Evaluating mismatch repair deficiency in colorectal cancer biopsy specimens.

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.

Responding to a school SARS-CoV-2 outbreak: Insights and policy implications emerging from the pandemic.

Background: The SARS-CoV-2 pandemic has affected also the school environment. Prolonged closures and the weakness of available data prevent a definitive answer to the question of school transmission. We report our experience of responding to COVID-19 cases in the school setting, presenting a case study of the management of an outbreak in a large school. Methods: The LHA/ASL Roma 1 has organized the School Units with a structure firmly rooted in the territory. At the local level, the District Unit mainly manages the relationship with schools, while the Hygiene and Public Health Service of the Prevention Department holds a coordinating and facilitating role. The HPHS carries out contact tracing activities facilitated by the schools, through the figure of the COVID-19 Contact Person, who is specifically trained to manage the preliminary stages of the reports. Results: Following several reports of COVID-19 suspect cases from two schools and, after a complex phase of contact tracing, it was possible to identify the major transmission chains. Furthermore, we performed a population-based screening on the entire school. Beyond the known transmission chains, for which quarantine was already in place, only five additional cases emerged, all asymptomatic, out of 1,231 swabs tested with RT-PCR. Conclusions: Our experience confirms that an active interaction between the school and the School Unit made it possible to quickly control a potentially dangerous outbreak. The large-scale screening test demonstrated the substantial absence of collateral transmission chains. Effective contact tracing allowed to set forth a successful response. Our model of intervention can be used to support public health protocols regarding school outbreaks.

Simplified Histologic Mucosal Healing Scheme (SHMHS) for inflammatory bowel disease: a nationwide multicenter study of performance and applicability.

BACKGROUND: Assessment of mucosal healing is important for the management of patients with inflammatory bowel disease (IBD), but endoscopy can miss microscopic disease areas that may relapse. Histological assessment is informative, but no single scoring system is widely adopted. We previously proposed an eight-item histological scheme for the easy, fast reporting of disease activity in the intestine. The aim of the present study was to evaluate the performance of our Simplified Histologic Mucosal Healing Scheme (SHMHS). METHODS: Between April and May 2021 pathologists and gastroenterologists in Italy were invited to contribute to this multicenter study by providing data on single endoscopic-histological examinations for their IBD patients undergoing treatment. Disease activity was expressed using SHMHS (maximum score, 8) and either Simple Endoscopic Score for Crohn's Disease (categorized into grades 0-3) or Mayo Endoscopic Subscore (range 0-3). RESULTS: Thirty hospitals provided data on 597 patients (291 Crohn's disease; 306 ulcerative colitis). The mean SHMHS score was 2.96 (SD = 2.42) and 66.8% of cases had active disease (score ≥ 2). The mean endoscopic score was 1.23 (SD = 1.05), with 67.8% having active disease (score ≥ 1). Histologic and endoscopic scores correlated (Spearman's ρ = 0.76), and scores for individual SHMHS items associated directly with endoscopic scores (chi-square p < 0.001, all comparisons). Between IBD types, scores for SHMHS items reflected differences in presentation, with cryptitis more common and erosions/ulcerations less common in Crohn's disease, and the distal colon more affected in ulcerative colitis. CONCLUSIONS: SHMHS captures the main histological features of IBD. Routine adoption may simplify pathologist workload while ensuring accurate reporting for clinical decision making.

Improving the efficacy of municipal solid waste collection with a communicative approach based on easily understandable indicators.

