Revealing Insights: A Comprehensive Overview of Gastric Outlet Obstruction Management, with Special Emphasis on EUS-Guided Gastroenterostomy.

Gastric outlet obstruction (GOO) poses a common and challenging clinical scenario, characterized by mechanical blockage in the pylorus, distal stomach, or duodenum, resulting in symptoms such as nausea, vomiting, abdominal pain, and early satiety. Its diverse etiology encompasses both benign and malignant disorders. The spectrum of current treatment modalities extends from conservative approaches to more invasive interventions, incorporating procedures like surgical gastroenterostomy (SGE), self-expandable metallic stents (SEMSs) placement, and the advanced technique of endoscopic ultrasound-guided gastroenterostomy (EUS-GE). While surgery is favored for longer life expectancy, stents are preferred in malignant gastric outlet stenosis. The novel EUS-GE technique, employing a lumen-apposing self-expandable metal stent (LAMS), combines the immediate efficacy of stents with the enduring benefits of gastroenterostomy. Despite its promising outcomes, EUS-GE is a technically demanding procedure requiring specialized expertise and facilities.

Reaching the Diagnosis of Checkpoint Inhibitor-Induced Diabetes Mellitus in Different Clinical Scenarios: A Real-World Application of Updated Diagnostic Criteria.

BACKGROUND: Checkpoint inhibitor (CPI)-associated diabetes mellitus (CPI-DM) is a rare immune-related adverse event (irAE) that presents with variable clinical manifestations. Data about its pathogenesis have not yet been adequately studied. METHODS: Applying the recently updated diagnostic criteria from the American Diabetes Association, we retrospectively reviewed the medical records of all CPI-treated patients referred to our endocrinological unit for managing their endocrine irAEs and analyzed the incidence of CPI-DM, its clinical characteristics, and its management. RESULTS: Among the 326 CPI-treated patients with endocrine irAEs, 4 patients met the updated criteria for the diagnosis of CPI-DM, representing 1.22% of all endocrine irAEs in our cohort. These four patients presented with distinct clinical scenarios regarding the irAE onset, the underlying malignancy, the administered CPI regimen, and the type of circulating autoantibodies. CONCLUSION: The variable presentation of CPI-DM and the non-standard sensitivity of the presence of the type 1 DM traditional autoantibodies highlight the need for distinct guidelines and increased awareness of its diagnosis and management.

New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3.

Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.

Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice.

PURPOSE: The pan-cancer presence of microsatellite instability (MSI)-positive tumors demonstrates its clinical utility as an agnostic biomarker for identifying immunotherapy-eligible patients. Additionally, MSI is a hallmark of Lynch syndrome (LS), the most prevalent cancer susceptibility syndrome among patients with colorectal and endometrial cancer. Therefore, MSI-high results should inform germline genetic testing for cancer-predisposing genes. However, in clinical practice, such analysis is frequently disregarded. METHODS: A next-generation sequencing (NGS)-based technique was used for MSI analysis in 4,553 patients with various tumor types. Upon request, somatic BRAF gene analysis was conducted. In addition, hereditary testing of cancer-associated genes was performed in MSI-high cases using a capture-based NGS protocol. MLH1 promoter methylation analysis was conducted retrospectively in patients with colorectal and endometrial cancer to further investigate the origin of MSI at the tumor level. RESULTS: The MSI positivity rate for the entire cohort was 5.27%. Endometrial, gastric, colorectal, urinary tract, and prostate cancers showed the highest proportion of MSI-high cases (15.69%, 8.54%, 7.40%, 4.55%, and 3.19%, respectively). A minority of 45 patients (22.73%) among the MSI-high cases underwent germline testing to determine whether the mismatch repair pathway deficiency was inherited. 24.44% of those who performed the genetic test carried a pathogenic variant in an LS-associated gene. Three MSI-high individuals had non-LS gene alterations, including BRCA1, BRCA2, and CDKN2A pathogenic variants, indicating the presence of non-LS-associated gene alterations among MSI-high patients. CONCLUSION: Although MSI analysis is routinely performed in clinical practice, as many as 77% of MSI-high patients do not undergo LS genetic testing, despite international guidelines strongly recommending it. BRAF and MLH1 methylation analysis could shed light on the somatic origin of MSI in 42.50% of the MSI-high patients; however, MLH1 analysis is barely ever requested in clinical practice.

