Venetoclax and Hypomethylating Agent Combination in Myeloid Malignancies: Mechanisms of Synergy and Challenges of Resistance.

There has been a widespread adoption of hypomethylating agents (HMA: 5-Azacytidine (5-Aza)/decitabine) and venetoclax (Ven) for the treatment of acute myeloid leukemia (AML); however, the mechanisms behind the combination's synergy are poorly understood. Monotherapy often encounters resistance, leading to suboptimal outcomes; however, the combination of HMA and Ven has demonstrated substantial improvements in treatment responses. This study elucidates multiple synergistic pathways contributing to this enhanced therapeutic effect. Key mechanisms include HMA-mediated downregulation of anti-apoptotic proteins, notably MCL-1, and the priming of cells for Ven through the induction of genes encoding pro-apoptotic proteins such as Noxa. Moreover, Ven induces sensitization to HMA, induces overcoming resistance by inhibiting the DHODH enzyme, and disrupts antioxidant pathways (Nrf2) induced by HMA. The combination further disrupts oxidative phosphorylation in leukemia stem cells, amplifying the therapeutic impact. Remarkably, clinical studies have revealed a favorable response, particularly in patients harboring specific mutations, such as IDH1/2, NPM1, CEBPA, or ASXL1. This prompts future studies to explore the nuanced underpinnings of these synergistic mechanisms in AML patients with these molecular signatures.

Role of sacituzumab govitecan in solid tumors.

OBJECTIVE: To evaluate the antibody-drug conjugate- sacituzumab govitecan, its pharmacological properties, toxicity, data supporting efficacy against a wide variety of solid tumors beyond breast cancer, and potential future uses. DATA SOURCES: Articles in MEDLINE/PubMed databases and the National Institutes of Health Clinical Trials Registry (http://www. clinicaltrials.gov) between January 1, 2015, and July 1, 2021 using MeSH terms sacituzumab govitecan(- hziy) and solid tumors were reviewed. DATA SUMMARY: Antibody-drug conjugates (ADC's) are a subclass of emerging cancer therapeutics which combines chemotherapy with targeted antibodies. Sacituzumab govitecan (SG) is a novel antibody drug conjugate that has recently been approved by the Food and Drug Administration (FDA) in adult patients for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. The approval of sacituzumab govitecan provides a new option for solid tumors that need to be further explored. In this review article, we discussed the pharmacokinetics, pharmacodynamics, safety profile of sacituzumab govitecan and various ongoing clinical trials on sacituzumab govitecan. CONCLUSION: Sacituzumab is a significant advancement made in cancer therapy. SG has showed significantly improved Health-related quality of life (HRQoL) in addition to prolonged progression free survival and Over all survival in addition to maintaining a good safety profile. Multiple clinical trials on SG are ongoing to evaluate the potential use of SG as neoadjuvant therapy in triple negative breast cancer, as an Adjuvant therapy, in combination with immunotherapy, and also for various solid tumors.

A successful initiation of treatment of Hodgkin's lymphoma with adriamycin-bleomycin-vinblastine-dacarbazine dose reduction in a patient with fulminant hepatic failure and co-infection with human immunodeficiency virus and hepatitis B.

