Out-patient high-dose-rate endobronchial brachytherapy for palliation of lung cancer: an observational study

Background and Aim. Out-patient high-dose-rate endobronchial brachytherapy (HDREB) is a possible option in the palliation of symptoms in patients with advanced lung cancer, but literature data is limited and the technique is still under development in Italy. Our aim was to evaluate safety and effectiveness of out-patient HDREB for palliation of malignant endobronchial tumours in the context of a multidisciplinary approach. Methods. Out-patient HDREB sessions were scheduled at weekly intervals (500-1000 cGy per session) with prior Diodi-laser resection in some cases. Response was assessed bronchoscopically, clinically and functionally at the end of treatment and one month after the last HDREB session. Inclusion criteria was: histological evidence of malignant tumour not susceptible to surgical treatment for extension or co-morbidity. Results. 150 outpatient HDREB sessions were carried out on consecutive 35 patients (mean age 69 yrs, M/F 29/6) with symptoms due to central airway obstruction. A shortterm endoscopic response was observed in 15/28 patients. After delivering 2000 cGy dyspnoea decreased significantly. After one month cough decreased and haemoptysis disappeared. Palliation was obtained in all patients except one during. Lung function tests did not significantly improve after HDREB. No fatal complication occurred. A temporary radiation bronchitis was observed in six patients. Conclusions. This non-comparative, prospective observational study showed a palliative response of HDREB in most of patients with advanced endoluminal lung cancer. The safety of the procedure was good and the rate of non-fatal serious complications was very low

Basics and frontiers on pancreatic cancer for radiation oncology: Target delineation, SBRT, SIB technique, MRgRT, particle therapy, immunotherapy and clinical guidelines

Pancreatic cancer represents a modern oncological urgency. Its management is aimed to both distal and local disease control. Resectability is the cornerstone of treatment aim. It influences the clinical presentation\u2019s definitions as up-front resectable, borderline resectable and locally advanced (unresectable). The main treatment categories are neoadjuvant (preoperative), definitive and adjuvant (postoperative). This review will focus on i) the current indications by the available national and international guidelines; ii) the current standard indications for target volume delineation in radiotherapy (RT); iii) the emerging modern technologies (including particle therapy and Magnetic Resonance [MR]-guided-RT); iv) stereotactic body radiotherapy (SBRT), as the most promising technical delivery application of RT in this framework; v) a particularly promising dose delivery technique called simultaneous integrated boost (SIB); and vi) a multimodal integration opportunity: the combination of RT with immunotherapy

Basics and frontiers on pancreatic cancer for radiation oncology: Target delineation, SBRT, SIB technique, MRgRT, particle therapy, immunotherapy and clinical guidelines

Pancreatic cancer represents a modern oncological urgency. Its management is aimed to both distal and local disease control. Resectability is the cornerstone of treatment aim. It influences the clinical presentation’s definitions as up-front resectable, borderline resectable and locally advanced (unresectable). The main treatment categories are neoadjuvant (preoperative), definitive and adjuvant (postoperative). This review will focus on i) the current indications by the available national and international guidelines; ii) the current standard indications for target volume delineation in radiotherapy (RT); iii) the emerging modern technologies (including particle therapy and Magnetic Resonance [MR]-guided-RT); iv) stereotactic body radiotherapy (SBRT), as the most promising technical delivery application of RT in this framework; v) a particularly promising dose delivery technique called simultaneous integrated boost (SIB); and vi) a multimodal integration opportunity: the combination of RT with immunotherapy

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity

Titin truncating variants affect heart function in disease cohorts and the general population

Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ~1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease

Phase II trial of docetaxel, cisplatin and fluorouracil followed by carboplatin and radiotherapy in locally advanced oesophageal cancer

This study was performed to assess the efficacy and safety of docetaxel, cisplatin and fluorouracil combination in patients with unresectable locally advanced oesophageal squamous cell carcinoma. Treatment consisted of docetaxel 60 mg m−2, cisplatin 75 mg m−2 on day 1 and fluorouracil 750 mg m−2 day−1 on days 2–5, repeated every 3 weeks for three cycles, followed by carboplatin 100 mg m−2 week−1 for 5 weeks and concurrent radiotherapy (45 Gy in 25 fractions, 5 days week−1). After radiotherapy, eligible patients either underwent an oesophagectomy or received high dose rate endoluminal brachytherapy (HDR-EBT). Thirty-one out of 37 enrolled patients completed the planned chemotherapy and 30 completed chemoradiation. After completion of chemotherapy, 49% (95% CI: 32.2–66.2) had a clinical response. Twelve patients (32%) underwent a resection, which was radical in 60% (postoperative mortality: 0%). A pathological complete response was documented in four patients (11% of enrolled, 30% of resected). The median survival was 10.8 months (95% CI: 8.1–12.4), and the 1- and 2-year survival rates were 35.1 and 18.9%, respectively. Grade 3–4 toxicities were neutropoenia 32%, anaemia 11%, non-neutropoenic infections 18%, diarrhoea 6% and oesophagitis 5%. Nine patients (24%) developed a tracheo-oesophageal fistula during treatment. Even if the addition of docetaxel to cisplatin and 5-fluorouracil (5-FU) seems to be more active than the cisplatin and 5-FU combination, an incremental improvement in survival is not seen, and the toxicity observed in this study population is of concern. In order to improve the prognosis of these patients, new drugs, combinations and strategies with a better therapeutic index need to be identified

Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population. OBJECTIVES: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults. METHODS: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status. RESULTS: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001). CONCLUSIONS: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease

Nationwide multidisciplinary consensus on the clinical management of Merkel cell carcinoma: a Delphi panel

Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma. The MCC incidence rate has rapidly grown over the last years, with Italy showing the highest increase among European countries. This malignancy has been the focus of active scientific research over the last years, focusing mainly on pathogenesis, new therapeutic trials and diagnosis. A national expert board developed 28 consensus statements that delineated the evolution of disease management and highlighted the paradigm shift towards the use of immunological strategies, which were then presented to a national MCC specialists panel for review. Sixty-five panelists answered both rounds of the questionnaire. The statements were divided into five areas: a high level of agreement was reached in the area of guidelines and multidisciplinary management, even if in real life the multidisciplinary team was not always represented by all the specialists. In the diagnostic pathway area, imaging played a crucial role in diagnosis and initial staging, planning for surgery or radiation therapy, assessment of treatment response and surveillance of recurrence and metastases. Concerning diagnosis, the usefulness of Merkel cell polyomavirus is recognized, but the agreement and consensus regarding the need for cytokeratin evaluation appears greater. Regarding the areas of clinical management and follow-up, patients with MCC require customized treatment. There was a wide dispersion of results and the suggestion to increase awareness about the adjuvant radiation therapy. The panelists unanimously agreed that the information concerning avelumab provided by the JAVELIN Merkel 200 study is adequate and reliable and that the expanded access program data could have concrete clinical implications. An immunocompromised patient with advanced MCC can be treated with immunotherapy after multidisciplinary risk/benefit assessment, as evidenced by real-world analysis and highlighted in the guidelines. A very high consensus regarding the addition of radiotherapy to treat the ongoing focal progression of immunotherapy was observed. This paper emphasizes the importance of collaboration and communication among the interprofessional team members and encourages managing patients with MCC within dedicated multidisciplinary teams. New insights in the treatment of this challenging cancer needs the contribution of many and different experts