Pembrolizumab plus epacadostat in patients with recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-669/ECHO-304): a phase 3, randomized, open-label study.

BACKGROUND: Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial. METHODS: KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019. RESULTS: Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%-49%) for pembrolizumab plus epacadostat, 21% (6%-46%) for pembrolizumab monotherapy, and 34% (19%-52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3-4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects. CONCLUSIONS: Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC. TRIAL REGISTRATION: NCT03358472. Date of trial registration: November 30, 2017.

What are the barriers towards cervical cancer screening for vulnerable women? A qualitative comparative analysis of stakeholder perspectives in seven European countries.

OBJECTIVES: The aim of this study was to map and compare stakeholders' perceptions of barriers towards cervical cancer screening for vulnerable women in seven European countries. DESIGN: In Collaborative User Boards, stakeholders were invited to participate to identify barriers towards participation in cervical cancer screening. SETTING: The study is nested in the European Union-funded project CBIG-SCREEN which aims to tackle inequity in cervical cancer screening for vulnerable women (www.cbig-screen.eu). Data collection took place in Bulgaria, Denmark, Estonia, France, Italy, Portugal and Romania. PARTICIPANTS: Participants represented micro-level stakeholders covering representatives of users, that is, vulnerable women, meso-level stakeholders covering healthcare professionals and social workers, and macro-level stakeholders covering programme managers and decision-makers. METHODS: Across the seven countries, 25 meetings in Collaborative User Boards with a duration of 2 hours took place between October 2021 and June 2022. The meetings were video recorded or audio recorded, transcribed and translated into English for a qualitative framework analysis. RESULTS: 120 participants took part in the Collaborative User Boards. Context-specific barriers were related to different healthcare systems and characteristics of vulnerable populations. In Romania and Bulgaria, the lack of a continuous screening effort and lack of ways to identify eligible women were identified as barriers for all women rather than being specific for women in vulnerable situations. The participants in Denmark, Estonia, France, Italy and Portugal identified providers' lack of cultural and social sensitivity towards vulnerable women as barriers. In all countries, vulnerable women's fear, shame and lack of priority to preventive healthcare were identified as psychological barriers. CONCLUSION: The study provides an overview of stakeholders' perceived barriers towards vulnerable women's cervical cancer screening participation in seven European countries. The organisation of healthcare systems and the maturity of screening programmes differ between countries, while vulnerable women's psychological barriers had several similarities.

Immune Response to SARS-CoV-2 Vaccination in Cancer Patients: A Prospective Study.

Introduction Cancer patients on active treatment are at increased risk of developing coronavirus disease 2019 (COVID-19), making effective immunization of the utmost importance. However, the effectiveness of vaccination in this population is still unclear. This study aims to evaluate the response against COVID-19 in a cohort of patients with active cancer under immunosuppressive therapy. Methods This was a prospective, cross-sectional, single-center study that included patients with cancer under immunosuppressive therapy vaccinated against COVID-19 between April and September 2021. Exclusion criteria were: previous known severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, single-dose vaccine or incomplete vaccination scheme. Immunoglobulin G (IgG) anti-SARS-CoV-2 antibody levels were assessed using 35.2 binding antibody units (BAU)/mL as the positive cut-off. Assessments were performed 14-31 days after the first and second dose and three months after the second dose. Results A total of 103 patients were included. The median age was 60 years. Most patients were being treated for gastrointestinal cancer (n=38, 36.9%), breast cancer (n=33, 32%) or head and neck cancer (n=18, 17.5%). At evaluation, 72 patients (69.9%) were being treated with palliative intent. The majority were being treated with chemotherapy (CT) alone (57.3%). At the first assessment, levels of circulating SARS-CoV-2 IgG consistent with seroconversion were present in 49 patients (47.6%). At the time of the second assessment, 91% (n=100) achieved seroconversion. Three months after the second dose, 83% (n=70) maintained levels of circulating SARS-CoV-2 IgG consistent with seroconversion. In this study, no SARS-CoV-2 infection was reported in the study population. Conclusions Our findings suggest that this group of patients had a satisfactory COVID-19 immunization response. Although promising, this study should be replicated on a wider scale in order to validate these findings.

