CD30+OX40+ Treg is associated with improved overall survival in colorectal cancer

Regulatory T cells (Tregs) are often enriched in tumors, where their immunosuppressive function has a key role in tumor persistence and progression. In colorectal cancer (CRC), however, Tregs are frequently associated with an improved clinical outcome. Tumor-infiltrating Tregs have been shown to exhibit a distinct signature comprising the co-stimulatory molecules (OX40, 4-1BB), cytokine receptors (IL1R2, IL21R, CCR8, CD30), and co-inhibitory molecules (PD-L1, TIGIT). Here, we showed by flow cytometry that circulating CD45RO+ Tregs from patients with CRC (n = 25) have elevated CD30 and OX40 expression compared to healthy subjects (n = 14). We identified co-expression of CD30 and OX40 on circulating CD45RO+ Tregs using single-cell images captured by the DEPArray™ system. The frequency of CD30+OX40+CD45RO+ Tregs was significantly higher in CRC patients than in healthy subjects (P < 0.001). Importantly, receiver operating characteristic analysis confirmed that this CD30+OX40+ Treg subset could strongly discriminate between CRC patients and healthy subjects with the highest accuracy of 92.3%, an AUC of 0.92, a sensitivity of 88%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 82.35%, and a trade-off value of 3.44%, compared to other Treg subsets. Consistently, multiplex-IHC/IF of tumor-infiltrating Tregs revealed a significant association between high densities of CD30+OX40+ Tregs and improved overall survival; no such association was found for other subsets. These data suggest a potential role for CD30+OX40+ Tregs as a diagnostic or prognostic biomarker in CRC.

Value of 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography in staging of patients with differentiated thyroid cancer after thyroidectomy during the first course of radioiodine therapy

The study objective is to evaluate value of 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (PET-CT) and whole-body scintigraphy (131I-WBS) performed during the first course of radioiodine therapy for its ability to detect persistence metastatic foci and for its role in the management of differentiated thyroid cancer patients.Materials and methods. Forty patients with DTC underwent both post-therapeutic 131I-WBS and PET-CT. PET-CT performed on a positron emission tomograph combined with a 16-slice computer tomograph. Post-therapeutic 131I-WBS performed during radioiodine therapy on the single-detector gamma camera.Results. Sensitivity in detecting of the tumor persistence for PET-CT was 84 %, for post-therapeutic 131I-WBS 66 % (р >0.05). In 17 (42.5 %) patients additional PET-CT foci were found that negative on 131I-WBS, including 11 (27.5 %) cases of distant metastases. Fifteen percent of patients had metastatic foci visualized only on 131I-WBS, including 4 (10 %) cases of distant metastases. In 17 (44 %) patients tumor foci were identified by both methods. A high pre-ablative level of stimulated thyroglobulin was the only independent predictor of the presence of PET-CTpositive metastatic foci (p = 0.001).Conclusion. 18F-fluorodeoxyglucose PET-CT can be recommended during the first radioiodine therapy in differentiated thyroid cancer patients with a high risk progression group, as well as with suspected the tumor persistence in case of a high pre-ablation thyroglobulin level, to complete staging, improve the quality of management and ongoing risk stratification.

Type I Interferons as Joint Regulators of Tumor Growth and Obesity

Type I interferons (IFN-I) are antiviral cytokines endowed with multiple biological actions, including antitumor activity. Studies in mouse models and cancer patients support the concept that endogenous IFN-I play important roles in the control of tumor development and growth as well as in response to several chemotherapy/radiotherapy treatments. While IFN-I signatures in the tumor microenvironment are often considered as biomarkers for a good prognostic response to antitumor therapies, prolonged IFN-I signaling can lead to immune dysfunction, thereby promoting pathogen or tumor persistence, thus revealing the “Janus face” of these cytokines in cancer control, likely depending on timing, tissue microenvironment and cumulative levels of IFN-I signals. Likewise, IFN-I exhibit different and even opposite effects on obesity, a pathologic condition linked to cancer development and growth. As an example, evidence obtained in mouse models shows that localized expression of IFN-I in the adipose tissue results in inhibition of diet–induced obesity, while hyper-production of these cytokines by specialized cells such as plasmacytoid dendritic cells in the same tissue, can induce systemic inflammatory responses leading to obesity. Further studies in mouse models and humans should reveal the mechanisms by which IFN-I can regulate both tumor growth and obesity and to understand the role of factors such as genetic background, diet and microbioma in shaping the production and action of these cytokines under physiological and pathological conditions.

