Paraneoplastic leukocytosis secondary to carcinosarcoma: a report of two cases and literature review.

BACKGROUND: Neutrophilia is an increase in the number of neutrophils over 7.5×103 /µL. An increase in leukocytes over 50×103 /µL is called a leukemoid reaction; and when it is associated with a solid tumor, it is considered a paraneoplastic syndrome called paraneoplastic leukemoid reaction (PLR). It is a very rare clinical condition and it is very unusual for it to be associated with carcinosarcoma. We present two cases of a leukemoid reaction observed in the Medical Oncology Department of the University Hospital of Salamanca between May and September 2023. The main objectives of our article are to describe the unusual appearance of paraneoplastic leukocytosis at the diagnosis of carcinosarcoma carcinosarcoma, explain in a detailed way its diagnostic procedure and to show the poor prognosis to which it is associated. CASE DESCRIPTION: In our presentation, we describe two similar cases: first of all, a 60-year-old woman without relevant medical history. She was referred by her primary physician to the Department of Internal Medicine in August 2023 with asthenia, lumbar pain, and weight loss of 12 kg of 3 months of evolution. The physical examination revealed a palpable hypogastric mass. An abdominal, pelvic, and thoracic computed tomography (CT) scan revealed a heterogenous solid mass with necrotic areas originating in the uterus. The anatomopathological diagnosis was carcinosarcoma. The patient showed a progressive worsening in her renal function associated with hyperviscosity secondary to hyperleukocytosis caused by 170×103 /µL neutrophils. In the second case we describe the diagnosis of a PLR secondary to a kidney carcinosarcoma. When the patient started chemotherapy, he presented 55.08×103 /µL leukocytes, 53.16×103 /µL neutrophils. Eight days after receiving chemotherapy, the patient was admitted as an emergency with oligoanuria and decreased consciousness. He presented creatinine 6.25 mg/dL, phosphate 12.4 mg/dL, leukocytes 1.05×103 /µL, and neutrophils 0.71×103 /µL. The clinical diagnosis was acute exacerbation of multifactorial mixed (renal and prerenal) chronic kidney disease associated with tumor lysis syndrome and grade 3 neutropenia. The patient presented a poor evolution, dying after 2 months. CONCLUSIONS: PLR is a severe paraneoplastic syndrome associated with different types of solid tumors. Its appearance at the time of diagnosis of a tumor implies a poor vital prognosis.

A rare case of hepatoid gastric adenocarcinoma.

Hepatoid gastric adenocarcinoma (HGA) is a rare subtype of gastric cancer. It usually presents with non-specific digestive tract symptoms and is usually diagnosed in advanced stages. It has radiological and histological similarities to hepatocarcinoma (HCC), and serum elevation of alpha-fetoprotein (AFP) is characteristic, as is positive staining for this marker on immunohistochemistry. Given the low incidence and poor prognosis of this type of tumour, it is essential to make a correct differential diagnosis and to initiate early surgical treatment in localised stages and systemic treatment in those where the disease is disseminated. In this context, we present the case of a GHA diagnosed this year in our centre.

Complications Secondary to the Use Of Sglt2 Inhibitors in Oncological Patients: A Series of 5 Cases.

Sodium-glucose cotransporter-2 (iSGLT2) inhibitors, which include dapagliflozin, canagliflozin and empagliflozin, are a class of drugs initially used in the oral treatment of diabetes, heart failure and renal failure. They target the reabsorption of glucose in the kidney. Although they bring benefit to patients with these conditions and in general produce few adverse effects, in some cases, iSGLT2 can cause serious adverse effects such as metabolic acidosis, and fungal or bacterial urinary infections. Oncology patients, who in general have a weak immune system and are usually treated with chemotherapy and/or immunotherapy, are more susceptible to this type of adverse events than other patients. For this reason, it is necessary to adequately select the patients eligible to receive this type of drug and evaluate the potential benefits for them. In this series of five cases, we present two cases of metabolic acidosis, two cases of bacterial urinary sepsis, and one case of fungal urinary sepsis that occurred in patients admitted to the Medical Oncology Department of the University Hospital of Salamanca in 2023. LEARNING POINTS: Adverse events associated with iSGLT2 can lead to serious complications in immunocompromised patients. There have been cases of prolonged admissions with high morbidity and mortality due to bacterial or fungal infections and metabolic acidosis, all of which are side effects derived from their use.In oncology patients, an adequate evaluation of the risk-benefit balance must be conducted before the introduction of new drugs.Studies should be conducted to assess the risk of serious adverse effects in oncology patients undergoing treatment with chemotherapy or immunotherapy.