INTRODUCTION: Hodgkin lymphoma is a highly curable lymphoproliferative malignancy with an overall relative survival rate of 87.4%. It is characterized by multinucleated Reed-Sternberg cells which are mostly derived from B cells in the germinal center. CASE REPORT: We present a case of a 40-year-old gentleman with acquired immunodeficiency syndrome who presented with Stage 4b Hodgkin lymphoma complicated with fulminant hepatic failure and direct hyperbilirubinemia. The initial presentation of Hodgkin lymphoma as cholestatic jaundice is extremely rare. MANAGEMENT AND OUTCOME: Though the survival rate with chemotherapy is high, the fulminant hepatic failure made the situation challenging with the use of chemotherapeutic regimens that require hepatic excretion. He received dose reduced adriamycin-bleomycin-vinblastine-dacarbazine regimen [doxorubicin 12.5 mg (6.75 mg/m2), bleomycin 18 units (10 units/m2), vinblastine 3 mg (1.5 mg/m2), dacarbazine 380 mg (190 mg/m2)] as well as bictegravir/emtricitabine/tenofovir alafenamide since admission for treatment of human immunodeficiency virus and hepatitis B. He started responding with the first cycle of dose reduced adriamycin-bleomycin-vinblastine-dacarbazine regimen with bilirubin levels trended down and normalized as well as his clinical condition improved. He received the full dose of adriamycin-bleomycin-vinblastine-dacarbazine on day 15. DISCUSSION: Our case report emphasizes that the early usage of dose reduced adriamycin-bleomycin-vinblastine-dacarbazine regimen can restore hepatic function and can achieve improvement in hepatic function allowing the delivery of full-dose chemotherapy.

Role of innate immunological/inflammatory pathways in myelodysplastic syndromes and AML: a narrative review.

Dysregulation of the innate immune system and inflammatory-related pathways has been implicated in hematopoietic defects in the bone marrow microenvironment and associated with aging, clonal hematopoiesis, myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). As the innate immune system and its pathway regulators have been implicated in the pathogenesis of MDS/AML, novel approaches targeting these pathways have shown promising results. Variability in expression of Toll like receptors (TLRs), abnormal levels of MyD88 and subsequent activation of NF-κß, dysregulated IL1-receptor associated kinases (IRAK), alterations in TGF-ß and SMAD signaling, high levels of S100A8/A9 have all been implicated in pathogenesis of MDS/AML. In this review we not only discuss the interplay of various innate immune pathways in MDS pathogenesis but also focus on potential therapeutic targets from recent clinical trials including the use of monoclonal antibodies and small molecule inhibitors against these pathways.

Splenic Marginal Zone Lymphoma With Histological Transformation to Hodgkin's Lymphoma.

Marginal zone lymphoma (MZL) is a rare, slow-growing/indolent B cell lymphoid neoplasm accounting for 10.5% to 11.8% of all B cell lymphomas. MZL originates from the mature B lymphocytes, which are usually present in the marginal zone of the lymphoid follicle. Histological transformation (HT) is defined as sheets of large cells arising in an indolent lymphoma with morphological and immunophenotypic changes suggestive of a high-grade lymphoma such as Hodgkin's lymphoma, diffuse large B cell lymphoma (DLBCL), or Burkitt lymphoma. The median time of transformation ranges from one year to 15 years following the initial diagnosis of MZL. Studies reported that the deletion of TP53 and 7q and mutations in NOTCH2 are commonly associated with HT in MZL. This case report outlines the rare happening of an MZL transformation into a nodular subtype of Hodgkin's lymphoma in a 56-year-old female, which prompted further investigations and a different therapeutic approach. By reporting this case, we emphasize that HT changes the natural history and significantly affects the overall survival of patients with MZL. Hence, it is necessary to get a core needle or excisional biopsy whenever there is a clinical suspicion of HT in MZL for early diagnosis and a better therapeutic approach.

A rare case of metastatic pancreatic adenocarcinoma presenting as a pulmonary embolism from nonbacterial thrombotic endocarditis.

Nonbacterial thrombotic endocarditis (NBTE) also called, "Marantic endocarditis" occurs due to an underlying hypercoagulable state causing tissue damage and upregulation of the coagulation cascade, with noninfective vegetation formation on heart valves. Mitral and aortic valves are most commonly involved. NBTE is rare, with an incidence of 1.6%, with 65 cases identified during a 10-year autopsy analysis. The most common malignancies associated with NBTE include gynecological cancers, lung cancer, gastric cancer, and pancreatic cancers with adenocarcinoma histology being the greatest risk. Herein, we present a rare case of a 55-year-old male who presented with acute hypoxic respiratory failure secondary to pulmonary embolism due to nonbacterial thrombotic endocarditis. He was found to have advanced pancreatic adenocarcinoma on further investigation of the 2.2 cm hypodense cystic mass in the distal pancreatic body and tail, and complex liver masses which were incidentally found on computed tomography angiography (CTA) of the chest. This is a rare phenomenon and clinicians have to consider the hypercoagulable state associated with cancers, particularly pancreatic adenocarcinoma, and the risk of NBTE.