The main aim of the study was to propose a useful methodological approach to define easily understandable indicators to use in communication campaigns organized to improve the efficacy of municipal solid waste collection. For this purpose, six economic-environmental indicators were defined, combining life cycle thinking and environmental communication. The indicators make it possible to obtain several combinations that can follow a variety of communication channels. Three indicators (quantity of recyclable materials recoverable from unsorted residual waste; total potential economic saving; number of jobs for young people as communicators) are expressed in absolute value and therefore refer to the whole community even if they are also good for single-targeted messages. The other three indicators (potential economic saving for each citizen; per capita saving of carbon dioxide equivalent; per capita saving of Disability Adjusted Life Years) are normalized with respect to the number of inhabitants and therefore refer to the individual citizen, but can also be used for global messages. As a case example, the methodology was applied to the collection of paper and cardboard in twelve Southern Italy cities obtaining very promising results. For example, the maximum quantity of paper and cardboard recoverable from unsorted waste would allow Naples and Palermo to recover more than €15 million. The maximum potential economic saving for each citizen was 25 €/capita. The economic saving obtained for Naples and Palermo could be translated in more than one thousand positions as young environmental communicators. Catania was the city with both the highest per capita potential saving of carbon dioxide (>60 kg CO2eq./capita) and maximum hypothetical per capita 'life-time recovery' (almost an hour). The innovative communication method used ('Greenopoli') assumed that school is the starting point to obtain a change of mindset because speaking with students (all potential communicators) means indirectly communicating with all other targets.

Diabetes associated with immune checkpoint inhibition: presentation and management challenges.

BACKGROUND: In recent years, immune checkpoint blockade has become a standard therapy for a wide range of cancers. Adverse events including endocrinopathies result from the induction of autoimmunity. CASE REPORT: We report a case series of nine individuals who presented with immunotherapy-induced type 1 diabetes between 2015-2017. DISCUSSION: Onset of diabetes occurred within 12 weeks of commencing therapy. Anti- GAD antibodies were present in six people. Retrospective testing of islet antibodies in pre-treatment samples was possible in two people and this revealed anti-GAD seroconversion in the first and high anti-GAD titres pre and post-treatment in the second person. Six people had high risk HLA haplotypes. Clinical and genetic factors are described and compared with previously published cases. This article is protected by copyright. All rights reserved.

Docetaxel-related fatigue in men with metastatic prostate cancer: a descriptive analysis.

PURPOSE: Fatigue is a prevalent and debilitating side effect of docetaxel chemotherapy in metastatic prostate cancer. A better understanding of the kinetics and nature of docetaxel-related fatigue may provide a framework for intervention. METHODS: This secondary analysis was performed using the MOTIF database, from a phase III, randomised, double-blind, placebo-controlled study of modafinil (200 mg/day for 15 days) for docetaxel-related fatigue in men with metastatic prostate cancer [1]. The pattern of fatigue was analysed using the MDASI (MD Anderson Symptom Inventory) score. The impact of modafinil, cumulative docetaxel exposure, age and smoking status on fatigue kinetics were explored. Fatigue-related symptoms were assessed using the SOMA6 (fatigue and related symptoms) subset of the SPHERE (Somatic and Psychological Health Report). Mood was tracked using the short form 36 health survey questionnaire (SF-36). RESULTS: Across four docetaxel cycles, fatigue scores were higher in the first week and decreased over weeks two and three. Whilst men randomised to modafinil had reduced fatigue scores, cumulative docetaxel had little impact. Younger men (55-68 years) had significantly reduced fatigue scores, whereas current and ex-smokers had higher scores. There was no significant change in mood status or haemoglobin across treatment cycles. Men described both 'somnolence' and 'muscle fatigue' contributing significantly to their symptom complex. CONCLUSIONS: Assessment and management of docetaxel-related fatigue remains an important challenge. Given the complex, multifactorial nature of fatigue, identification through structured interview and interventions targeted to specific 'at risk' groups may be the most beneficial. Understanding the temporal pattern (kinetics) and nature of fatigue is critical to guide this process.

Timely initiation of chemotherapy: a systematic literature review of six priority cancers - results and recommendations for clinical practice.