Survival predictors and outcomes of patients with recurrent and/or metastatic head and neck cancer treated with chemotherapy plus cetuximab as first-line therapy: A real-world retrospective study.

BACKGROUND: In patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) the estimated prognosis is usually poor. Patient-specific factors that affect prognosis should be considered when choosing therapy. We conducted a retrospective, single-center analysis in patients treated with first line platinum and antiEGFR antibody-containing regimen. The objective was to generate real-world data considering treatment outcomes and to identify predictors of survival. PATIENTS/METHODS: Clinical charts of patients treated with cetuximab and platinum-based chemotherapy (CT) for R/M HNSCC in first-line setting, between January-2009 and December-2018 were assessed. In these 103 patients, the prognostic value of site of the primary tumor, age at diagnosis, gender, Cetuximab induced skin toxicity and prior treatments were studied multivariately. To evaluate progression free survival (PFS) and overall survival (OS), Kaplan-Meier curves and the log-rank test were used. The Coxregression model was used to investigate the effect of these variables on OS. RESULTS: Longer OS was associated with oral cavity tumor location (p = 0,003), European Cooperative Oncology Group-Performance Status 0 (ECOG-PS) (p = 0,01), complete/partial response (p<0,0001), cetuximab monotherapy until disease progression or unacceptable toxicity (p = 0,037) and Grade 2-4 cetuximab induced skin toxicity (p = 0,037). The median follow-up period was 11,7 months. The mortality rate was 90,3% during this retrospective cohort assessment. The PFS was 7,1 months (95% confidence interval (CI), 5,6-8.6). The OS was 11,7 months (95%CI, 10,5-12,8). CONCLUSIONS: The present study demonstrates that the combination of cetuximab with platinum-based CT was effective in R/M HNSCC. Among patients with R/M HSCC treated with platinum plus cetuximab as first-line therapy, primary site, ECOG-PS, grade 2-4 cetuximab induced toxicity, and weekly cetuximab monotherapy have a marked impact on OS.

Case Report of a Rare Adrenocortical Oncocytoma Suspected to be an Adrenal Carcinoma.

An adrenal oncocytic neoplasm is an extremely rare tumour arising from the adrenal gland and it should be considered in the differential diagnosis of an adrenal incidentaloma, since it is frequently non-functioning. The suspicion for malignancy is high when an adrenal incidentaloma is >4 cm in size; however, adrenal oncocytomas are large, measuring an average of 8 cm, are round and encapsulated, and normally have a benign behaviour. We present a case of a 55-year-old male patient with dyslipidaemia, medicated with simvastatin. Upon complaints of abdominal pain, the general physician asked for an abdominal ultrasound that revealed an adrenal lesion, further characterized with a computed tomography scan, which showed an adrenal lesion measuring 49 × 64 × 56 mm and a calcification focus. The patient was referred to the general surgery and endocrinology department. The analytical study was negative for pheochromocytoma or Cushing's syndrome, which allowed surgery to be conducted, as is recommended. The aim of this case report is to contribute to the knowledge on adrenal oncocytomas, since there is scarce information based on singular experiences.

Esophageal Gastrointestinal Stromal Tumor with Rare Intracranial Metastasis.

Introduction. Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors and constitute the largest group of nonepithelial digestive neoplasms. However, they do not represent more than 1% of primary digestive tumors. They commonly metastasize to the liver and peritoneum, but brain metastases are extremely rare. Clinical Case. A 76-year-old woman with a diagnosis of esophageal GIST with liver and lung metastases for 13 years, medicated with imatinib, is presented. She was brought to the emergency department after falling and due to changes in behavior and vertigo with 24 hours of evolution. On physical examination, she presented changes in behavior, dysarthria, dysmetria on the right, gait imbalance, and no motor or sensory deficits. On brain computed tomography and posteriorly on magnetic resonance, 2 lesions were observed, left frontal and right cerebellar, compatible with metastatic lesions. After contribution of neurosurgery, histology was obtained that confirmed the lesions were GIST metastases. Imatinib was maintained, and whole brain radiotherapy was performed. After 6 months, she died. Discussion. The rarity of GIST brain metastases is noteworthy, and because of that, there is not enough experience to be certain of the best treatment. Our patient lived for 13 years with excellent disease control with imatinib, but the fact that it does not cross the blood-brain barrier makes it not useful in preventing or treating brain lesions. New tyrosine kinase inhibitors that may cross the blood-brain barrier could be the answer to these cases.