Plasma-derived extracellular vesicle analysis and deconvolution enable prediction and tracking of melanoma checkpoint blockade outcome

Immune checkpoint inhibitors (ICIs) show promise, but most patients do not respond. We identify and validate biomarkers from extracellular vesicles (EVs), allowing non-invasive monitoring of tumor- intrinsic and host immune status, as well as a prediction of ICI response. We undertook transcriptomic profiling of plasma-derived EVs and tumors from 50 patients with metastatic melanoma receiving ICI, and validated with an independent EV-only cohort of 30 patients. Plasma-derived EV and tumor transcriptomes correlate. EV profiles reveal drivers of ICI resistance and melanoma progression, exhibit differentially expressed genes/pathways, and correlate with clinical response to ICI. We created a Bayesian probabilistic deconvolution model to estimate contributions from tumor and non-tumor sources, enabling interpretation of differentially expressed genes/pathways. EV RNA-seq mutations also segregated ICI response. EVs serve as a non-invasive biomarker to jointly probe tumor-intrinsic and immune changes to ICI, function as predictive markers of ICI responsiveness, and monitor tumor persistence and immune activation.

Intensity modulated radiation therapy boost in locally-advanced cervical cancer in the absence of brachytherapy

ObjectiveStandard treatment in locally-advanced cervical cancer is external beam radiotherapy concomitant with platinum-based chemotherapy, followed by brachytherapy. The goal of our study was to determine whether an intensity modulated radiation therapy (IMRT) boost is feasible in patients unfit for brachytherapy.MethodsWe retrospectively analyzed data of 25 patients unfit for brachytherapy with median age 55 years (range, 30–82) with locally-advanced/metastatic cervical cancer who underwent external beam radiotherapy to pelvis ±para-aortic lymph nodes and sequential IMRT boost between July 2014 and December 2017. Total dose of 45–50.4 Gy in 25–28 fractions (1.8 Gy/fraction) was administered to the cervix, uterus, parametria, ovaries, vaginal tissues (based on vaginal extension), involved lymph nodes, or relevant draining lymph-nodal groups. Para-aortic nodes were included if involved at radiological staging or if common iliac nodes were positive. The IMRT boost included all residual tumor after external beam radiotherapy identified on MRI. The Kaplan–Meier method was used to calculate 2 years' overall survival, 2 years' progression-free survival, and 2 years' local control. Overall survival- and progression-free survival were calculated considering the starting of radiotherapy or neo-adjuvant chemotherapy if prescribed, while local control was calculated from the end of radiotherapy.ResultsMedian radiation dose to pelvis ±para-aortic lymph nodes was 50.4 Gy (45–50.4), boost treatment was homogeneously performed to a total dose of 25 Gy in five fractions every other day.After a median follow-up of 26 months (range, 4–77), tumor persistence at cervix at 6 months from the end of radiotherapy or local recurrence occurred in five women (20%), eight (32%) experienced a further distant progression (two of them had also tumor persistence). Two-year local control and overall survival rates for all stages were 78% and 67%, respectively. According to Common Terminology Criteria for Adverse Events v.4 scoring criteria, 10 patients experienced gastrointestinal and/or genitourinary grade G1-2 acute toxicity. G2 rectal late toxicity requiring laser-coagulation was registered in two patients, there were no gastrointestinal and/or genitourinary acute or late toxicities≥G3.ConclusionThe combination of external beam radiotherapy and brachytherapy remains the standard of care, however our preliminary data show the feasibility of IMRT boost in terms of toxicity with promising results in terms of local control and overall survival.

Giant Non-Functioning Pituitary Adenoma: Clinical Characteristics and Therapeutic Outcomes

Background Giant pituitary adenoma (≥4 cm) is a rare tumor whose clinical features and prognosis are not well known. Aim To evaluate the clinical characteristics and therapeutic outcomes of giant non-functioning PA (gNFPA). Patients and Methods A retrospective multicenter study of gNFPA patients diagnosed in a 12-year period was performed. In each patient, clinical data and therapeutic outcomes were registered. Results Forty patients (24 men, age 54.2 ± 16.2 years) were studied. The maximum tumor diameter [median (interquartile range)] was 4.6 cm (4.1–5.1). Women had larger tumors [4.8 cm (4.2–5.4) vs. 4.5 cm (4.0–4.9); p=0.048]. Hypopituitarism [partial (n=22, 55%) or complete (n=9, 22.5%)] at diagnosis was present in 77.5% of the patients. Visual field defects were found in 90.9%. The most used surgical technique was endoscopic endonasal transsphenoidal (EET) surgery (n=31, 77.5%). Radiotherapy was used in 11 (27.5%) patients (median dose 50.4 Gy, range 50–54). Thirty-seven patients were followed for 36 months (10–67 months). Although more than half of these patients showed tumor persistence (n=25, 67.6%), tumor size was significantly reduced [0.8 cm (0–2.5); p<0.001]. At last visit, 12 patients (32.4%) showed absence of tumor on MRI. Hypopituitarism rate was similar (75.0%), although with significant changes (p<0.001) in the distribution of the type of hypopituitarism. The absence of tumor at the last visit was positively associated with positive immunohistochemical staining for FSH (p=0.01) and LH (p=0.006) and negatively with female sex (p=0.011), cavernous sinus invasion (p=0.005) and the presence of Knosp grade 4 (p=0.013). Conclusion gNFPAs are more frequent in men but tumors are larger in women. Surgical treatment is followed by a complete tumor resection rate of approximately 30%. Positive immunostaining for gonadotropins is associated with tumor absence at last revision, while female sex and invasion of the cavernous sinuses with tumor persistence.

