Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy.

The advent of comprehensive genomic profiling using next-generation sequencing (NGS) has unveiled an abundance of potentially actionable genetic aberrations that have shaped our understanding of the cancer biology landscape. Isocitrate dehydrogenase (IDH) is an enzyme present in the cytosol (IDH1) and mitochondria (IDH2 and IDH3). In the mitochondrion, it catalyzes the irreversible oxidative decarboxylation of isocitrate, yielding the production of α-ketoglutarate and nicotinamide adenine dinucleotide phosphate (NADPH) as well as carbon dioxide (CO2). In the cytosol, IDH catalyzes the decarboxylation of isocitrate to α-ketoglutarate as well as the reverse reductive carboxylation of α-ketoglutarate to isocitrate. These rate-limiting steps in the tricarboxylic acid cycle, as well as the cytoplasmic response to oxidative stress, play key roles in gene regulation, cell differentiation, and tissue homeostasis. Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy.

Claudins in Cancer: A Current and Future Therapeutic Target.

Claudins are a family of 27 proteins that have an important role in the formation of tight junctions. They also have an important function in ion exchange, cell mobility, and the epithelial-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. Therapeutic targeting of claudins has been investigated to improve cancer outcomes. Recent evidence shows improved outcomes when combining monoclonal antibodies against claudin 18.2 with chemotherapy for patients with gastroesophageal junction cancer. Currently, chimeric antigen receptor T-cells targeting claudin 18 are under investigation. In this review, we will discuss the major functions of claudins, their distribution in the normal as well as cancerous tissues, and their effect in cancer metastasis, with a special focus on the therapeutic targeting of claudins to improve cancer outcomes.

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer.

In the realm of cancer therapeutics, targeting the hypoxia-inducible factor (HIF) pathway has emerged as a promising strategy. This study delves into the intricate web of HIF-associated mechanisms, exploring avenues for future anticancer therapies. Framing the investigation within the broader context of cancer progression and hypoxia response, this article aims to decipher the pivotal role played by HIF in regulating genes influencing angiogenesis, cell proliferation, and glucose metabolism. Employing diverse approaches such as HIF inhibitors, anti-angiogenic therapies, and hypoxia-activated prodrugs, the research methodologically intervenes at different nodes of the HIF pathway. Findings showcase the efficacy of agents like EZN-2968, Minnelide, and Acriflavine in modulating HIF-1α protein synthesis and destabilizing HIF-1, providing preliminary proof of HIF-1α mRNA modulation and antitumor activity. However, challenges, including toxicity, necessitate continued exploration and development, as exemplified by ongoing clinical trials. This article concludes by emphasizing the potential of targeted HIF therapies in disrupting cancer-related signaling pathways.

Mutations highly specific for secondary AML are associated with poor outcomes in ELN favorable risk NPM1-mutated AML.

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous malignancy with outcomes largely predicted by genetic abnormalities. Mutations of NPM1 are common in AML, occurring in ∼30% of cases, and generally considered a favorable risk factor. Mutations highly specific for secondary AML (sMut) have been shown to confer poor prognosis, but the overall impact of these mutations in the setting of favorable-risk AML defined by mutant NPM1 remains unclear. In this multicenter study of patients with AML (n = 233) with NPM1 mutation at diagnosis, we observed that patients with sMut had worse overall survival (OS) than those without sMut (15.3 vs 43.7 months; P = .002). Importantly, this finding persisted in the European LeukemiaNet (ELN) 2017-defined favorable risk subset (14.7 months vs not reached; P < .0001). Among patients who achieved NPM1 measurable residual disease (MRD) negativity, longer OS was observed in the entire cohort (P = .015) as well as in both the sMut subset (MRD negative: median OS (mOS) 73.9 months vs MRD positive: 12.3 months; P = .0170) and sMut ELN 2017-favorable subset (MRD negative: mOS 27.3 vs MRD positive: 10.5 months; P = .009). Co-occurrence of sMut and mutant NPM1 confers a poor prognosis in AML.

Pancreatic adverse events in patients treated with immune checkpoint inhibitors.

Background and Aim: The inhibition of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) has been a target for multiple drugs to enhance the T-cell antitumor activity. However, these immune checkpoint inhibitors (ICIs) come with a panel of immune-related adverse events (irAEs) that include mainly endocrine, skin, and gastrointestinal effects. We report seven cases of pancreatic irAEs in patients treated with ICIs at our institute. Methods: This is a case series; data was collected through chart review by 3 different data collectors and was analyzed separately by 2 physicians. Results: Of these seven cases, two had diabetic ketoacidosis (DKA), while five had pancreatitis diagnosed by a substantial rise in serum lipase. Pancreatitis was asymptomatic in two cases. A pancreatic biopsy in one case revealed type 2 autoimmune pancreatitis. The ICIs used included pembrolizumab, nivolumab, durvalumab, and avelumab. Treatment included steroids and holding the ICI therapy: three cases had complete resolution of pancreatitis while two cases required either a prolonged taper or a second course of prednisone for recurrence of pancreatitis. On the other hand, the DKA cases were treated with withdrawal of the ICI and starting insulin with no steroid therapy. Conclusions: Pancreatitis and DKA are rare adverse events of ICIs that can be controlled by holding the ICI with or without starting steroids. Rechallenging the patient with the same ICI is possible in selected cases.

Hypereosinophilic Syndrome, Multiorgan Involvement and Response to Imatinib.