Case Report: Sarcoidosis mimicking head and neck cancer progression.

Several case reports have been published describing the coexistence of sarcoidosis and cancer. In the literature, simultaneous occurrence of head and neck cancer and sarcoidosis is rarely reported. In this paper we present a case of a 42-year-old man with squamous cell carcinoma of the oral cavity, locally advanced, which after surgery and adjuvant radiotherapy developed local persistence and progression in the mediastinal lymph nodes. The patient was submitted to chemotherapy and after a complete response, new suspicious mediastinal and hilar lymph nodes appeared in the thoracic computed tomography (CT) scan and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan. To enroll the patient in a clinical trial, the patient underwent mediastinoscopy with mediastinal lymph node dissection. The histopathological findings were consistent with sarcoidosis and no metastatic disease was found. Since the patient had no symptoms and the levels of serum angiotensin converting enzyme were normal, no further pharmacological intervention was done. After 4 years of follow up the patient remains without evidence of cancer. This case shows that although imagological techniques (CT and FDG-PET scan) are extensively used to assess the tumor response, false-positive cases can occur. Whenever it is possible a biopsy of the suspected metastatic site should always be performed.

Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells.

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Transcriptomic analysis of stem and progenitor populations in MDS and AML demonstrated overexpression of STAT3 that was validated in an independent cohort. STAT3 overexpression was predictive of a shorter survival and worse clinical features in a large MDS cohort. High STAT3 expression signature in MDS CD34+ cells was similar to known preleukemic gene signatures. Functionally, STAT3 inhibition by a clinical, antisense oligonucleotide, AZD9150, led to reduced viability and increased apoptosis in leukemic cell lines. AZD9150 was rapidly incorporated by primary MDS/AML stem and progenitor cells and led to increased hematopoietic differentiation. STAT3 knockdown also impaired leukemic growth in vivo and led to decreased expression of MCL1 and other oncogenic genes in malignant cells. These studies demonstrate that STAT3 is an adverse prognostic factor in MDS/AML and provide a preclinical rationale for studies using AZD9150 in these diseases.

Prolactinoma management: predictors of remission and recurrence after dopamine agonists withdrawal.

OBJECTIVE: Prolactinomas are the most common functional pituitary tumour. Dopamine agonists (DA) are its principal treatment. The criteria that should guide therapy withdrawal and the factors that influence disease remission or relapse are not yet fully established. Our purpose is to evaluate the proportion of patients who attempted DA withdrawal, and to identify the factors that influence clinicians to try it. In addition, we aim to study the factors that are involved in prolactinoma remission/relapse after therapy withdrawal. METHODS: We retrospectively evaluated 142 patients with prolactinoma diagnosis who had been treated exclusively with DA. Firstly, the patients were divided in two groups, according to whether DA withdrawal had been attempted, or not, and the factors that might predict clinicians' decision to discontinue the therapy were then analysed. Secondly, patients who attempted withdrawal were further divided into two subgroups, based on their remission or relapse status and predictors of remission were evaluated. RESULTS: DA withdrawal was attempted in 35.2% of our patients. Females, subjects with lower initial serum prolactin (PRL) levels, those with microadenomas and those with longer treatment duration all had a higher probability of seeing their therapy discontinued. In the withdrawal group, the remission rate was 72%. Macroprolactinomas relapse more often than microprolactinomas (p < 0.05). The recurrence group had higher median initial serum PRL levels and a lower mean duration of therapy, however these variables did not reach statistical significance. CONCLUSION: We found a low percentage of attempt of withdrawal of DA therapy in the subjects with prolactinoma. Our data confirms that DA therapy can be discontinued with a high remission rate. Tumour size was the main variable that affected the withdrawal outcome in our patients.

Leukemic Stem Cells S(p)liced Off.