This review evaluated the association between time-to-chemotherapy (TTC) and survival in six priority cancers. A systematic review of the literature was undertaken for papers indexed in the MEDLINE and Cochrane Library databases from the earliest index until April 2014. The methodology used has been published in a separate paper (Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services). The optimal timing of chemotherapy in breast cancer is unclear as available studies are of low quality, report inconsistent results and are limited to the adjuvant setting. However, increased TTC may have a negative prognostic impact, and delays beyond 4 weeks should be avoided. Studies suggest that the optimal timing for initiation of adjuvant chemotherapy for surgically resected colorectal cancer is 4-8 weeks post-surgery. Timing of chemotherapy for metastatic colorectal cancer does not influence survival. There is a paucity of studies to guide the timing of chemotherapy for the treatment of lymphoma and myeloma; no definitive conclusions can be drawn, and clinician discretion should be applied. The optimal timing of chemotherapy in lung cancer is unclear; however, rapid tumour growth and poor disease prognosis suggest that delays should be avoided wherever possible. The optimal timing of chemotherapy in ovarian cancer is unclear as available studies are of low level, report inconsistent results and are limited to the post-surgery setting; however, increased TTC may have a negative prognostic impact; therefore, delays beyond 4 weeks should be avoided.

Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services.

These guidelines, informed by the best available evidence and consensus expert opinion, provide a framework to guide the timely initiation of chemotherapy for treating cancer. They sit at the intersection of patient experience, state-of-the-art disease management and rational efficient service provision for these patients at a system level. Internationally, cancer waiting times are routinely measured and publicly reported. In Australia, there are existing policies and guidelines relating to the timeliness of cancer care for surgery and radiation therapy; however, until now, equivalent guidance for chemotherapy was lacking. Timeliness of care should be informed, where available, by evidence for improved patient outcomes. Independent of this, it should be recognised that shorter waiting periods are likely to reduce patient anxiety. While these guidelines were developed as part of a proposed framework for consideration by the Victorian Department of Health, they are clinically relevant to national and international cancer services. They are intended to be used by clinical and administrative staff within cancer services. Adoption of these guidelines, which are for the timely triage, review and treatment of cancer patients receiving systemic chemotherapy, aims to ensure that patients receive care within a timeframe that will maximise health outcomes, and that access to care is consistent and equitable across cancer services. Local monitoring of performance against this guideline will enable cancer service providers to manage proactively future service demand.

Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy.

BACKGROUND: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. METHODS: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. RESULTS: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. CONCLUSIONS: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.

'First, do no harm': managing the metabolic impacts of androgen deprivation in men with advanced prostate cancer.

Androgen deprivation therapy (ADT) is a standard systemic treatment for men with prostate cancer. Men on ADT may be elderly and have comorbidities that are exacerbated by ADT, such as cardiovascular disease, diabetes, obesity, sedentary lifestyle and osteoporosis. Studies on managing the impacts of ADT have focused on men with non-metastatic disease, where ADT is given for a limited duration. However, some men with advanced or metastatic prostate cancer will achieve long-term survival with palliative ADT and therefore also risk morbidity from prolonged ADT. Furthermore, ADT is continued during the use of other survival-prolonging therapies for men with advanced disease, and there is a general trend to use ADT earlier in the disease course. As survival improves, management of the metabolic effects of ADT becomes important for maintaining both quality and quantity of life. This review will outline the current data, offer perspectives for management of ADT complications in men with advanced prostate cancer and discuss avenues for further research.

Immigrants' perceptions of the quality of their cancer care: an Australian comparative study, identifying potentially modifiable factors.