Late recurrence of lobular breast carcinoma presented as gastric metastasis.

A 81-year-old woman with a history of mild chronic heart failure and invasive lobular breast carcinoma pT2N0M0 diagnosed in 2009 and treated by mastectomy, chemotherapy, radiotherapy and adjuvant endocrine therapy with letrozole until 2016. Since then the patient has been disease-free. She presented to the Emergency Room in April 2023 due to severe postprandial epigastric pain and a 7 kg weight loss in the last 3 months. Abdominal computed tomography was performed showing thickening of the gastric antrum and proximal duodenum walls, peritoneal implants and ascites that suggested primary gastric tumor or lymphoma as the first possibility. An endoscopic ultrasound was schedule, performing a biopsy of the gastric lesion and placing a Hot-Axios® stent. The sample showed infiltration by lobular breast carcinoma CK7 (+), CK20 (-), CDX2 (-), GATA3 (+) GCDFP15 (+) RE (+) RP (-) HER2 (-). Treatment with capecitabine was started, with which it continues currently.

Immune checkpoint inhibitors in non-small cell lung cancer: from current perspectives to future treatments-a systematic review.

Background: The introduction of immunotherapy in the treatment of non-small cell lung cancer (NSCLC) has resulted in a radical change in patients' treatment responses and survival rates. The increased percentage of long survivors, improved toxicity profiles compared to chemotherapy, and the possible applications for different NSCLC scenarios, have led to immune checkpoint inhibitors (ICIs) becoming the cornerstone of NSCLC treatment. Therefore, the objective of this review is to describe the current and future perspectives of NSCLC treatment. Methods: A systematic review according to the PRISMA criteria has been performed based on clinical trials with immunotherapy in NSCLC from the start of these treatments until June 2022. Results: The use of ICIs is widespread across both first- and second-line treatments with anti-PD-1, anti-PD-L1, and anti-CTLA-4 drugs. New indications for immunotherapy in NSCLC have focused on adjuvant (atezolizumab) and neoadjuvant (nivolumab), with ICIs now present in all stages of NSCLC treatment. Given the promising results seen in clinical trials, new ICIs [anti- lymphocyte activation gene-3 (LAG-3) or IDO1] currently under development, will soon be used as standard treatment for NSCLC. Conclusions: Immunotherapy is the mainstay of NSCLC treatment in all stages, including adjuvant, neoadjuvant and advanced tumors. The development of new molecules will revolutionize the treatment of NSCLC in the coming years.

Cardiotoxicity Secondary to Immune Checkpoint Inhibitors in the Elderly: Safety in Real-World Data.

INTRODUCTION: Immunotherapy represents a key pillar of cancer treatments, with high response rates and long survival. Its use is increasing, mainly at the expense of the geriatric population due to the ageing of this population. However, despite its benefit, its safety in certain areas such as cardiotoxicity is largely unknown. The aim of this study is to assess the safety of immunotherapy in elderly patients using real-world data. METHODS: This is an ambispective study of patients ≥ 70 years old with solid tumours who were treated with immunotherapy at the University Hospital of Salamanca. Cardiotoxicity was assessed using the CTCAEv5.0 criteria. RESULTS: In total, 195 patients were included (76.9% male and 23.1% female), with a mean age of 75 years [70-93]. The percentage of patients with cardiotoxicity was 1.54%; 1.35% of patients with previous heart disease were diagnosed with cardiotoxicity, and 1.65% of those without previous heart disease were diagnosed with cardiotoxicity. The median time from the initiation of treatment until the cardiac event was 45 days [14-96]. The most frequent toxicity was myocarditis in 66.7% of patients, followed by arrhythmias in 33.3% of patients. CONCLUSIONS: Immunotherapy is shown to be a safe treatment in elderly cancer patients in terms of cardiotoxicity. The event rate shows no difference between patients with or without cardiac comorbidity.

The relationship between PARP inhibitors with the relapse and leukemisation of lymphomas: a case report.