Isolated Myeloid Sarcoma: A Diagnostic Dilemma.

Myeloid sarcoma (MS)/granulocytic sarcoma/myeloblastoma/chloroma is a rare extramedullary proliferation of blast cells of one or more myeloid lineages along with the destruction of the normal architecture of adjacent tissue. Isolated MS is a rare entity with an incidence of 0.7 out of 1 million children and 2 out of 1 million adults. Varied clinical presentation, the rarity of the diagnosis, inadequate immunophenotyping, and lack of available literature makes the disease difficult to manage. Here, we report a case of MS in a 44-year-old male with an initial presentation of testicular mass without bone marrow involvement, causing diagnostic challenges. In this case report, we discuss the pathogenesis, diagnostic challenges, and therapeutic options of MS.

Epstein-Barr Virus-Positive Primary Diffuse Large B-cell Lymphoma of the Colon in a Patient With Human Immunodeficiency Virus.

Colorectal lymphomas of primary origin are rare neoplasms accounting for 3% of all lymphomas involving the gastrointestinal (GI) tract, and of that 3%, 0.1-0.5% involve the colorectal region. Among the types of non-Hodgkin's lymphomas involving the GI tract, diffuse large B-cell lymphoma (DLBCL) is the most common type. While extranodal involvement of DLBCL in the GI is common, DLBCL of the colon with Epstein-Barr virus positivity is a rare entity with only a few cases reported in the literature. Here, we present a rare case of a 53-year-old female with human immunodeficiency virus (HIV) who presented with generalized abdominal pain, weight loss, night sweats, and fevers. A computed tomography scan of the abdomen and pelvis showed a mass on the right side of the colon with associated retroperitoneal and right inguinal lymphadenopathy. She later underwent a colonoscopy with a biopsy. Histopathology showed DLBCL of the ascending colon and chemotherapy was initiated.

An Unexpected Transformation: Malignant Spindle Cell Carcinoma Developed From Primary Basal Cell Carcinoma.

Spindle cell carcinoma (SpCC)/sarcomatoid carcinoma is a biphasic tumor with molecular and histopathological properties of both epithelial and mesenchymal tumors. SpCC usually occurs either in sun-exposed areas like the head, neck, upper extremities, and chest or in the areas of skin with prior radiation exposure or in immuno-suppressed individuals. Cutaneous SpCC is a very rare disease, with only a handful of reported cases so far. SpCC differs from conventional squamous cell carcinoma (SCC) with dermal infiltration of atypical keratinocytes as single cells with hyperchromatic eosinophilic cytoplasm and elongated, pleomorphic nuclei with multiple nucleoli, in contrast to cohesive nests or islands in SCC. The objective of this study is to complete a review of the current literature and present a rare manifestation of malignant SpCC which developed from a localized basal cell carcinoma following excision and radiation therapy (RT) in a 79-year-old female. We plan to elucidate the importance of a timely and accurate diagnosis of this disease in order to maximize treatment options and improve survival outcomes.

A Rare Case of Aggressive Metastatic Laryngeal Chondrosarcoma Presenting as Bilateral Necrotizing Pneumonia.