BACKGROUND: Recent data show a falling cancer mortality in the general population without a similar shift in immigrant outcomes, leading to a greater cancer burden and mortality for immigrants. Our aims were to compare perceived patterns of care in immigrants and native-born cancer patients. PATIENTS AND METHODS: This was a hospital-based sample of first-generation immigrants and Australian-born Anglo patients in the first year following diagnosis. It was restricted to Chinese, Arabic, or Greek speakers. Eligible participants, recruited via 16 oncology clinics, were over 18, with cancer (any type or stage), and having commenced treatment at least 1 month previously. Five hundred and seventy-one CALD patients (comprising 145 Arabic, 248 Chinese, and 178 Greek) and a control group of 274 Anglo-Australian patients participated. RESULTS: Immigrants had difficulty communicating with the doctor (73% versus 29%) and understanding the health system (38% versus 10%). Differences were found in 'difficulty knowing who to see' (P = 0.0002), 'length of time to confirm diagnosis' (P = 0.04), wanting more choice about a specialist and hospital (P < 0.0001); being offered the opportunity to see a counselor (P < 0.0001); and actually seeing one (P < 0.0001). There were no significant self-reported differences regarding how cancer was detected, time to see a health professional, or type first seen; however, immigrants reported difficulty knowing who to see. Previous studies showed differences in patterns of care according to socioeconomic status (SES) and educational level. Despite adjusting for age, sex, education, marital status, SES, time since diagnosis, and type of cancer, we did not find significant differences. Instead, we found that understanding of the health system and confidence understanding English were important factors. CONCLUSIONS: This study confirmed that immigrants with cancer perceive an inferior quality of cancer care. We highlight potentially modifiable factors including assistance in navigating the health system, translated information, and cultural competency training for health professionals.

Dietary consumption of meat, fat, animal products and advanced glycation end-products and the risk of Barrett's oesophagus.

BACKGROUND: Advanced glycation end-products (AGEs) are found in high quantity in high-fat foods and meat cooked at high temperature. AGEs have been shown to contribute to chronic inflammation and oxidative stress in humans. AIM: To investigate the associations between consumption of meat, fat and AGEs, and the risk of Barrett's oesophagus (BO). METHODS: We conducted a case-control study using data from the patients who were scheduled for elective esophagogastroduodenoscopy (EGD) and from a random sample of patients who were identified at primary care clinics. Daily consumption of meat, fat and Nε-(carboxymethyl) lysine (CML), a major type of AGEs, was derived from the food frequency questionnaire (FFQ). Multivariate logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI) for BO. RESULTS: A total of 151 cases with BO and 777 controls without BO completed the FFQ. The multivariate OR (95% CI) for BO was 1.91 (1.07-3.38) for total meat, 1.80 (1.02-3.16) for saturated fat and 1.63 (0.96-2.76) for CML-AGE, when the highest tertile of intake was compared with the lowest. The association for total meat was attenuated to 1.61 (0.82-3.16), and that for saturated fat to 1.54 (0.81-2.94) after adjusting for CML-AGE. CONCLUSIONS: Higher consumption of total meat, saturated fat or possibly CML-AGE was associated with an increased risk of Barrett's oesophagus. CML-AGE may partly explain the association between total meat and saturated fat consumption and the risk of Barrett's oesophagus.

Developing a national database for metastatic colorectal cancer management: perspectives and challenges.

BACKGROUND: The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian-centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed. AIMS: To establish a collection of a consensus dataset capturing treatment and outcomes at multiple public and private hospitals across Australia. METHODS: An electronic database was developed by a panel of clinicians, to capture an agreed dataset for patients with newly diagnosed metastatic colorectal cancer. Of particular interest were clinician decision-making, the impact of comorbidities and the frequency of major adverse events. RESULTS: Since July 2009, data collection has been established at six public and eight private hospitals across three Australian states and territories. Successful linkage and analysis, with support from BioGrid Australia, of selected data on the initial 864 patients demonstrates that data can be captured from diverse sites, including public and private practice, that multiple factors impact on treatment delivered and outcomes achieved and that comprehensive data on rare but important adverse events can be captured. As a clinical research tool, the project has been highly successful, generating multiple presentations at national and international conferences related to a diverse range of research questions. CONCLUSIONS: Multistate, project-specific data collection involving large numbers of patients is achievable. Providing invaluable insight into the routine clinical management of metastatic colorectal cancer in the era of targeted therapies, this also creates a significant resource for research, including many questions not being addressed by clinical trials.

