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Background Comprehensive next-generation sequencing is widely used for precision oncology and precision prevention approaches. We aimed to determine the yield of actionable gene variants, the capacity to uncover hereditary predisposition and liquid biopsy appropriateness instead of, or in addition to, tumor tissue analysis, in a real-world cohort of cancer patients, who may benefit the most from comprehensive genomic profiling. Methods Seventy-eight matched germline/tumor tissue/liquid biopsy DNA and RNA samples were profiled using the Hereditary Cancer Panel (germline) and the TruSight Oncology 500 panel (tumor tissue/cfDNA) from 23 patients consecutively enrolled at our center according to at least one of the following criteria: no available therapeutic options; long responding patients potentially fit for other therapies; rare tumor; suspected hereditary cancer; primary cancer with high metastatic potential; tumor of unknown primary origin. Variants were annotated for OncoKB and AMP/ASCO/CAP classification. Results The overall yield of actionable somatic and germline variants was 57% (13/23 patients), and 43.5%, excluding variants previously identified by somatic or germline routine testing. The accuracy of tumor/cfDNA germline-focused analysis was demonstrated by overlapping results of germline testing. Five germline variants in BRCA1 , VHL , CHEK1, ATM genes would have been missed without extended genomic profiling. A previously undetected BRAF p.V600E mutation was emblematic of the clinical utility of this approach in a patient with a liver undifferentiated embryonal sarcoma responsive to BRAF/MEK inhibition. Conclusions Our study confirms the clinical relevance of performing extended parallel tumor DNA and cfDNA testing to broaden therapeutic options, to longitudinally monitor cfDNA during patient treatment, and to uncover possible hereditary predisposition following tumor sequencing in patient care.

Mismatch repair (MMR) testing on all new cases of colorectal cancer (CRC) has customarily been preferably performed on surgical specimens, as more tissue is available; however, new clinical trials for the use of immune checkpoint inhibitors in the neoadjuvant setting require MMR testing on biopsy samples. This study aims at identifying advantages, disadvantages and any potential pitfalls in MMR evaluation on biopsy tissue and how to cope with them. The study is prospective-retrospective, recruiting 141 biopsies (86 proficient (p)MMR and 55 deficient (d)MMR) and 97 paired surgical specimens (48 pMMR; 49 dMMR). In biopsy specimens, a high number of indeterminate stains was observed, in particular for MLH1 (31 cases, 56.4%). The main reasons were a punctate nuclear expression of MLH1, relatively weak MLH1 nuclear expression compared to internal controls, or both (making MLH1 loss difficult to interpret), which was solved by reducing primary incubation times for MLH1. A mean of  ≥ 5 biopsies had adequate immunostains, compared to ≤ 3 biopsies in inadequate cases. Conversely, surgical specimens rarely suffered from indeterminate reactions, while weaker staining intensity (p < 0.007) for MLH1 and PMS2 and increased patchiness grade (p < 0.0001) were seen. Central artefacts were almost exclusive to surgical specimens. MMR status classification was possible in 92/97 matched biopsy/resection specimen cases, and all of these were concordant (47 pMMR and 45 dMMR). Evaluation of MMR status on CRC biopsy samples is feasible, if pitfalls in interpretation are known, making laboratory-specific appropriate staining protocols fundamental for high-quality diagnoses.

Standardization in immunohistochemistry is a priority in modern pathology and requires strict quality control. Cost containment has also become fundamental and auditing of all procedures must take into account both these principles. Positive controls must be routinely performed so that their positivity guarantees the appropriateness of the immunohistochemical procedure. The aim of this study is to develop a low cost (utilizing a punch biopsy—PB—tool) procedure to construct positive controls which can be integrated in the patient’s tissue slide. Sixteen frequently used control blocks were selected and multiple cylindrical samples were obtained using a 5-mm diameter punch biopsy tool, separately re-embedding them in single blocks. For each diagnostic immunoreaction requiring a positive control, an integrated PB-control section (cut from the appropriate PB-control block) was added to the top right corner of the diagnostic slide before immunostaining. This integrated control technique permitted a saving of 4.75% in total direct lab costs and proved to be technically feasible and reliable. Our proposal is easy to perform and within the reach of all pathology labs, requires easily available tools, its application costs is less than using external paired controls and ensures that a specific control for each slide is always available.

Portal vein embolisation (PVE) is used to increase the remnant liver volume before major liver resection for colorectal metastases. The resection rate after PVE is 60–70%, mainly limited by disease progression. The effect of PVE on tumour growth rate has not been investigated. The objective of this study was to compare the growth characteristics of resected colorectal liver metastases in patients undergoing pre-operative PVE with those of matched controls who had not undergone PVE. There were 22 patients who had undergone preoperative PVE and 20 matched controls. Tumour growth rate was calculated by the change in tumour volume (CT/MRI volumetric assessment) from diagnosis to resection. Resected histological specimens were examined by two histopathologists independently for cell differentiation, percentage tumour cell necrosis and mitotic rate. Immunochemical staining with Ki67 was carried out using the MIB-1 monoclonal antibody and quantified using a Glasgow cell-counting graticule. The groups were comparable in demographics, stage of primary disease, volume of liver metastases at presentation and chemotherapy received. The tumour growth rate calculated from imaging was more rapid in the PVE group compared with that in controls (control: 0.05±0.25 ml day −1 , PVE: 0.36±0.68 ml day −1 , P =0.06). Histology showed no difference in the degree of differentiation, extent of necrosis or apoptosis between the two groups. However, mitotic rate was higher post PVE, as was the proliferation index Ki67 ( P =0.04). This study has confirmed that tumour growth rate increased following PVE and that this is related to increased tumour cell division.

