Sex dimorphism and cancer immunotherapy: May pregnancy solve the puzzle?

In the immunoncology era, growing evidence has shown a clear sex dimorphism in antitumor immune response with a potential impact on outcomes upon immunecheckpoint blockade (ICI) in patients with cancer. Sex dimorphism could affect tumor microenvironment composition and systemic anticancer immunity; however, the modifications induced by sex are heterogeneous. From a clinical perspective, six metanalyses have explored the role of sex in cancer patients receiving ICI with conflicting results. Environmental and reproductive factors may further jeopardize the sex-related heterogeneity in anticancer immune response. In particular, pregnancy is characterized by orchestrated changes in the immune system, some of which could be long lasting. A persistence of memory T-cells with a potential fetal-antigen specificity has been reported both in human and mice, suggesting that a previous pregnancy may positively impact cancer development or response to ICI, in case of fetal-antigen sharing from tumor cells. On the other hand, a previous pregnancy may also be associated with a regulatory memory characterized by increased tolerance and anergy towards cancer-fetal common antigens. Finally, fetal-maternal microchimerism could represent an additional source of chronic exposure to fetal antigens and may have important immunological implications on cancer development and ICI activity. So far, the role of pregnancy dimorphism (nulliparous vs parous) in women and the impact of pregnancy-related variables remain largely underexplored in cancer patients. In this review, we summarize the evidence regarding sex and pregnancy dimorphism in the context of immune response and anticancer immunotherapy and advocate the importance of analyzing pregnancy variables on ICIs clinical trials.

Intratumoral Cellular Heterogeneity: Implications for Drug Resistance in Patients with Non-Small Cell Lung Cancer.

Tailored therapies based on the identification of molecular targets currently represent a well-established therapeutic scenario in the treatment of non-small cell lung cancer (NSCLC) patients. However, while aiming to improve patients' response to therapy, development of resistance is frequently observed in daily clinical practice. Intratumoral heterogeneity is a frequent event in NSCLC, responsible for several critical issues in patients' diagnosis and treatment. Advances in single-cell sequencing technologies have allowed in-depth profiling of tumors and attributed intratumoral heterogeneity to genetic, epigenetic, and protein modification driven diversities within cancer cell populations. This review highlights current research on the biological role of tumor heterogeneity and its impact on the development of acquired resistance in NSCLC patients.

History of Extensive Disease Small Cell Lung Cancer Treatment: Time to Raise the Bar? A Review of the Literature.

Several trials have tried for decades to improve the outcome of extensive disease small cell lung cancer (ED-SCLC) through attempts to modify the standard treatments. Nevertheless, platinum/etoposide combination and topotecan have remained respectively the first and the second line standard treatments for the last 40 years. With the advent of immunotherapy, this scenario has finally changed. Our review aims to provide an overview of the primary studies on the actual therapeutic strategies available for ED-SCLC patients, and to highlight emerging evidence supporting the use of immunotherapy in SCLC patients.

Metabolism and Immune Modulation in Patients with Solid Tumors: Systematic Review of Preclinical and Clinical Evidence.

Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available immunotherapies. It is therefore of paramount importance to identify the prognostic and predictive factors of tumor response/resistance and to design effective therapeutic strategies to overcome primary resistance and improve the efficacy of immunotherapy. The aim of this review is to underline the influence of the tumor and host metabolism on the antitumor immune response and to discuss possible strategies to improve the efficacy of available treatments by targeting the specific metabolic pathways in tumors or immune cells and by modifying patients' nutritional statuses. A systematic search of the Medline and EMBASE databases was carried out to identify scientific papers published until February 2020, which reported original research articles on the influence of tumor or host metabolism on antitumor immune response. The literature data showed the key role of glycolysis and mitochondrial oxidative phosphorylation, arginine, tryptophan, glutamine, lipid metabolism and microbiome on immune cell function. Moreover, specific nutritional behaviors, such as a low dietary intake of vitamin C, low glycemic index and alpha-linolenic acid, eicosapentenoic acid, docosahexaenoic acid, ornithine ketoglutarate, tryptophan and probiotic supplementation were associated with the potential clinical benefits from the currently available immunotherapies.