The prevalence of oesophageal eosinophilia and eosinophilic oesophagitis: a prospective study in unselected patients presenting to endoscopy.

BACKGROUND: Oesophageal eosinophilia (EE) is encountered in clinical practice as oesophageal biopsies are being obtained in patients with GI symptoms other than classical symptoms of eosinophilic oesophagitis (EoE). The prevalence, determinants and clinical relevance of EE identified irrespective of symptoms are unclear. AIM: To determine the prevalence and risk factors of EE with or without EoE in a nonselected group of patients undergoing endoscopy and in primary care patients. METHODS: A cross-sectional study in a single VA centre in which we obtained at least one oesophageal biopsy from patients presenting to elective endoscopy, as well as a sample of patients eligible for screening colonoscopy recruited from primary care clinics. EE was defined by >15 eosinophils in a single HPF; and EoE was defined as definite, probable or none depending on the presence of EE, acid-suppressive therapy and oesophageal symptoms. RESULTS: EE was identified in 33 of 1357 patients (2.4%, 95% CI: 1.7-3.4); of whom 9 had definite EoE (0.66%, 95% CI: 0.23-1.10), 17 had probable EoE (1.25%), and the only 7 patients had EE without EoE. The prevalence of EE was 2.3% among patients undergoing elective endoscopy and 0.1% among patients eligible for screening colonoscopy. Seasonal allergies (adjusted OR: 2.78; 95% CI: 1.26-6.11) and oesophageal strictures (4.50; 0.90-22.40) were associated with EE. CONCLUSIONS: The prevalence of EE was 2.3% among unselected patients presenting to endoscopy most of whom have EoE. EE was present in 0.1% in primary care patients none of whom had EoE.

Effect of highly dispersed yttria addition on thermal stability of hydroxyapatite.

The capability of the colloidal method to produce yttria (Y(2)O(3)) dispersed hydroxyapatite (HA) has been investigated as an alternative method to the conventional method of mechanical mixing and sintering for developing HA-based materials that could exhibit controllable and enhanced functional properties. A water based colloidal route to produce HA materials with highly dispersed Y(2)O(3) has been applied, and the effect of 10 wt.% Y(2)O(3) addition to HA investigated by thermal analysis, X-ray diffraction and Fourier transform infrared spectroscopy. These measurements evidence a remarkable effect of this Y(2)O(3) addition on decomposition mechanisms of synthetic HA. Results show that incorporation of Y(2)O(3) as dispersed second phase is beneficial because it hinders the decomposition mechanisms of HA into calcium phosphates. This retardation will allow the control of the sintering conditions for developing HA implants with improved properties. Besides, substitution of Ca(2+) with Y(3+) ions appears to promote the formation of OH(-) vacancies, which could improve the conductive properties of HA favorable to osseointegration.

Functionalizing Ti-surfaces through the EPD of hydroxyapatite/nanoY2O3.

Ceramic materials for skeletal repair and reconstruction are expanding to a number of different applications. Present research is addressing new compositions and performances to promote osseo-integration through metal coatings. Nanotechnology plays a key role in this research because nanostructures can be introduced into implants to functionalize them and/or to enhance their properties, such as the thermal or mechanical response. In this work, the insertion of Y(2)O(3) nanoparticles into a hydroxyapatite (HA) coating of Ti using colloidal processing technology was developed. The suspensions of HA and Y(2)O(3) nanoparticles were formulated with a focus on zeta potential, particle size distribution, and viscosity for the codeposition of both phases by electrophoresis. The microstructure of the nanocomposite coating was optimized by adjusting the main parameters of the electrophoretic deposition process. A threshold value of the applied electric field for the composite shaping was identified. The results demonstrate that the Y(2)O(3) nanoparticles are homogeneously distributed in the coating and decrease in concentration as the distance from the substrate increases. As a consequence of the presence of the Y(2)O(3), delays in the HA thermal decomposition and the improvement of metal-ceramic joining were observed.