Background: Nowadays the poly-ADP ribose polymerase inhibitors (iPARPs) are the mainly treatment for the ovarian cancer and other solid tumours. However, given its recent use, long-term toxicity is still under study. The occurrence of acute leukaemias and myelodysplastic syndromes (MDS) secondarily to iPARPs is known (0.5-1%). Case Description: We present the case of a 78-year-old patient with a serous carcinoma of ovary in maintenance treatment with Niraparib after response to platinum. Along with the ovarian carcinoma the patient developed a diffuse large cell B lymphoma (DLBCL) five years ago, treated with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) with complete response. The patient was evaluated in the emergency due to constitutional syndrome, objectifying a bicytopenia (platelets 28,000/mcL, haemoglobin 9.6 g/dL). In the study of bicytopenia, a bone marrow infiltration by high-grade B lymphoma was diagnosed. Conclusions: The action of iPARPs on the selection of acquired mutations in clonal haematopoiesis maybe have been able to accelerate the process of relapse and leukemisation of the previous lymphoma. The association of treatment with iPARPs and the development of lymphomas is key for increasing knowledge of the safety profiles these drugs.

Efficacy and safety of PARP inhibitor in non-small cell lung cancer: a systematic review with meta-analysis.

BACKGROUND: Non-small cell lung cancer (NSCLC) has undergone a major change in the last decade in terms of survival and prognosis due to the introduction of new drugs in the last 10 years. One of the drugs with the most promising preliminary results in NSCLC are PARP inhibitors (iPARPs), whose clinical trials have very heterogeneous results. The use of iPARPs in NSCLC may lead to increased survival in several selected patients, and their use may become a standard in the coming years. However, there is currently controversy about the efficacy and safety of these drugs in NSCLC. Therefore, future studies are needed to evaluate their role in these tumours. The aim of this review is to evaluate the efficacy and safety of iPARPs in the treatment of NSCLC. METHODS: We performed a systematic review with meta-analysis using the different clinical trials (PubMed, COCHRANE, Science Direct, EMBASE and the clinical trial registry) that evaluated the efficacy and safety of iPARP in NSCLC by PRISMA criteria. The primary endpoint was to evaluate the efficacy of iPARPs in the treatment of NSCLC through overall and progression-free survival (OS and PFS). Two authors independently reviewed the articles and abstracts (A.O.H. and J.R.R.), with subsequent confirmation by a third independent reviewer (E.B.M.). The heterogeneity of the included studies in the meta-analysis was assessed by using the I2 statistic. RESULTS: A total of 14 articles were included for analysis (2,651 patients). A total of 1,503 patients were randomised in iPARP arms and 1,148 patients were included in control arms. Three clinical trials were conducted in localised or locally advanced NSCLC and 11 in advanced or metastatic stages. The global OS of the meta-analysis showed a hazard ratio (HR) of 0.85 [95% confidence interval (CI): 0.74-0.97] with a heterogeneity (I2) of 0% (P=0.84). PFS showed a HR of 0.93 (95% CI: 0.74-1.17) with an I2=51% (P=0.07). The overall adverse event rate (grade 1-5) was similar in both iPARP and placebo arms. CONCLUSIONS: iPARPs are a future promising in the treatment of NSCLC in terms of efficacy and safety. Proper patient selection [homologous recombination deficiency (HRD) positive] is key for future clinical trials. The studies conducted to date open a new approach for a novel treatment modality in NSCLC.

Autoimmune Haemolytic Anaemia Due to Cold Antibodies in a Renal Cancer Patient.

Autoimmune haemolytic anaemia (AIHA) is an acquired disorder in which antibodies are produced against self-erythrocyte antigens. We distinguish those produced by cold antibodies (IgM), which may be associated with lymphoproliferative syndromes, infectious diseases, other autoimmune phenomena, as well as drugs or solid tumours. We report a case of AIHA due to cold antibodies as a paraneoplastic syndrome (PNS) in a patient with metastatic renal carcinoma. A 67-year-old man with newly diagnosed stage IV renal carcinoma with hepatic, bone, and lymph node involvement was consulted for abdominal pain. Laboratory tests showed grade 4 anaemia (4.5 g/dL), with positive direct Coombs' test C3bC3d and agglutinated red blood cells in the blood smear. AIHA by cold antibodies was labelled as PNS in the context of the patient; therefore, blood transfusion as well as treatment of the underlying disease with tyrosine kinase inhibitors (sunitinib) were initiated, with subsequent clinical and analytical improvement. AIHA due to cold antibodies is a well-known PNS in lymphoproliferative disorders, although association with solid tumours, such as Kaposi's sarcoma and non-small-cell lung cancer have also been described in a small percentage. However, there are few reported cases of AIHA due to cold antibodies associated with renal carcinoma. Management with corticosteroids and immunosuppressors is effective in the majority of cases, but treatment of the underlying disease is critical.