PD-1 Inhibitors-Related Neurological Toxicities in Patients with Non-Small-Cell Lung Cancer: A Literature Review.

The advent of immune checkpoint inhibitors gave rise to a new era in oncology and general medicine. The increasing use of programmed death-1 (PD-1) inhibitors in non-small cell lung cancer and in other malignancies means clinicians have to face up to new challenges in managing immune-related adverse events (irAEs), which often resemble autoimmune diseases. Neurological irAEs represent an emerging toxicity related to immunotherapy, and it is mandatory to know how to monitor, recognize, and manage them, since they can rapidly lead to patient death if untreated. Guidelines for the diagnosis and treatment of these irAEs have been recently published but sharing some of the most unusual clinical cases is crucial, in our opinion, to improve awareness and to optimize the approach for these patients. A literature review on the diagnosis and treatment of immune-related neurotoxicity's has been conducted starting from the report of four cases of neurological irAEs regarding cases of polyneuropathy, myasthenia gravis, Bell's palsy, and encephalopathy, all of which occurred in oncological patients receiving PD-1 inhibitors (pembrolizumab and nivolumab) for the treatment of non-oncogene addicted advanced non-small cell lung cancer. The exclusion of other differential diagnoses and the correlation between the suspension of immunotherapy and improvement of symptoms suggest that immunotherapy could be the cause of the neurological disorders reported.

Historical Evolution of Second-Line Therapy in Non-Small Cell Lung Cancer.

Innovative therapeutic agents have significantly improved outcome with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients, who depend on oncogenic molecular alterations for their malignant phenotype. Despite the survival improvement achieved with first-line chemotherapy, about 30% of patients do not obtain a tumor response. Moreover, those patients, initially sensitive to treatment, acquire resistance and develop tumor progression after a median of about 5 months. Approximately 60% of the patients progressing from first-line chemotherapy receive further systemic treatment in the second-line setting. Moreover, new options have emerged in the second-line armamentarium for the treatment of patients with NSCLC, including immune checkpoint inhibitors and antiangiogenic agents. The current review provides an overview on the clinical studies that gained the approval of chemotherapy agents (docetaxel and pemetrexed) and epidermal growth factor receptor gene-tyrosine kinase inhibitors as second-line treatment options for NSCLC patients, not carrying molecular alterations.

HHV-8 DNA replication correlates with the clinical status in AIDS-related Kaposi's sarcoma.

BACKGROUND: The value of plasma levels of human herpesvirus 8 (HHV-8) DNA as a marker of clinical status in acquired immunodeficiency syndrome-related Kaposi's sarcoma (AIDS-KS) remains to be elucidated. OBJECTIVES: To investigate the relationship between the plasma HHV-8 DNA viral load and the clinical status of AIDS-KS. STUDY DESIGN: A total of 378 blood samples were obtained from 62 patients with AIDS-KS followed longitudinally. All patients received antiretroviral therapy (ART) or anti-neoplastic therapy. The patients were divided into four groups according to their clinical status: onset disease (OD), progressive disease (PD), stable or partial remission (S/PR) and complete remission (CR). RESULTS: Plasma HHV-8 DNAaemia was detected in all samples obtained from patients with OD or PD (100%); in contrast, HHV-8 DNAaemia was found only in a minority of patients with CR (8%) and was invariably undetectable in patients with stable CR. HHV-8 DNA detection in plasma was strongly associated with an unfavourable outcome (odds ratio=231.9; p<0.0001). Conversely, neither the HIV-1 viral load nor peripheral CD4(+) T-cell counts were associated with the KS clinical status, though both parameters did affect HHV-8 DNAaemia levels (p<0.0001). Multivariate analysis confirmed that HHV-8 DNAaemia was strongly and independently correlated with both clinical status (p<0.05) and HIV-1 plasma viraemia (p=0.027). CONCLUSIONS: The strong association of plasma HHV-8 DNAaemia with onset or progressive disease is compatible with an active role of replicating virus in clinically active AIDS-KS. An accurate evaluation of the plasma HHV-8 load might be useful for monitoring AIDS-KS under antiretroviral or antineoplastic therapy.

Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study.

Platinum-based chemotherapy is the standard treatment for patients with advanced non-small cell lung cancer (NSCLC), but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard chemotherapy in these patients. No prospective randomized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2. CAPPA-2 was a multicenter, randomized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI edition) and adequate organ function. Patients in standard arm received gemcitabine 1200 mg/m(2) days 1 and 8. Patients in experimental arm received cisplatin 60 mg/m(2) day 1 plus gemcitabine 1000 mg/m(2) days 1 and 8. All treatments were repeated every 3 weeks, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. The study was stopped in June 2012 after the enrolment of 57 patients, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine (HR 0.52, 95% CI 0.28-0.98, p = 0.039). Combination chemotherapy produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p = 0.017) and higher response rate (4% vs. 18%, p = 0.19), without substantial increase in toxicity. The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC.

Changes in plasma mass-spectral profile in course of treatment of non-small cell lung cancer patients with epidermal growth factor receptor tyrosine kinase inhibitors.

INTRODUCTION: Our previous study showed that pretreatment serum or plasma Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry may predict clinical outcome of non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In this study, plasma proteomic profiles of NSCLC patients were evaluated in the course of EGFR TKIs therapy. MATERIALS AND METHODS: Plasma samples were collected at baseline, in the course of gefitinib therapy and at treatment withdrawal. Samples were analyzed by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. Acquired spectra were classified by the VeriStrat test into "good" and "poor" profiles. The association between VeriStrat classification and progression-free survival (PFS) and overall survival (OS), and types of clinical progression, was analyzed. RESULTS: Plasma samples from 111 NSCLC patients treated with gefitinib were processed. VeriStrat "good" classification at baseline correlated with longer PFS (hazard ratio [HR], 0.54; 95% confidence interval, 0.35-0.83; p = 0.005) and OS (HR, 0.40; 95% confidence interval, 0.26-0.61; p < 0.0001), when compared with VeriStrat "poor." Multivariate analysis confirmed longer PFS (HR, 0.52; p = 0.025) and OS (HR, 0.44; p = 0.001) in patients classified as VeriStrat "good", when VeriStrat was considered as a time-dependent variable. About one-third of baseline "good" classifications had changed to "poor" at the time of treatment withdrawal; progression in these patients was associated with the development of new lesions. CONCLUSIONS: Our findings support the role of VeriStrat in the assistance in treatment selection of NSCLC patients for EGFR TKI therapy and its potential utility in treatment monitoring.

Cetuximab and gemcitabine in elderly or adult PS2 patients with advanced non-small-cell lung cancer: The cetuximab in advanced lung cancer (CALC1-E and CALC1-PS2) randomized phase II trials.

BACKGROUND: Two parallel randomized phase 2 trials were performed to choose the optimal way of combining cetuximab with gemcitabine in the first-line treatment of elderly (CALC1-E) and adult PS2 (CALC1-PS2) patients with advanced NSCLC. METHODS: Stage IV or IIIB NSCLC patients, aged > or =70 years with PS 0-2 for CALC1-E or aged <70 with PS2 for CALC1-PS2, not selected for EGFR expression, were eligible. Patients were randomized to concomitant (gemcitabine, for a maximum of 6 cycles, plus cetuximab until progression) or sequential (gemcitabine, for a maximum of 6 cycles, followed by cetuximab) strategy. A selection design, with 1-year survival rate as the primary endpoint, was applied, requiring 58 elderly and 42 PS2 patients. RESULTS: All planned patients were randomized. In sequential arms, 34.5% and 60.0% patients were not able to receive cetuximab after gemcitabine in CALC1-E and CALC1-PS2, respectively. Survival rates (95% CI) at 1-year for concomitant and sequential arms were 41.4% (23.5-61.1) and 31.0% (15.3-50.8) in CALC1-E and 27.3% (10.7-50.2) and 35.0% (15.4-59.2) in CALC1-PS2. In both studies, survival curves crossed at about 10 months and the worse arm until that time became the better one at 1-year. Toxicity was similar across treatment groups. In concomitant arm of CALC1-E (but not of CALC1-PS2), survival was longer for patients who developed skin toxicity within the first two cycles of treatment. CONCLUSION: In both groups of patients, sequential strategy cannot be proposed for future trials because of low compliance. Inconsistency of survival outcomes makes also concomitant treatment not a candidate for further testing in unselected elderly and PS2 NSCLC patients.