Only 32.3% of Breast Cancer Families with Pathogenic Variants in Cancer Genes Utilized Cascade Genetic Testing.

BACKGROUND: Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. METHODS: Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. RESULTS: In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, respectively. Although CFT was recommended to all families, only 117 families (32.3%) agreed to proceed with genetic testing. Among the first-degree relatives who underwent CFT, 70.3% were female, and 108 of 121 (89.3%) were cancer free. Additionally, 42.7%, 36.7%, and 20.6% were offspring, siblings, and parents of the subject, respectively. Our data suggest that CFT was mostly undertaken (104/117, 88.8%) in families with positive findings in high-risk genes. CONCLUSIONS: Cascade family testing can be a powerful tool for primary cancer prevention by identifying at-risk family members. It is of utmost importance to implement genetic counseling approaches leading to increased awareness and communication of genetic testing results.

Copy Number Variations (CNVs) Account for 10.8% of Pathogenic Variants in Patients Referred for Hereditary Cancer Testing.

BACKGROUND/AIM: Germline copy number variation (CNV) is a type of genetic variant that predisposes significantly to inherited cancers. Today, next-generation sequencing (NGS) technologies have contributed to multi gene panel analysis in clinical practice. MATERIALS AND METHODS: A total of 2,163 patients were screened for cancer susceptibility, using a solution-based capture method. A panel of 52 genes was used for targeted NGS. The capture-based approach enables computational analysis of CNVs from NGS data. We studied the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and of the non-commercial tool panelcn.MOPS. Additionally, we tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA). RESULTS: Pathogenic/likely pathogenic variants (P/LP) were identified in 464 samples (21.5%). CNV accounts for 10.8% (50/464) of pathogenic variants, referring to deletion/duplication of one or more exons of a gene. In patients with breast and ovarian cancer, CNVs accounted for 10.2% and 6.8% of pathogenic variants, respectively. In colorectal cancer patients, CNV accounted for 28.6% of pathogenic/likely pathogenic variants. CONCLUSION: In silico CNV detection tools provide a viable and cost-effective method to identify CNVs from NGS experiments. CNVs constitute a substantial percentage of P/LP variants, since they represent up to one of every ten P/LP findings identified by NGS multigene analysis; therefore, their evaluation is highly recommended to improve the diagnostic yield of hereditary cancer analysis.

Spontaneous tumor lysis syndrome in patients with solid tumors: a scoping review of the literature.

No systematic synthesis of all cases of spontaneous tumor lysis syndrome (STLS) in adult patients with solid tumors is available to date. Herein, we aim to recognize specific STLS characteristics and parameters related to a worse prognosis. We conducted a systematic search for randomized controlled trials, cohorts, case-control studies, and case reports. The primary endpoints were death and the need for renal replacement therapy (RRT) due to STLS. We estimated crude odds ratios (ORs) with 95% confidence intervals (95%CI) via univariate binary logistic regression. We included one cohort of 9 patients and 66 case reports of 71 patients [lung cancer 15(21.1%)]. Regarding the case reports, most patients [61(87.1%)] had metastatic disease [liver 46(75.4%)], developed acute kidney injury [59(83.1%)], needed RRT [25(37.3%)], and died due to STLS [36(55.4%)]. Metastatic disease, especially in the liver [p = 0.035; OR (95%CI): 9.88 (1.09, 89.29)] or lungs [p = 0.024; 14.00 (1.37, 142.89)], was significantly associated with STLS-related death compared to no metastasis. Cases resulting in death had a significantly higher probability of receiving rasburicase monotherapy than receiving no urate-lowering agents [p = 0.034; 5.33 (1.09, 26.61)], or the allopurinol-rasburicase combination [p = 0.023; 7.47 (1.40, 39.84)]. Patients receiving allopurinol were less likely to need RRT compared to those not receiving it or those receiving rasburicase. In conclusion, current anecdotal evidence demonstrated that metastatic disease, especially in the liver and lungs, may be associated with STLS-related death compared to no metastatic status. Careful surveillance of high-risk cases within larger studies is essential to identify markers predicting morbidity or mortality.

EUS-Guided Diagnosis of Gastric Subepithelial Lesions, What Is New?