Myeloid malignancies often arise from an aging hematopoietic system and are currently incurable due to therapy-resistant, disease-reinitiating leukemic stem cells. In this issue of Cell Stem Cell, Crews et al. (2016) report RNA splice isoform signatures unique to patient-derived leukemic stem cells that constitute a therapeutic Achilles' heel of myeloid leukemia.

Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells.

BACKGROUND: High-grade non-muscle invasive bladder cancer (NMIBC) has a high risk of recurrence and progression to muscle-invasive forms, which seems to be largely related to the presence of tumorigenic stem-like cell populations that are refractory to conventional therapies. Here, we evaluated the therapeutic potential of Natural Killer (NK) cell-based adoptive immunotherapy against chemoresistant bladder cancer stem-like cells (CSCs) in a pre-clinical relevant model, using NK cells from healthy donors and NMIBC patients. METHODS: Cytokine-activated NK cells from healthy donors and from high-grade NMIBC patients were phenotypically characterized and assayed in vitro against stem-like and bulk differentiated bladder cancer cells. Stem-like cells were isolated from two bladder cancer cell lines using the sphere-forming assay. The in vivo therapeutic efficacy was evaluated in mice bearing a CSC-induced orthotopic bladder cancer. Animals were treated by intravesical instillation of interleukin-activated NK cells. Tumor response was evaluated longitudinally by non-invasive bioluminescence imaging. RESULTS: NK cells from healthy donors upon activation with IL-2 and IL-15 kills indiscriminately both stem-like and differentiated tumor cells via stress ligand recognition. In addition to cell killing, NK cells shifted CSCs towards a more differentiated phenotype, rendering them more susceptible to cisplatin, highlighting the benefits of a possible combined therapy. On the contrary, NK cells from NMIBC patients displayed a low density on NK cytotoxicity receptors, adhesion molecules and a more immature phenotype, losing their ability to kill and drive differentiation of CSCs. The local administration, via the transurethral route, of activated NK cells from healthy donors provides an efficient tumor infiltration and a subsequent robust tumoricidal activity against bladder cancer with high selective cytolytic activity against CSCs, leading to a dramatic reduction in tumor burden from 80 % to complete remission. CONCLUSION: Although pre-clinical, our results strongly suggest that an immunotherapeutic strategy using allogeneic activated NK cells from healthy donors is effective and should be exploited as a complementary therapeutic strategy in high-risk NMIBC patients to prevent tumor recurrence and progression.

Functional and molecular characterization of cancer stem-like cells in bladder cancer: a potential signature for muscle-invasive tumors.

Striking evidence associates cancer stem cells (CSCs) to the high recurrence rates and poor survival of patients with muscle-invasive bladder cancer (BC). However, the prognostic implication of those cells in risk stratification is not firmly established, mainly due to the functional and phenotypic heterogeneity of CSCs populations, as well as, to the conflicting data regarding their identification based on a single specific marker. This emphasizes the need to exploit putative CSC-related molecular markers with potential prognostic significance in BC patients.This study aimed to isolate and characterize bladder CSCs making use of different functional and molecular approaches. The data obtained provide strong evidence that muscle-invasive BC is enriched with a heterogeneous stem-like population characterized by enhanced chemoresistance and tumor initiating properties, able to recapitulate the heterogeneity of the original tumor. Additionally, a logistic regression analysis identified a 2-gene stem-like signature (SOX2 and ALDH2) that allows a 93% accurate discrimination between non-muscle-invasive and invasive tumors.Our findings suggest that a stemness-related gene signature, combined with a cluster of markers to more narrowly refine the CSC phenotype, could better identify BC patients that would benefit from a more aggressive therapeutic intervention targeting CSCs population.

Toxicokinetics and tissue distribution of cadmium-based Quantum Dots in the marine mussel Mytilus galloprovincialis.

