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.

Differentially Expressed Genes Involved in Primary Resistance to Immunotherapy in Patients with Advanced-Stage Pulmonary Cancer.

In the last few years, nivolumab has become the standard of care for advanced-stage lung cancer patients. Unfortunately, up to 60% of patients do not respond to this treatment. In our study, we identified variations in gene expression related to primary resistance to immunotherapy. Bronchoscopy biopsies were obtained from advanced non-small cell lung cancer (NSCLC) patients previously characterized as responders or non-responders after nivolumab treatment. Ten tumor biopsies (from three responders and seven non-responders) were analyzed by the differential expression of 760 genes using the NanoString nCounter platform. These genes are known to be involved in the response to anti-PD1/PD-L1 therapy. All the patients were treated with nivolumab. Examining the dysregulated expression of 24 genes made it possible to predict the response to nivolumab treatment. Supervised analysis of the gene expression profile (GEP) revealed that responder patients had significantly higher levels of expression of CXCL11, NT5E, KLRK1, CD3G, GZMA, IDO1, LCK, CXCL9, GNLY, ITGAL, HLA-DRB1, CXCR6, IFNG, CD8A, ITK, B2M, HLA-B, and HLA-A than did non-responder patients. In contrast, PNOC, CD19, TP73, ARG1, FCRL2, and PTGER1 genes had significantly lower expression levels than non-responder patients. These findings were validated as predictive biomarkers in an independent series of 201 patients treated with nivolumab (22 hepatocellular carcinomas, 14 non-squamous cell lung carcinomas, 5 head and neck squamous cell carcinomas, 1 ureter/renal pelvis carcinoma, 120 melanomas, 4 bladder carcinomas, 31 renal cell carcinomas, and 4 squamous cell lung carcinomas). ROC curve analysis showed that the expression levels of ITK, NT5E, ITGAL, and CD8A were the best predictors of response to nivolumab. Further, 13/24 genes showed an adverse impact on overall survival (OS) in an independent, large series of patients with NSCLC (2166 cases). In summary, we found a strong association between the global GEP of advanced NSCLC and the response to nivolumab. The classification of NSCLC patients based on GEP enabled us to identify those patients who genuinely benefited from treatment with immune checkpoint inhibitors (ICIs). We also demonstrated that abnormal expression of most of the markers comprising the genomic signature has an adverse influence on OS, making them significant markers for therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these biomarkers.

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.

Immunohistochemical Assessment of the P53 Protein as a Predictor of Non-Small Cell Lung Cancer Response to Immunotherapy.

BACKGROUND: Determining predictive biomarkers for immune checkpoint inhibitors (ICIs) is a current challenge in oncology. Previous studies on non-small cell lung cancer (NSCLC) have shown how TP53 gene mutations are correlated with different responses to ICIs. Strong and diffuse immuno-expression of p53 by immunohistochemistry (IHC) is interpreted as a likely indicator of a TP53 gene mutation. We aimed to assess the p53 protein expression via IHC in NSCLC as a predictive biomarker of the response to ICIs. METHODS: This was a retrospective hospital-based study of patients with NSCLC treated with Nivolumab in the University Hospital of Salamanca. All diagnostic biopsies were studied via IHC (measuring p53 protein expression, peroxidase anti-peroxidase immunohistochemistry technique using Leica BOND Polymer development kits). Survival analysis was performed by subgroups of expression of p53 and other factors using the Kaplan-Meier estimator and Cox proportional-hazards model. RESULTS: Seventy-three patients were included (59 men and 14 women). The median age was 68 (44-84) years. Thirty-six biopsies were adenocarcinoma, 34 were squamous, and three were undifferentiated. In 41 biopsies (56.2%), the cellular expression of p53 was <5% (Group A), and in 32 biopsies (43.8%), the expression was ≥5% (Group B). In the general analysis, no differences were observed in overall survival (OS) (A: 12 months vs B: 20 months; p = 0.070) or progression-free survival (PFS) (A: 4 m vs B: 7 m; p = 0.064). Significant differences were observed in adenocarcinomas for both OS (A: 8 m vs B: median not reached; p = 0.002) and PFS (A: 3 m vs 8 m; p = 0.013). No differences in PFS and OS were observed in squamous cell carcinoma. Significant differences were observed in OS in the PD-L1 negative group (0% expression) (A: 13 m vs B: 39 m; p = 0.024), but not in PFS (A: 3 m vs B: 7 m; p = 0.70). No differences were observed in the PD-L1 positive group. CONCLUSIONS: A trend toward a greater response to ICIs was observed in the PFS and OS of patients with high expression of p53 by IHC (TP53 mutation), especially in the PD-L1 negative adenocarcinoma subgroup. These results will make it possible to make future modifications to the clinical guidelines of NSCLC according to the expression of p53.

Influence of DNA Mismatch Repair (MMR) System in Survival and Response to Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC): Retrospective Analysis.