Gastric subepithelial lesions (SELs) are intramural lesions that arise underneath the gastric mucosa. SELs can be benign, but can also be malignant or have malignant potential. Therefore, correct diagnosis is crucial. Endosonography has been established as the diagnostic gold standard. Although the identification of some of these lesions can be carried out immediately, solely based on their echo characteristics, for certain lesions histological examination is necessary. Sometimes histology can be inconclusive, especially for smaller lesions. Therefore, new methods have been developed in recent years to assist decision making, such as contrast enhanced endosonography, EUS elastography, and artificial intelligence systems. In this narrative review we provide a complete overview of the gastric SELs and summarize the new data of the last ten years concerning the diagnostic advances of endosonography on this topic.

Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment.

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody-drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response.

Clinical and Oncological Impact of the Toll-like Receptor-3 and -4 in Esophageal and Gastro-esophageal Junction Adenocarcinoma.

BACKGROUND/AIM: Esophageal and gastro-esophageal junction cancer is a major cause of cancer-related mortality, with poor prognosis. Toll-like receptors (TLRs) play a significant role in the innate immune system; their increased expression has been associated with esophageal adenocarcinoma. This study aimed to determine the association between TLR-3 and TLR-4 expression with clinical and oncological outcomes of patients that underwent esophagectomy for cancer. PATIENTS AND METHODS: This is a retrospective analysis of prospectively collected data from consecutive patients within a 2-year period. Primary endpoints of the study were the assessment of the expression of TLR-3 and TLR-4 in primary tumors as well as in metastatic lymph nodes. Secondary endpoints were the correlation of TLR-3 and TLR-4 values with the clinical, pathological, and oncological outcomes. RESULTS: A significantly higher expression of TLR-3 and TLR-4 in primary tumors and metastatic-lymph nodes was observed. There was a significant association between TLR-3 expression and T-stage, as well as TLR-4 expression and grade of differentiation in the primary site. Additionally, metastatic-lymph node TLR-4 expression was significantly correlated with N-stage. A strong correlation between TLR-4 expression and overall or progression-free survival rates was detected. CONCLUSION: This study found a significantly increased TLR expression in malignant tissue/metastatic lymph nodes, as well as a significant positive correlation between TLRs and worse clinical outcomes. TLRs have a pivotal role in the inflammation pathway in the esophagus and during esophageal carcinogenesis. This study highlights the need for further investigation into TLR-mediated signaling pathways and their potential role as diagnostic and therapeutic targets.

Impact of Minimally Invasive Intrathoracic Hand-sewn Esophago-gastric Anastomosis in Esophagectomy for Cancer.

BACKGROUND/AIM: Ivor Lewis esophagectomy is considered the gold standard approach for the treatment of distal esophageal and gastro-esophageal junction Siewert I-II tumors. Minimally invasive esophagectomy has provided improved outcomes compared to the open approach, offering reduced morbidity, and improved clinical and oncological outcomes. This is the largest study so far reporting the impact of hand-sewn esophago-gastric anastomosis in the prone position, during the 2-stage totally minimally invasive esophagectomy. PATIENTS AND METHODS: A retrospective analysis of prospectively collected data regarding consecutive patients with distal-esophageal and gastroesophageal junction Siewert I-II tumors was conducted. All patients underwent 2-stage totally minimally invasive esophagectomy with thoracoscopic manual esophago-gastric anastomosis in the prone position. Clinical and oncological outcomes were examined and presented. RESULTS: One hundred and fifty consecutive patients were included in the study during a period of five years. Median operative time was 320 minutes, while median time for the construction of anastomosis was 45 minutes. We had no conversions to open esophagectomy. Anastomotic leakage was observed in 2% of the patients; anastomotic stricture rate reached up to 7.33%. Respiratory complications were seen in 18% and cardiac complications in 6.66% of the patients, respectively. Thirty-day mortality and 90-day mortality rates were 1.33% and 2.66%, accordingly. CONCLUSION: Intrathoracic hand-sewn esophago-gastric anastomosis in the prone position during totally minimally invasive esophagectomy has provided favorable outcomes in our cohort of patients, offering significantly reduced anastomotic-related complications, compared to other standardized techniques. Further prospective comparative studies are needed, to better interpret and amplify our results, that may lead to a paradigm shift regarding the preferred method of reconstruction from esophageal surgeons.

Cytomegalovirus Infections in Patients Treated With Immune Checkpoint Inhibitors for Solid Malignancies.