Hypereosinophilic syndrome (HES) is an uncommon syndrome characterized by peripheral blood eosinophils count of more than 1,500/mm3 with associated tissue damage. It can be either primary or secondary, for example, due to parasitic infections or inflammation. We present a case of a 49-year-old Asian female with recurrent hospital admissions for cholecystitis, gastritis, urinary cystitis, and pancreatitis. Her peripheral blood count showed excessive eosinophils 15,600-19,000/mm3 on different occasions. Pathology of her gallbladder and her gastric biopsies showed eosinophilic infiltration. Her bone marrow biopsy showed a normocellular marrow with active trilineage hematopoiesis, eosinophilia, mild megakaryocytic hyperplasia with a few atypical forms, and mild T-cell lymphocytosis. Flow cytometry showed no evidence of acute leukemia, or T-cell or B-cell lymphoproliferative disorder. On fluorescent in-situ hybridization (FISH), myeloproliferative neoplasms (MPN) testing was negative for platelet-derived growth factor receptor-alpha (PDGFRA), platelet-derived growth factor receptor-beta (PDGFRB), and fibroblast growth factor receptor-1 (FGFR1) rearrangement. Despite not having the FIP1L1-PDGFRA (factor interacting with PAPOLA and CPSF1-platelet-derived growth factor receptor, alpha polypeptide) gene fusion, our patient responded to the treatment with a significant decrease in her absolute eosinophils count and resolution of her symptoms.

Reversible Endoscopic Medial Maxillectomy: Endonasal Approach to Diseases of the Maxillary Sinus

Abstract Introduction The endoscopic access has reduced the morbidity associated with external approaches in diseases of themaxillary sinus. A reversible endoscopic medialmaxillectomy (REMM) is presented as an alternative for treatment of benign maxillary diseases. Objective To describe the REMM technique and report four cases of patients with benign maxillary sinus conditions treated through this approach. Methods The present study was divided into two parts: anatomical and case series. Two cadaveric dissections confirmed the feasibility of the REMMapproach. The same technique was performed on four consecutive patients with benign maxillary sinus disease. Results The cadaveric dissections confirmed wide exposure to the maxillary cavity, preserving the anatomy of the maxillary sinus. In the patient series, one patient presented with an antrochoanal polyp, one had a silent sinus syndrome, one had a chronic maxillary sinusitis secondary to a gunshot, and the last one had an inverted papilloma in the maxillary sinus. In all of the cases, the REMM approach provided excellent access and adequate resection, as well as preservation of the inferior turbinate, nasolacrimal duct, and lateral wall of the nose (including its osteomucosal component). Finally, all of the patients had an uneventful postoperative course. Conclusion The REMM technique is an excellent surgical approach to benign conditions of the maxillary sinus. It has few limitations and appears to be associated with less morbidity than conventional techniques.

Reversible Endoscopic Medial Maxillectomy: Endonasal Approach to Diseases of the Maxillary Sinus.

Introduction The endoscopic access has reduced the morbidity associated with external approaches in diseases of the maxillary sinus. A reversible endoscopic medial maxillectomy (REMM) is presented as an alternative for treatment of benign maxillary diseases. Objective To describe the REMM technique and report four cases of patients with benign maxillary sinus conditions treated through this approach. Methods The present study was divided into two parts: anatomical and case series. Two cadaveric dissections confirmed the feasibility of the REMM approach. The same technique was performed on four consecutive patients with benign maxillary sinus disease. Results The cadaveric dissections confirmed wide exposure to the maxillary cavity, preserving the anatomy of the maxillary sinus. In the patient series, one patient presented with an antrochoanal polyp, one had a silent sinus syndrome, one had a chronic maxillary sinusitis secondary to a gunshot, and the last one had an inverted papilloma in the maxillary sinus. In all of the cases, the REMM approach provided excellent access and adequate resection, as well as preservation of the inferior turbinate, nasolacrimal duct, and lateral wall of the nose (including its osteomucosal component). Finally, all of the patients had an uneventful postoperative course. Conclusion The REMM technique is an excellent surgical approach to benign conditions of the maxillary sinus. It has few limitations and appears to be associated with less morbidity than conventional techniques.

Testicular schistosomiasis as differential diagnosis for testicular nodules: a case report.

Despite its infrequent occurrence, testicular schistosomiasis forming pseudo-tumors can be considered in the differential diagnosis of testicular tumors, especially in areas where the parasitic disease is endemic. In this report, we present a case of testicular schistosomiasis caused by Schistosoma mansoni and mimicking a testicular neoplasm. We describe the patterns of a testicular nodule on ultrasonography and magnetic resonance images in a 46-year-old man. The nodule was removed after a pre-operative diagnosis of a non-malignant lesion. Histology demonstrated granulomas with epithelioid macrophages and eosinophils around S. mansoni eggs within a fibrous tissue that formed a nodular structure.

Testicular schistosomiasis as differential diagnosis for testicular nodules: a case report

Despite its infrequent occurrence, testicular schistosomiasis forming pseudo-tumors can be considered in the differential diagnosis of testicular tumors, especially in areas where the parasitic disease is endemic. In this report, we present a case of testicular schistosomiasis caused by Schistosoma mansoni and mimicking a testicular neoplasm. We describe the patterns of a testicular nodule on ultrasonography and magnetic resonance images in a 46-year-old man. The nodule was removed after a pre-operative diagnosis of a non-malignant lesion. Histology demonstrated granulomas with epithelioid macrophages and eosinophils around S. mansoni eggs within a fibrous tissue that formed a nodular structure.