Clinical Significance of Skin Toxicity due to EGFR-Targeted Therapies.

Many small molecules and monoclonal antibodies blocking the activity of Epidermal Growth factor receptor (EGFR) have been developed and have shown clinical activity in patients with non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer (CRC), and are in clinical development for a range of other solid tumors. The toxicity profile of such agents is characterized by a typical pattern of cutaneous reactions. In this paper we reviewed the current available data regarding the clinical significance of skin reaction due to EGFR targeted agents. We show that skin toxicity can be considered as predictive marker of response to such drugs and that it is not disease specific; however its potential prognostic value is still to be proven.

Prognostic value of circulating chromogranin A and soluble tumor necrosis factor receptors in advanced nonsmall cell lung cancer.

BACKGROUND: Increased levels of chromogranin A (CgA), a protein secreted by many neuroendocrine cells, have been detected in sera of patients with neuroendocrine tumors or renal, hepatic, or heart failure. In patients with heart failure, serum CgA correlates with tumor necrosis factor-alpha (TNF) and soluble TNF receptors (sTNF-Rs), with important prognostic implications. The prognostic value of CgA and sTNF-Rs was investigated in advanced nonsmall cell lung cancer (NSCLC), a histologically heterogeneous group of tumors that may undergo neuroendocrine differentiation. METHODS: CgA and sTNF-Rs were analyzed in the sera of 88 patients with NSCLC before chemotherapy by enzyme-linked immunoadsorbent assay (ELISA) and in tumors by immunohistochemistry. RESULTS: Thirteen percent of patients had CgA values greater than the highest value observed in normal subjects (distribution range, 9-724 ng/mL and 28-196 ng/mL, respectively). Immunohistochemical studies showed no correlation between CgA expression in tumors and serum levels. Conversely, circulating CgA was associated with worse Eastern Cooperative Oncology Group (ECOG) performance status (PS) (P = .0005), more advanced stage (P = .042), and survival, with CgA being an independent prognostic factor of poor outcome (hazards ratio [HR] 1.31 for 100 ng/mL increase; 95% confidence interval [95% CI], 1.08-1.60 [P = .0071]). sTNF-R1 and sTNF-R2 were also associated with ECOG PS (P = .0001 and P = .02, respectively). sTNF-Rs was weakly correlated with circulating CgA (r = 0.39 for TNF-R1 and r = 0.40 for TNF-R2), suggesting a regulatory link between sTNF-Rs and CgA secretion. CONCLUSIONS: Increased serum levels of CgA in NSCLC are independent from protein expression in tumors and more likely related to neuroendocrine response associated with worsening of patient condition. In addition to ECOG PS and stage, CgA is an independent indicator of poor prognosis.

Adhesive capsulitis of the shoulder in human immunodeficiency virus-positive patients during highly active antiretroviral therapy.

Many adverse events have been described in patients treated with highly active antiretroviral therapy (HAART). Recently, among these, adhesive capsulitis of the shoulder has been described in some patients using protease inhibitors. We report our experience with 6 human immunodeficiency virus-positive patients in whom adhesive capsulitis of the shoulder developed during HAART. All 6 patients were treated with the same antiretroviral drug combination (HAART) including nucleoside reverse transcriptase (stavudine and lamivudine) and protease inhibitors (indinavir). The clinical pattern of adhesive capsulitis during HAART is similar to the classical form of adhesive capsulitis. Examining our case studies, we postulate a correlation between HAART and adhesive capsulitis. Discontinuation or reduction of the dosage of protease inhibitors associated with conventional conservative treatment is effective in reducing the symptoms and resolving the disease.