Cytomegalovirus (CMV) infection/disease has been repeatedly reported in patients treated with immune-checkpoint inhibitors (ICIs) and most commonly involves patients with relapsed/refractory (R/R) immune-related adverse events (irAEs). In the current study, we present a patient with melanoma who developed CMV gastritis during treatment with pembrolizumab in the absence of irAEs and without previous or current immunosuppression. Moreover, we review the literature regarding CMV infection/disease in patients treated with ICIs for solid malignancies. We present the currently available data on the pathogenesis, clinical characteristics, endoscopic findings, and histologic features and highlight the potential differences among cases complicating R/R irAEs versus those occurring in patients who are immunosuppression naive. Finally, we discuss the currently available data regarding potential useful diagnostic tools as well as the management of these patients.

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancers, either in adjuvant or metastatic settings. Regarding safety, endocrine adverse events (AEs) are some of the most common AEs in ICI-treated patients, with thyroid dysfunction and hypophysitis being the most frequent disorders. However, there are also some rare and very rare immune-related (ir) endocrine complications (incidence between ≥1/10,000 to <1/1000 and <1/10,000, respectively, according to the established classification) that have been reported in isolated case reports, with limited data about their management. In this systematic review, we summarize all published cases with primary adrenal insufficiency, central diabetes insipidus, primary hypoparathyroidism, lipodystrophy, osteoporosis, hypergonadotrophic hypogonadism, or Cushing disease and discuss their diagnostic and therapeutic approaches as well as the current knowledge on their pathophysiology. In these ICI-treated cancer patients, the presentation of symptoms unrelated to their underlying malignancy has led to further diagnostic tests, including hormonal profile and functional assays which subsequently confirmed endocrinopathy, while the assessment of autoantibodies was rarely available. In most of these cases, the exact pathogenesis remained unknown, and the endocrine dysfunction was permanent, requiring lifelong supplementation. Although endrocine irAEs are rare, physicians must be aware of these irAEs to recognize them on time and treat them appropriately.

Diabetes insipidus: A rare endocrine complication of immune check point inhibitors: A case report and literature review.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 (PD-1), anti-programmed cell death protein ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies, are novel therapeutic agents widely used in numerous malignancies. They are known to cause multiple immune-related endocrine adverse events (irAEs); however, anterior pituitary hypophysitis with secondary hypopituitarism is the most frequently reported irAE, especially in patients receiving anti-CTLA-4 treatment. By contrast, posterior pituitary involvement, such as central diabetes insipidus (CDI), is relatively rare and only few case reports have been published. The present report describes the case of a 53-year-old woman with metastatic melanoma treated with nivolumab an anti-PD-L1 monoclonal antibody. At 6 months after the initiation of nivolumab treatment, the patient was diagnosed with deficiency of the corticotrope and thyreotrope axes and in the following 2 months the patient was diagnosed with progressive development of polyuria-polydipsia syndrome. The diagnosis of partial CDI was retained based on plasma and urinary osmolalities, the water deprivation test and baseline copeptin levels as well as on the absence of the bright spot in the posterior pituitary in magnetic resonance imaging. Systematic research of the literature revealed a total of 13 cases reports (including 14 patients) presenting with CDI treated with monotherapy with CTLA-4 (n=5) or PD-1/PD-L1 Abs (n=6) or combined treatments (n=3). The improved understanding of the mechanisms of ICI action along with their extensive use should contribute to the early recognition of irAE symptoms. We hypothesized that clinicians should be aware of this clinical entity and its symptoms and treat it appropriately.

Mechanisms of resistance to immune checkpoint inhibitors in melanoma: What we have to overcome?

