.

BACKGROUND: The emergence of molecularly targeted agents (MTAs) has altered the treatment landscape for hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) /metastatic breast cancer (MBC). Multiple guidelines recommend molecularly targeted therapy as first-line treatment for HR+/HER2- ABC/MBC. However, optimal treatment for disease progression during MTA therapy remains undetermined. This study evaluated the suitability of different MTA types for this patient subgroup.
METHODS: In this retrospective study, we analyzed the electronic health records of 56 patients with HR+/HER2- ABC/MBC receiving treatment with palbociclib, abemaciclib, or everolimus in our center between April 2014 and June 2021.
RESULTS: Overall, 39, 14, and 35 regimens using palbociclib, abemaciclib, and everolimus, respectively, were identified. Three and 53 patients were premenopausal and postmenopausal, respectively. MTAs were included in the 1st-11th lines of treatment. Time to failure (TTF) was significantly different among the three MTAs. In contrast, TTF did not significantly differ among the 50 regimens that included CDK4/6 inhibitors, with/without prior mTOR inhibitor use, and the 35 regimens that included mTOR inhibitors, with/without prior CDK4/6 inhibitor use.
CONCLUSIONS: The sequential use of different MTA classes did not affect the TTF of another MTA. mTOR inhibitor + exemestane is a favorable treatment option after CDK4/6 inhibitor + hormone therapy, and CDK4/6 inhibitor + hormone therapy is suitable for patients previously treated with mTOR inhibitor + exemestane. Although this study was retrospective and conducted at a single center, the present findings are useful for treatment selection in clinical practice.

BACKGROUND: Human malignancies are composed of heterogeneous subpopulations of cancer cells with phenotypic and functional diversity. Among them, a unique subset of cancer stem cells (CSCs) has both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties. As such, CSCs are promising cellular targets for effective cancer therapy. At the molecular level, hyper-activation of multiple stemness regulatory signaling pathways and downstream transcription factors play critical roles in controlling CSCs establishment and maintenance. To regulate CSC properties, these stemness pathways are controlled by post-translational modifications including, but not limited to phosphorylation, acetylation, methylation, and ubiquitination.
CONCLUSIONS: In this review, we focus on E3 ubiquitin ligases and their roles and mechanisms in regulating essential hallmarks of CSCs, such as self-renewal, invasion and metastasis, metabolic reprogramming, immune evasion, and therapeutic resistance. Moreover, we discuss emerging therapeutic approaches to eliminate CSCs through targeting E3 ubiquitin ligases by chemical inhibitors and proteolysis-targeting chimera (PROTACs) which are currently under development at the discovery, preclinical, and clinical stages. Several outstanding issues such as roles for E3 ubiquitin ligases in heterogeneity and phenotypical/functional evolution of CSCs remain to be studied under pathologically and clinically relevant conditions. With the rapid application of functional genomic and proteomic approaches at single cell, spatiotemporal, and even single molecule levels, we anticipate that more specific and precise functions of E3 ubiquitin ligases will be delineated in dictating CSC properties. Rational design and proper translation of these mechanistic understandings may lead to novel therapeutic modalities for cancer procession medicine.