Isolated bone marrow manifestation of HIV-associated Hodgkin lymphoma.

Human immunodeficiency virus-associated Hodgkin lymphoma frequently involves the bone marrow and is usually recognized at staging after Hodgkin lymphoma diagnosis on a lymph node or other tissue biopsies, but occasionally the marrow involvement is the only apparent manifestation of disease. In the latter setting, diagnosis can be problematic. From a total of 42 patients with newly diagnosed human immunodeficiency virus-associated Hodgkin lymphoma, 22 subjects had positive marrow involvement at diagnosis; 16 of them had additional substantial histological and/or clinical extramedullary Hodgkin lymphoma. In the remaining 6 patients the bone marrow was the only site of disease at diagnosis. In all six cases, bone marrow biopsy revealed obvious lymphomatous involvement. Reed-Sternberg cells were identified both morphologically and immunophenotypically in all cases. Spared marrow tissue consistently showed fibrosis. All patients were males with a median age of 35 years (range, 31-58 years). All presented with fever, blood cytopenias, and severe CD4+ lymphocyte depletion (median, 70 cells/mm(3)). After diagnosis, all staging procedures were negative, and all patients were treated with chemotherapy. Median survival was 4 months (range, 2-118 mo). Longer survival was achieved in the patients who completed chemotherapy regimens; three subjects, however, died shortly before the full completion of chemotherapy, two of them from Hodgkin lymphoma. Isolated bone marrow HIV-associated Hodgkin lymphoma may be an underestimated condition in HIV-infected patients; in those individuals with unexplained fever and blood cytopenias, bone marrow biopsy should be performed with the aim of assessing for Hodgkin lymphoma, even in the absence of nodal and visceral lymphomatous involvement. A rapid diagnosis of isolated bone marrow HIV-associated Hodgkin lymphoma could expedite therapy.

Epstein-Barr virus DNA load in cerebrospinal fluid and plasma of patients with AIDS-related lymphoma.

Detection of Epstein-Barr virus (EBV) DNA in the cerebrospinal fluid (CSF) is associated with acquired immunodeficiency syndrome (AIDS)-related brain lymphoma. Real-time polymerase chain reaction (PCR) was performed to quantify EBV DNA in CSF and plasma from 42 patients with AIDS-related non-Hodgkin's lymphoma (NHL). Twenty patients had primary central nervous system lymphoma (PCNSL) and 22 systemic NHL, including 12 with central nervous system involvement (CNS-NHL). As controls, 16 HIV-infected patients with other CNS disorders were examined. EBV DNA was detected in the CSF from 16/20 (80%) patients with PCNSL, 7/22 (32%) with systemic NHL, 8/12 (67%) with CNS-NHL, and 2/16 (13%) of the controls. The viral EBV DNA levels were significantly higher in the CSF from patients with PCNSL or CNS-NHL compared to patients with systemic NHL or controls. EBV DNA was detected in plasma from 5/16 (31%) patients with PCNSL, 9/16 (56%) with systemic NHL, 4/9 (44%) with CNS-NHL, and 4/15 (27%) controls. No difference in plasma viral load was found between patient groups. From the patients with CNS-NHL, plasma samples drawn prior to CNS involvement contained significantly higher EBV DNA levels than those from systemic NHL patients without subsequent CNS involvement. EBV DNA levels in the CSF, but not in plasma, from patients treated with antiherpes drugs were significantly lower than in untreated patients. High CSF EBV DNA levels were found in HIV-associated brain lymphomas and the viral load can be clinically useful. High plasma EBV DNA levels might predict CNS involvement in systemic NHL.