Marching into the second decade after the approval of ipilimumab, it is clear that immune checkpoint inhibitors (ICIs) have dramatically improved the prognosis of melanoma. Although the current edge is already high, with a 4-year OS% of 77.9% for adjuvant nivolumab and a 6.5-year OS% of 49% for nivolumab/ipilimumab combination in the metastatic setting, a high proportion of patients with advanced melanoma have no benefit from immunotherapy, or experience an early disease relapse/progression in the first few months of treatment, surviving much less. Reasonably, the primary and acquired resistance to ICIs has entered into the focus of clinical research with positive (e.g., nivolumab and relatlimab combination) and negative feedbacks (e.g., nivolumab with pegylated-IL2, pembrolizumab with T-VEC, nivolumab with epacadostat, and combinatorial triplets of BRAF/MEK inhibitors with immunotherapy). Many intrinsic (intracellular or intra-tumoral) but also extrinsic (systematic) events are considered to be involved in the development of this resistance to ICIs: i) melanoma cell immunogenicity (e.g., tumor mutational burden, antigen-processing machinery and immunogenic cell death, neoantigen affinity and heterogeneity, genomic instability, melanoma dedifferentiation and phenotypic plasticity), ii) immune cell trafficking, T-cell priming, and cell death evasion, iii) melanoma neovascularization, cellular TME components(e.g., Tregs, CAFs) and extracellular matrix modulation, iv) metabolic antagonism in the TME(highly glycolytic status, upregulated CD39/CD73/adenosine pathway, iDO-dependent tryptophan catabolism), v) T-cell exhaustion and negative immune checkpoints, and vi) gut microbiota. In the present overview, we discuss how these parameters compromise the efficacy of ICIs, with an emphasis on the lessons learned by the latest melanoma studies; and in parallel, we describe the main ongoing approaches to overcome the resistance to immunotherapy. Summarizing this information will improve the understanding of how these complicated dynamics contribute to immune escape and will help to develop more effective strategies on how anti-tumor immunity can surpass existing barriers of ICI-refractory melanoma.

Digging into the NGS Information from a Large-Scale South European Population with Metastatic/Unresectable Pancreatic Ductal Adenocarcinoma: A Real-World Genomic Depiction.

Despite ongoing oncological advances, pancreatic ductal adenocarcinoma (PDAC) continues to have an extremely poor prognosis with limited targeted and immunotherapeutic options. Its genomic background has not been fully characterized yet in large-scale populations all over the world. Methods: Replicating a recent study from China, we collected tissue samples from consecutive Greek patients with pathologically-confirmed metastatic/unresectable PDAC and retrospectively investigated their genomic landscape using next generation sequencing (NGS). Findings: From a cohort of 409 patients, NGS analysis was successfully achieved in 400 cases (56.50% males, median age: 61.8 years). Consistent with a previous study, KRAS was the most frequently mutated gene in 81.50% of tested samples, followed by TP53 (50.75%), CDKN2 (8%), and SMAD4 (7.50%). BRCA1/2 variants with on-label indications were detected in 2%, and 87.50% carried a variant associated with off-label treatment (KRAS, ERBB2, STK11, or HRR-genes), while 3.5% of the alterations had unknown/preliminary-studied actionability (TP53/CDKN2A). Most of HRR-alterations were in intermediate- and low-risk genes (CHEK2, RAD50, RAD51, ATM, FANCA, FANCL, FANCC, BAP1), with controversial actionability: 8% harbored a somatic non-BRCA1/2 alteration, 6 cases had a high-risk alteration (PALB2, RAD51C), and one co-presented a PALB2/BRCA2 alteration. Elevated LOH was associated with HRR-mutated status and TP53 mutations while lowered LOH was associated with KRAS alterations. Including TMB/MSI data, the potential benefit from an NGS-oriented treatment was increased from 1.91% to 13.74% (high-MSI: 0.3%, TMB > 10 muts/MB: 12.78%). TMB was slightly increased in females (4.75 vs. 4.46 muts/MB) and in individuals with age > 60 (4.77 vs. 4.40 muts/MB). About 28.41% showed PD-L1 > 1% either in tumor or immune cells, 15.75% expressed PD-L1 ≥ 10%, and only 1.18% had PD-L1 ≥ 50%. This is the largest depiction of real-world genomic characteristics of European patients with PDAC, which offers some useful clinical and research insights.

Beyond Immunotherapy: Seizing the Momentum of Oncolytic Viruses in the Ideal Platform of Skin Cancers.

Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice.

Latest evidence on immune checkpoint inhibitors in metastatic colorectal cancer: A 2022 update.