Mutations in the mismatch repair (MMR) system predict the response to immune checkpoint inhibitors (ICIs) like colon or gastric cancer. However, the MMR system's involvement in non-small cell lung cancer (NSCLC) remains unknown. Addressing this issue will improve clinical guidelines in the case of mutations in the main genes of the MMR system (MLH1, MSH2, MSH6, and PMS2). This work retrospectively assessed the role that these gene mutations play in the response to and survival of ICIs in NSCLC. Patients with NSCLC treated with nivolumab as the second-line treatment in the University Hospital of Salamanca were enrolled in this study. Survival and response analyses were performed according to groups of MMR system gene expression (MMR expression present or deficiency) and other subgroups, such as toxicity. There was a statistically significant relationship between the best response obtained and the expression of the MMR system (p = 0.045). The presence of toxicity grade ≥ 3 was associated with the deficiency expression of MMR (dMMR/MSI-H) group (p = 0.022; odds ratio = 10.167, 95% confidence interval (CI) 1.669-61.919). A trend towards greater survival and response to ICIs was observed in NSCLC and dMMR. Assessing the genes in the MMR system involved in NSCLC is key to obtaining personalized immunotherapy treatments.

Acute esophageal necrosis induced by immune checkpoint inhibitors.

A 73-year-old male with a history of chronic obstructive pulmonary disease and stage IV lung adenocarcinoma, being treated with the PD-1 inhibitor nivolumab, presented to the Emergency Room with a two-day history of coffee ground emesis and melena. On examination, he was tachycardic (130 per minute) and hypotensive (95/55 mmHg). Laboratory studies revealed anemia (6.9 g/dl), leukocytosis and hyper-lactatemia (lactate 6.3 mmol/l). Esophagogastroduodenoscopy was performed which showed diffuse circumferential blackish, necrotic-appearing mucosa of the first third of the esophagus. These findings were consistent with a diagnosis of acute esophageal necrosis (AEN). A biopsy of the esophageal mucosa demonstrated fragments of necrotic tissue with predominant lymphocyte infiltration. He was managed with a strict restriction of oral intake, total parenteral nutrition, double-dose proton pump inhibitors and broad-spectrum antibiotics (piperacillin/tazobactam). Despite the measures adopted, the patient presented a progressive clinical deterioration and died of multiple organ failure 12 days after admission.

Ileal plasmablastic lymphoma presenting as intestinal occlusion in an HIV-negative patient with chronic lymphocytic leukemia.

We report the case of a 56-year-old male with a history of chronic lymphocytic leukemia (CLL), RAI 0 and Binet Stage A in therapeutic abstention, who presented to the Emergency Department with a two-week history of low abdominal pain and constipation. Physical examination was unremarkable except for mild diffuse abdominal pain on palpation. Laboratory studies revealed lymphocytosis and anemia (Hb: 10.2 g/dl). An abdominal computed tomography (CT) scan showed a partial small bowel obstruction secondary to a proximal ileal neoplasm.

Immune System Disorders, Cancer and Viral Infections: A New Treatment Opportunity for the Immune Checkpoint Inhibitors.

The relationship between viral infections and cancer is well known and has been established for decades. Multiple tumours are generated from alterations secondary to viral infections 2 resulting from a dysregulation of the immune system in many cases. Certain causal relationships, such as that between the Epstein-Barr virus (EBV) in nasopharyngeal cancer or hepatitis C and B viruses in hepatocarcinoma, have been clearly established, and their implications for the prognosis and treatment of solid tumours are currently unknown. Multiple studies have evaluated the role that these infections may have in the treatment of solid tumours using immunotherapy. A possible relationship between viral infections and an increased response to immune checkpoint inhibitors (ICIs) has been established at a theoretical level in solid neoplasms, such as EBV-positive cavum cancer and human papillomavirus (HPV)-positive and oropharyngeal cancer. These could yield a greater response associated with the activation of the immune system secondary to viral infection, the consequence of which is an increase in survival in these patients. That is why the objective of this review is to assess the different studies or clinical trials carried out in patients with solid tumours secondary to viral infections and their relationship to the response to ICIs.

Anakinra as a potential alternative in the treatment of severe acute respiratory infection associated with SARS-CoV-2 refractory to tocilizumab.

SARS-CoV-2 is a new RNA virus which causes coronavirus disease 2019 (COVID-19), declared a pandemic by the World Health Organization (WHO). It triggers an atypical pneumonia that can progress to multiorgan failure. COVID-19 can cause dysregulation of the immune system, triggering an inflammatory response, and simulate haemophagocytic lymphohistiocytosis. Several studies have proposed that anti-IL-6 receptor antibodies, such as tocilizumab, play an important role in the treatment of severe acute respiratory infection associated with SARS-CoV-2. However, the role of anti-IL-1 receptor antibodies, such as anakinra, in the treatment of COVID-19 has not been established. We present a case report of a 51-year-old man diagnosed with severe respiratory infection associated with SARS-CoV-2 that was refractory to antiviral and anti-IL-6 treatment, with a favourable clinical outcome and analytical improvement after treatment with anti-IL-1 (anakinra).