Background: The role of chemotherapy for neuroendocrine tumours remains controversial and there is no standard regimen. Method: We report the outcome for a consecutive series of chemonaive patients with metastatic or locally advanced neuroendocrine tumours treated with a combination of 5-fluorouracil (500 mg m −2 ), cisplatin (70 mg m −2 ) and streptozocin (1000 mg m −2 ) (FCiSt) administered three weekly for up to six cycles. Patients were assessed for radiological response, toxicity and survival. Results: In the 79 patients assessable for response, treatment with FCiSt was associated with an overall response rate of 33% (38% for pancreatic primary sites and 25% for non-pancreatic primary sites). Stable disease occurred in a further 51%, with progression in 16%. The median time to progression was 9.1 months and median overall survival was 31.5 months. The most common grade 3–4 toxicity was neutropaenia (28% patients) but grade 3–4 infection was rare (7%). The most frequent non-haematological grade 3–4 toxicity was nausea and vomiting (17%). Prognostic factors included Ki-67, mitotic index, grade and chromogranin A, whereas response to chemotherapy was predicted by mitotic index, grade and α -fetoprotein. Conclusions: FCiSt is an effective regimen for neuroendocrine tumours with an acceptable toxicity profile. Grade and mitotic index are the best predictors of response.

The steel production enhancement in recent decades has increased the solid waste generation in the steel plants. Due to the increase in the environmental policies stringency, efforts have been made to give them a more appropriate destination. In this context, the internal reuse of these materials is a solution often applied by the industry to reduce production costs and to decrease slag generation. Therefore, the aim of this research is to replace calcitic lime by limestone waste and KR slag in hot metal desulfurization, which are wastes from steel production. The KR slag is the waste generated by the desulfurization process in Kambara Reactor. Experimental desulfurization tests were carried out in a resistance furnace at a temperature of 1350?C, in an inert atmosphere with constant stirring of 500 rpm. Along with the tests, simulations were carried out with FactSage 7.0 software in order to obtain the phases present in each mixture at the working temperature and compare them with the practical results. It was found that the tricalcium silicate phase (3CaO?SiO2) was present in mixtures with lower desulfurization efficiency, which shows its kinetic limitation. The use of limestone waste proved to be more efficient than the use of KR slag.

Background Local therapy for early rectal cancer is a valid alternative to the classical radical operation, which has a higher morbidity and mortality rate. The use of high-dose preoperative radiation appears to enhance the options for sphincter-saving surgery even for T2–T3 rectal cancer patients with effective local control. The authors report their experience with transanal endoscopic microsurgery (TEM) used to manage selected cases of distal rectal cancer without evidence of nodal or distant metastasis (N0–M0). Methods The study enrolled 196 patients with rectal cancer (51 T1, 84 T2, and 61 T3). All the patients staged preoperatively as T2 and T3 underwent preoperative high-dose radiotherapy, and since 1997, patients younger than 70 years in good general condition also have undergone preoperative chemotherapy. Results Minor complications were observed in 17 patients (8.6%) and major complications in only 3 patients (1.5%). The definitive histology was 33 pT0 (17%), 73 pT1 (37%), 66 pT2 (34%), and 24 pT3 (12%). Eight patients (5 pT2 and 3 pT3) experienced local recurrence (4.1%). The rectal cancer-specific survival rate at the end of the follow-up period was 100% for pT1, 90% for pT2, and 77% for pT3 patients. Conclusions Patients with T1 cancer and favorable histologic features may undergo local excision alone, whereas those with T2 and T3 rectal cancer require preoperative radiochemotherapy. The results in the authors’ experience after TEM appear not to be substantially different in terms of local recurrence and survival rate from those described for conventional surgery.

The non-thermal nature of self-propelling colloids offers new insights into non-equilibrium physics. The central mathematical model to describe their trajectories is active Brownian motion, where a particle moves with a constant speed, while randomly changing direction due to rotational diffusion. While several feedback strategies exist to achieve position-dependent velocity, the possibility of spatial and temporal control over rotational diffusion, which is inherently dictated by thermal fluctuations, remains untapped. Here, we decouple rotational diffusion from thermal fluctuations. Using external magnetic fields and discrete-time feedback loops, we tune the rotational diffusivity of active colloids above and below its thermal value at will and explore a rich range of phenomena including anomalous diffusion, directed transport, and localization. These findings add a new dimension to the control of active matter, with implications for a broad range of disciplines, from optimal transport to smart materials. Active colloidal systems can serve as an enabling platform to study complex out-of-equilibrium physical phenomena. Using a magnetic control with a feedback loop, here the authors program the dynamics of active Brownian particles by updating their rotational diffusion coefficient depending on their locations.