Environmental health hazards of Quantum Dots (QDs) are of emergent concern, but limited data is available about their toxicokinetics (TK) and tissue distribution in marine bivalves. This study investigated the QDs behavior in seawater, their TK and tissue distribution in Mytilus galloprovincialis, in comparison with soluble Cd. Mussels were exposed to CdTe QDs and soluble Cd for 21 days at 10 µgCd L(-1) followed by a 50 days depuration. TK of QDs in mussels is related to the homo-aggregate uptake, surface charge, aggregation and precipitation as key factors. There were tissue- and time-dependent differences in the TK of both Cd forms, and soluble Cd is the most bioavailable form. Digestive gland is a preferential site for QDs storage and both Cd forms are not eliminated by mussels (t1/2>50 days). Results indicate that the TK model of CdTe QDs in marine mussels is distinct from their soluble counterparts.

Drug transporters play a key role in the complex process of Imatinib resistance in vitro.

Imatinib resistance has been associated with BCR-ABL alterations, but other mechanisms might be involved, like drug transporters. Additionally, the impact of poor adherence in resistance has been little explored. Using sensitive and resistance CML cell lines, we investigated the expression of influx/efflux transporters, like P-gP and OCT1. In the therapeutic interruption model, we observed decrease of influx and increase in efflux transporters combined with BCR-ABL over-expression. Comparatively, resistant cells obtained by continuous TKI exposure only demonstrated alterations in drug's transporters. By exploring P-gP expression of resistant cells, we observed the potential of P-gP inhibitor in circumventing Imatinib resistance. Our results revealed the importance of treatment interruptions for expected response levels and show the complexity of Imatinib resistant process. Efflux transports appear as not only relevant for acquisition of resistant phenotype, but also as valid therapeutic tool for managing resistance.

Immunocytotoxicity, cytogenotoxicity and genotoxicity of cadmium-based quantum dots in the marine mussel Mytilus galloprovincialis.

There is an increased use of Quantum Dot (QDs) in biological and biomedical applications, but little is known about their marine ecotoxicology. So, the aim of this study was to investigate the possible immunocytotoxic, cytogenotoxic and genotoxic effects of cadmium telluride QDs (CdTe QDs) on the marine mussel Mytilus galloprovincialis. Mussels were exposed to 10 µg L(-1) of CdTe QDs or to soluble Cd [Cd(NO3)2] for 14 days and Cd accumulation, immunocytotoxicity [hemocyte density, cell viability, lysosomal membrane stability (LMS), differential cell counts (DCC)], cytogenotoxicity (micronucleus test and nuclear abnormalities assay) and genotoxicity (comet assay) were analyzed. Results show that in vivo exposure to QDs, Cd is accumulated in mussel soft tissues and hemolymph and induce immunotoxic effects mediated by a decrease in LMS, changes in DCC, as well as genotoxicity (DNA damage). However, QDs do not induce significant changes in hemocytes density, cell viability and cytogenetic parameters in opposition to Cd(2+). Soluble Cd is the most cytotoxic and cytogenotoxic form on Mytilus hemocytes due to a higher accumulation of Cd in tissues. Results indicate that immunotoxicity and genotoxicity of CdTe QDs and Cd(2+) are mediated by different modes of action and show that Mytilus hemocytes are important targets for in vivo QDs toxicity.

Integration of dissolved gas flotation and nanofiltration for M. aeruginosa and associated microcystins removal.

The removal of Microcystis aeruginosa and associated microcystins was investigated by a dissolved gas flotation (preceded by coagulation/flocculation)-nanofiltration (NF) sequence. The experiments were conducted with a freshwater spiked with M. aeruginosa cell aggregates to simulate a naturally occurring bloom. Two types of gases were used in the flotation pre-treatment, air (DAF) and a mixture of CO(2)/air. Very good results in terms of NF fluxes, overall removal efficiencies and final water quality were achieved with both sequences. However, the CO(2)/air mixture presented no benefit to the overall sequence, both in terms of toxin release to water during flotation and lower natural organic matter removal by NF, which was due to an overall negative effect of the acid pH. NF was able to completely remove cyanobacteria (100% removal efficiency of chlorophyll a) and microcystins (always under the quantification limit), regardless of the pre-treatment used and the water recovery rate (up to 84%). Therefore, DAF-NF sequence is a safe barrier against M. aeruginosa and microcystins in drinking water. In addition, it ensures an excellent control of particles, disinfection by-products formation, and other micropollutants that may be present in raw water.