Laryngeal chondrosarcomas are rare tumors that account for only 0.2% of malignant tumors of the larynx. Approximately 80% of these tumors are low grade and well differentiated and are associated with a good long-term prognosis. Herein, we report a case of a 77-year-old male presenting with acute hypoxic respiratory failure that required intubation and mechanical ventilation. Chest CT showed multiple pulmonary nodules and cavities. He then required a tracheostomy, and a soft tissue mass in the subglottic mass was discovered. A laryngoscopy-guided excisional biopsy of the mass was performed. Histopathological examination confirmed the diagnosis of laryngeal chondrosarcoma. Clinicians should consider metastatic laryngeal chondrosarcoma as a differential diagnosis for lung cavities. Overall, we believe this to be the first case of aggressive laryngeal chondrosarcoma with mediastinal and pulmonary metastasis mimicking necrotizing pneumonia.

A Case of Chronic Myelomonocytic Leukemia Unmasked After Receiving J&J COVID-19 Vaccine.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disease that comes under the overlap syndrome (myelodysplastic and myeloproliferative disorders). CMML is characterized by peripheral blood monocytosis and bone marrow dysplasia. The pathogenesis of CMML is poorly understood. Although cytogenetic and molecular abnormalities are common, they are not diagnostic. Herein, we present a rare case of CMML after receiving the J&J COVID-19 vaccine with the rare association of limited scleroderma. Based on the Surveillance, Epidemiology, and End Result (SEER) cancer statistics review 2014-2018, the five-year age-adjusted incidence rate of CMML in both sexes is 0.5/100,000, with greater incidence in males (0.7/100,000) compared to females (0.3/100,000). We emphasize the fact that, based on the previous studies reported, the association of scleroderma with CMML is very rare. Our patient had concomitant CMML and scleroderma, which were unmasked after the patient received the COVID-19 vaccine. Our case suggests the possibility of developing CMML after receiving the J&J COVID vaccine. Immunization has always been a life-saving intervention in history. As the world is foreseeing getting the COVID-19 vaccine, it is essential to report all the possible adverse events for safety monitoring. Physicians should be aware of this unusual complication of the vaccine, and more cases are needed to confirm the association between them.

Restoration of the Original Inhabitants: A Systematic Review on Fecal Microbiota Transplantation for Graft-Versus-Host Disease.

A compelling intervention to maintain healthy gut microbiota in graft-versus-host-disease (GVHD) is fecal microbial transplantation (FMT). To examine its role in GVHD, we conducted a systemic literature search using multiple electronic databases. Upon pooling of data, 79 patients from six studies and five case reports were included. Complete remission (CR) occurred in 55.9% of patients, and partial remission (PR) occurred in 26.5% of patients (82.4% overall response rate). A limited number of patients had treatment-related mortality (TRM), while few showed mild gastrointestinal (GI)-related and non-GI adverse effects. None of the studies directly examined the role of FMT in the prevention of GVHD. In conclusion, FMT seems to be a safe and effective strategy for the management of GVHD based on the current evidence. Due to the small number of patients evaluated and the absence of randomized data, one cannot portray FMT as a standard of care yet; however, the low toxicity along with the clinical improvement justifies this modality to be tested in a randomized fashion.

A Case Series of SARS-CoV-2 and Influenza Co-infection.

The novel coronavirus 2019, a disease associated with SARS-CoV-2 infections has resulted in significant morbidity and mortality across the globe. In the United States, influenza has been one of the leading causes of hospitalization during the winter season. To date, the co-infection of SARS-CoV-2 and influenza virus has created a unique challenge for healthcare workers, especially during the cold season. Both viruses have similar clinical presentation and transmission characteristics. Many reports are available for either SARS-CoV-2 and influenza individual infections, but limited data are available for the co-infection. Herein, we present a case series of five cases of SARS-CoV-2 and influenza co-infection as well as their clinical characteristics, laboratory findings, management, and outcome.

A Case of Co-occurrence of COVID-19 and Group A Streptococcal Pharyngitis.