The long-term remissions induced by immune-checkpoint inhibitors (ICIs) in many types of cancers have opened up the possibility of a broader use of immunotherapy in less immunogenic but genetically heterogeneous tumours. Regarding metastatic colorectal cancer (mCRC), in first-line setting, pembrolizumab has been approved as preferred option and nivolumab, alone or in combination with ipilimumab as alternative option for patients with mismatch-repair-deficient and microsatellite instability-high (dMMR/MSI-H) disease, independently of their eligibility for intensive chemotherapy. In subsequent lines, both these immunotherapeutic regimens (e.g., pembrolizumab and nivolumab+/-ipilimumab) as well as dostarlimab-gxly are currently recommended for patients with dMMR/MSI-H chemo-resistant mCRC who have not previously received an ICI. Beginning from the rationale behind the immune-mediated interplay in the dMMR/MSI-H bowel microenvironment, we provide here an update on the evolution status of all available, approved or not, ICIs in mCRC, describing their efficacy and toxicity profile with an emphasis on the pivotal trials supporting current colorectal indications. For each ICI agent, the results from combinations under investigation, particularly for those being upgraded in clinical phasing, the perspectives but also the limitations of main ongoing trials are thoroughly discussed. In the close future, upcoming data are expected to confirm the clinical benefit of ICIs and to further expand their role in mCRC.

Histone deacetylase inhibitors as a novel therapeutic approach for pheochromocytomas and paragangliomas.

Epigenetic mechanisms, such as DNA methylation and histone modifications (e.g., acetylation and deacetylation), are strongly implicated in the carcinogenesis of various malignancies. During transcription, the expression and functionality of coding gene products are altered following the histone acetylation and deacetylation. These processes are regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. HDAC inhibitors (HDACis) have been developed as promising therapeutic agents, to limit exposure to traditional and toxic chemotherapies and offer more alternatives for some specific malignant diseases with limited options. Mechanistically, these agents affect many intracellular pathways, including cell cycle arrest, apoptosis and differentiation, and their mechanism of action mainly depends on the type of cancer. Currently, five HDACis have been approved for the treatment of several hematological malignancies (e.g., T-cell lymphoma subtypes and multiple myeloma); while, many of them are tested for further therapeutic indications in solid tumors (e.g., colorectal, thyroid, breast, lung and pancreatic cancer). Herein, we review the literature and gather all available evidence, from in vitro and in vivo data to clinical trial results, that recognizes the antitumor activity of HDACis on pheochromocytomas and paragangliomas; and supports their clinical implementation in the treatment of these rare neuroendocrine tumors at metastatic setting.

Neuromuscular Complications of Targeted Anticancer Agents: Can Tyrosine Kinase Inhibitors Induce Myasthenia Gravis? Getting Answers From a Case Report up to a Systematic Review.

More than 40 tyrosine kinase inhibitors (TKIs) have received hematological or oncological indications over the past 20 years, following the approval of imatinib, and many others are currently being tested in clinical and preclinical level. Beyond their common toxicities, no certain agent from this large class of molecularly targeted therapies was strongly associated with "off-target" impairment of neuromuscular transmission, and although myasthenia gravis (MG) is a well-characterized autoimmune disorder, only few sporadic events proven by serologically detected causative autoantibodies and/or by positive electrophysiological tests are reported in the literature. Herein, we present the first case of anti-MUSK (+) MG in a woman with metastatic BRAF-mutant melanoma after long-term treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Triggered by this report, a systematic literature review was conducted, summarizing all other cancer cases that developed MG, after exposure to any type of targeted agent and regardless of the underlying malignancy. All available data on the clinical diagnosis, the potential of administered TKIs to induce a seropositive myasthenic syndrome, the immune and non-immune-mediated pathogenesis of postsynaptic damage, and the challenging management of this neuromuscular toxicity were collected and discussed. In the presented case, MG was confirmed by both autoantibodies and nerve-conduction tests, while its reactivation after TKIs rechallenge supports a more than coincidental association. The following review identified 12 cancer cases with TKI-related MG in six case reports and one case series. In most of them, the myasthenia diagnosis was challenging, since the clinical symptomatology of fatigable weakness was not corroborating with consistent laboratory and electrophysiological findings. In fact, anti-AchR titers were positive in five and anti-MuSK only in the abovementioned individual. The symptomatology corresponded to TKI discontinuation and standard treatment with pyridostigmine and prednisolone; intravenous immunoglobulin was added only in three, and two required mechanical ventilation. In an era where TKIs will be prescribed more frequently for various malignancies, even in combinations with immune-checkpoint inhibitors, this report synthesizes their risk for neuromuscular complications and increases the clinicians' awareness in order to extend the on-treatment and overall survival of TKI-treated cancer patients.