Preoperative Imaging Evaluation after Downstaging of Pancreatic Ductal Adenocarcinoma: A Multi-Center Study

Introduction: Evaluation of pancreatic ductal adenocarcinoma (PDAC) after chemoradiotherapy downstaging is challenging due to computed tomography (CT) overestimation of tumor extension and residual vascular involvement, limiting access to surgery to some patients with potentially resectable tumors. With this study, we wanted to assess which radiological findings are most reliable at pre-operative imaging in the evaluation of PDAC after chemoradiotherapy in order to achieve complete resection. Methods: We retrospectively enrolled 71 patients with locally advanced and borderline resectable PDAC who underwent neoadjuvant chemoradiotherapy. Pre-operative CT or magnetic resonance (MR) have been evaluated by three radiologists to assess major qualitative and quantitative parameters of lesions. Accuracy, sensitivity, and specificity compared to anatomopathological results were evaluated for each parameter. Cohen’s K-coefficient has been calculated to evaluate the inter-observer agreement (IOA). Both single and consensus lecture have been tested. Different dimensional cut-offs were tested to categorize tumors according to their major axis and to compare with anatomopathological diameter, tumor persistence, and margin infiltration. Results: A 25 mm cut-off was 67% sensitive, 90% specific, and 77% accurate in assessing real tumor dimension. 25 mm cut-off reported a 64% sensitivity, 78% specificity, and 69% accuracy in assessing R0 resection. Each 5 mm increment of major axis dimension there is an odds ratio (OR) 1.79 (95% CI 1.13–2.80, p = 0.012) for R+ resection. Imaging presence of the perivascular cuff is not associated with tumor persistence and resection margin infiltration (p = 0.362). Lesion enhancement and pattern homogeneity were not accurate in determining tumor persistence. IOA was generally poor to fair, except for >25 mm cut-off classification where IOA was moderate. Diagnostic accuracy is superior in consensus lecture rather than single lecture. Conclusion: Imaging methods tend to underestimate PDAC resectability after neoadjuvant-CRT. IOA is poor to fair in evaluating most of the qualitative parameters of downstaged pancreatic adenocarcinoma. Surgery should be considered for downstaged borderline resectable PDACs, independently from perivascular cuff presence, especially for tumors smaller than 25 mm.

Prognostic impact of vascular invasion in differentiated thyroid carcinoma: a systematic review and meta-analysis

Background The role of vascular invasion (VI) as a prognostic marker in thyroid cancer is continuously debated among investigators. In this systematic review and meta-analysis, we aimed to investigate the association of VI with tumor recurrence and patient mortality in differentiated thyroid cancers (DTCs). Methods We searched five electronic databases for cases of DTC matching our criteria. Data of tumor persistence, locoregional recurrence (LRR), distant recurrence (DR) and overall recurrence/persistence (RP) were extracted and pooled into odds ratios (OR) and corresponding 95% confidence intervals (CIs) using random effect model. Pooled hazard ratio (HR) for disease-specific survival (DSS) was calculated using random effect model weighted by inverse variance method. Publication bias was examined by using Egger’s test and funnel plot. Results From 1650 studies, we included 26 studies comprising 11 961 DTCs for meta-analyses. In DTC patients, we found significant associations of VI with tumor persistence (OR = 2.75; 95% CI = 1.46–5.18), LRR (OR = 4.44; 95% CI = 2.94–6.71), DR (OR = 5.08; 95% CI = 2.95–8.75), overall RP (OR = 3.53; 95% CI = 2.09–5.96) and worse DSS (HR = 2.47; 95% CI = 1.45–4.21). Our results also demonstrated that the presence of extensive VI is associated with a significantly higher risk for DR in follicular thyroid carcinomas as compared with focal VI. Conclusion Our study demonstrated a significant impact of VI on tumor recurrence and patient survival in DTC patients. The presence and extent of VI should be considered an adverse prognostic factor in DTCs.

Epstein-Barr virus DNA in serum as an early prognostic marker in children and adolescents with Hodgkin lymphoma

Key Points EBV DNA in cell-free blood in patients with Hodgkin lymphoma correlated with the presence of virus in tumor. Persistence of EBV DNA in cell-free blood 1 week after initiation of therapy predicted inferior event-free survival.