Fulminant myocarditis in a patient with a lung adenocarcinoma after the third dose of modern COVID-19 vaccine. A case report and literature review.

Introduction COVID-19 disease has caused a global health and economic crisis. The introduction of the different COVID-19 vaccines has resulted in a significant decrease in the morbidity and mortality associated with this disease. Adverse effects have been reported, including cardiological ones such as myocarditis or pericarditis after administration. Likewise, tyrosine kinase inhibitor drugs such as osimertinib used in lung cancer patients with epidermal growth factor receptor (EGFR) mutation are associated with heart failure or prolongation of the QT interval. Case report 62-year-old woman diagnosed in September 2019 of lung adenocarcinoma stage IV with bilateral lung and lymph node involvement, carrier of an EGFR mutation (Ex19Del) on treatment with osimertinib. She attended emergency department for fever and hypotension 24 h after administration of the third dose of Moderna® COVID-19 vaccine in the context of acute myocarditis with evidence of severe left ventricular (LV) dysfunction in cardiogenic shock. She required vasoactive support, non-invasive mechanical ventilation, corticotherapy, immunoglobulins and subsequent ventricular support with Impella, with improvement of the clinical picture after 3 days. Cardiac magnetic resonance imaging (MRI) showed evidence of global myocardial oedema compatible with acute myocarditis. Coronary CT showed a lesion in the anterior descending coronary artery requiring revascularization. A few days later, she presented febrile symptoms with isolation of Staphylococcus aureus in the central line catheter and antibiotherapy with cloxacillin was started, with subsequent resolution of the infectious symptoms. Conclusion This is an exceptional and controversial case of fulminant myocarditis probably related to the Modern COVID-19 vaccine in a patient diagnosed with metastatic lung adenocarcinoma on treatment with osimertinib. An increasing number of cases of myocarditis and pericarditis have been reported following vaccination with COVID-19 mRNA vaccines. In addition, retrospective data have shown an increased risk of QT prolongation and heart failure in patients treated with tyrosine kinase inhibitors. Hence, the need for close monitoring of cardiac function during treatment of these patients. Future studies will be necessary to evaluate unknown adverse reactions of these vaccines and their possible interaction with other antineoplastic drugs.

Severe Hyponatremia Masking Central Diabetes Insipidus in a Patient with a Lung Adenocarcinoma.

Altered natremia is a common electrolyte disorder in clinical practice and a paraneoplastic manifestation. The syndrome of inappropriate antidiuretic hormone secretion is the first diagnostic suspicion in a patient with cancer and hyponatremia, although entities such as adrenal insufficiency primary or secondary to metastatic involvement must be taken into account. Likewise, immunorelated endrocrinopathies such as hypophysitis have been reported after the introduction of checkpoint inhibitors. A 46-year-old man diagnosed with metastatic adenocarcinoma of the lung with severe hyponatremia (111 mmol/L) consulted due to altered level of consciousness. The initial cranial CT scan did not reveal pituitary brain metastatic involvement; however, an MRI could not be performed due to the patient's clinical situation and subsequent exitus. The water restriction test confirmed the diagnostic suspicion of central diabetes insipidus. Medical treatment with desmopressin was started to avoid fluid depletion with improvement of natremia figures. It represents an exceptional case of central diabetes insipidus masked by severe hyponatremia in a patient with metastatic lung adenocarcinoma without initial evidence of pituitary metastatic involvement by CT imaging in treatment with nivolumab (anti-PD-1 agent). Secondary adrenal insufficiency due to pituitary metastatic involvement and endocrinologic toxicity immunorelated to the new checkpoint inhibitors should be considered as possible etiologic agents of central diabetes insipidus, even with hyponatremia.