Coronavirus disease 2019 (COVID-19) has swept the world with over hundred million of cases and millions of deaths. Upper respiratory tract symptoms including acute pharyngitis are the common symptoms of COVID-19, with a reported incidence of about 5%-17.4%. Group A Streptococcus (GAS) pharyngitis is a common cause of bacterial pharyngitis, with highest incidence between age 5 and 15, and it can still occur in adults with peak incidence at age 40. Herein, we report a case of co-occurrence of GAS and COVID-19 in a middle-aged man who presented with fever, sore throat, cough, and runny nose. To the best of our knowledge, we are the first to report this unique co-occurrence. Our case report aimed to raise the awareness among physician particularly in ambulatory and emergency department of not to have a singular focus on COVID-19 and forget to screen patient with acute pharyngitis for GAS.

A Rare Case of Sarcomatoid Variant of Mixed Germ Cell Tumor of the Testis Presenting With Malignant Hypercalcemia and Tumor Lysis Syndrome.

Hypercalcemia of malignancy is relatively common in several cancers. However, in testicular cancer, paraneoplastic hypercalcemia is uncommon. We describe the first case of severe tumor lysis syndrome associated with hypercalcemia from bone metastasis of testicular origin. Classically, tumor lysis syndrome is associated with hypocalcemia. This was a diagnostic and therapeutic challenge.

Ipsilateral Zoster Ophthalmicus Post COVID-19 Vaccine in Healthy Young Adults.

Herpes zoster ophthalmicus (HZO), which is an ophthalmological emergency, accounts for 10%-20% of all Herpes zoster (HZ) cases. HZ infection in COVID-19 vaccinated individuals who are immunocompetent can be attributed to vaccine-induced immunomodulation allowing the varicella-zoster virus (VZV) to escape from the dorsal root ganglia. Another theory is similar to immune reconstitution syndrome (IRS). HZ infection in a young immunocompetent individual is a rare entity. As per our literature review, only four cases have been reported thus far. We are reporting two cases of two young individuals with no known risk factors who developed ipsilateral HZO after receiving the COVID-19 vaccination. The increasing incidence of HZ cases post COVID-19 vaccine indicates that this is not a mere coincidence. Awareness must be created among physicians, as well as the general population, for early recognition and early antiviral usage, which can halt the progression of the disease and thus prevent debilitating complications.

Bleeding Diathesis in Multiple Myeloma: A Rare Presentation of a Dreadful Emergency With Management Nightmare.

Multiple myeloma is a neoplastic disorder of plasma cells. An abnormal coagulation profile, though commonly seen in multiple myeloma, can rarely manifest as life-threatening hemorrhagic complications. Bleeding tendencies in multiple myeloma can be explained by a variety of mechanisms such as dysfibrinogenemia, paraprotein-induced platelet dysfunction, shortened platelet survival, damage to the vascular endothelium, and acquired von-Willebrand syndrome. Herein, we report a 61-year-old female who presented with the signs and symptoms of hemorrhagic shock with multiple myeloma, which remained refractory to a massive transfusion protocol. Her condition stabilized when she was started on dexamethasone and antifibrinolytic infusion targeting acquired dysfibrinogenemia. To the best of our knowledge, hemorrhagic shock secondary to dysfibrinogenemia is an unusual phenomenon in multiple myeloma.

A Rare Case Report of Persistent Hiccups as an Atypical Presentation of COVID-19.

Sudden, involuntary spasm of the diaphragm associated with closure of the glottis will lead to a hiccup sound. Brief episodes of hiccups are often self-limiting and may be physiologically encountered in everyday life. However, prolonged attacks of hiccups are associated with significant morbidity. Herein, we present a rare and interesting case of coronavirus disease 2019 (COVID-19) induced persistent hiccups in a 61-year-old gentleman with no signs or symptoms of gastric pathology. As the patient required less oxygen supplementation, with inflammatory markers down-trending, his hiccups improved. The timeline of the symptom presentation and his response to treatment highly suggested that his hiccups were associated with COVID-19 infection. To the best of our knowledge, there are only two cases of persistent hiccups secondary to COVID-19 that have been reported thus far. Our case will add to the existing literature and highlight the potential association of COVID-19 with hiccups.