Is oligometastatic disease an applicable and useful concept in haematologic malignancies? A narrative review of radiation therapy standards, modern techniques, and innovations.

PURPOSE: Haematologic malignancies are particular in that they can generally be cured, even when distant metastases are present at diagnosis, unlike solid malignancies. Systemic treatments, including chemotherapy, targeted therapies, and immunotherapy, are the standard of care with excellent results. The considerable progress made in the management of these diseases in the last 20years has redefined the role of radiation therapy as minor in many clinical situations. We propose a literature review of data, showing that radiation therapy still has a role in curative, salvage, and palliative therapy situations. MATERIAL AND METHODS: A document and literature search was carried out in the following databases: Medline and ClinicalTrial.gov, for the terms "radiotherapy", "haematologic malignancies", "Hodgkin lymphoma", "non-Hodgkin lymphoma", "CAR T cells", "multiple myeloma", "solitary plasmocytoma", "intensity-modulated radiotherapy", "extracranial stereotactic body radiation therapy" and "proton therapy references". RESULTS: Haemopathological malignancies include a wide range of diseases and radiation therapy indications have been assessed over the past 20years. Currently, radiation therapy is indicated for localized disease (solitary plasmocytoma), as an adjuvant (Hodgkin lymphoma), in palliative settings, or after systemic treatment in relapsed patients (chimeric antigen receptor [CAR] T-cells) with a low recurrence burden, which can therefore be considered "oligorecurrence". Radiation therapy, through total body irradiation, has important indications, thanks to its immunomodulatory and/or myeloablative effects. Moreover, recent technological developments have made possible significant improvement in safety, contributing to radiation therapy being positioned in the treatment strategy of several indications. CONCLUSIONS: Given the effectiveness of systemic treatments in hematologic malignancies, the oligometastasis stage is of little importance. A curative intent after local radiation therapy, even advanced stage, is possible, both with residual disease for advanced Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, or solitary plasmocytoma, and even without evidence of disease after chemotherapy for Hodgkin or non-Hodgkin lymphoma. The role of new treatments, such as CAR T cells, allows us to consider radiation therapy after systemic treatment of relapsed diseases with low volume recurrence, which can be considered oligorecurrence.

Food-specific attribution of selected gastrointestinal illnesses: estimates from a Canadian expert elicitation survey.

The study used a structured expert elicitation survey to derive estimates of food-specific attribution for nine illnesses caused by enteric pathogens in Canada. It was based on a similar survey conducted in the United States and focused on Campylobacter spp., Escherichia coli O157:H7, Listeria monocytogenes, nontyphoidal Salmonella enterica, Shigella spp., Vibrio spp., Yersinia enterocolitica, Cryptosporidium parvum, and Norwalk-like virus. A snowball approach was used to identify food safety experts within Canada. Survey respondents provided background information as well as self-assessments of their expertise for each pathogen and the 12 food categories. Depending on the pathogen, food source attribution estimates were based on responses from between 10 and 35 experts. For each pathogen, experts divided their estimates of total foodborne illness across 12 food categories and they provided a best estimate for each category as well as 5th and 95th percentile limits for foods considered to be vehicles. Their responses were treated as triangular probability distributions, and linear aggregation was used to combine the opinions of each group of experts for each pathogen-food source group. Across the 108 pathogen-food groups, a majority of experts agreed on 30 sources and 48 nonsources for illness. The number of food groups considered to be pathogen sources by a majority of experts varied by pathogen from a low of one food source for Vibrio spp. (seafood) and C. parvum (produce) to a high of seven food sources for Salmonella spp. Beta distributions were fitted to the aggregated opinions and were reasonable representations for most of the pathogen-food group attributions. These results will be used to quantitatively assess the burden of foodborne illness in Canada as well as to analyze the uncertainty in our estimates.

An empirical model of perceived mortality risks for selected U.S. Arsenic hot spots.

Researchers have long recognized that subjective perceptions of risk are better predictors of choices over risky outcomes than science-based or experts' assessments of risk. More recent work suggests that uncertainty about risks also plays a role in predicting choices and behavior. In this article, we develop and estimate a formal model for an individual's perceived health risks associated with arsenic contamination of his or her drinking water. The modeling approach treats risk as a random variable, with an estimable probability distribution whose variance reflects uncertainty. The model we estimate uses data collected from a survey given to a sample of people living in arsenic-prone areas in the United States. The findings from this article support the fact that scientific information is essential to explaining the mortality rate perceived by the individuals, but uncertainty about the probability remains significant.

[Adjuvant and neoadjuvant radiotherapy in breast cancer: A literaure review and update on the state of the evidence in 2020]. / Radiothérapie adjuvante et néoadjuvante des cancers du sein : mise au point sur les données de la littérature disponibles en 2020.

Radiation therapy has benefited from many developments over the past 20 years. These developments are mainly linked to the technology, imaging and informatics evolutions which allow better targets definitions, ensure better organs-at-risk sparing and excellent reproducibility of treatments, with a perfect control of patient positioning. In breast cancer radiotherapy, the evolution was marked by the possibility of reducing the duration of treatments from 6-7 to 3-4 weeks by using hypofractionated regimens, or by further reducing the irradiation to one week when treatment is solely focalised to the tumour bed. This concept of accelerated partial breast irradiation has challenged the paradigm of the obligation to irradiate the whole breast after conservative surgery in all patients. In addition, the technical mastery of accelerated partial breast irradiation and the development of stereotactic radiotherapy techniques are currently contributing to the development of research projects in neoadjuvant settings. Thus, numerous ongoing studies are evaluating the impact of high-dose preoperative tumour irradiation, alone or in combination with systemic treatments, on biological tumor changes, on anti-tumour immunity, and on the pathologic complete response, which is considered as predictive of better long-term survival in some molecular breast cancer subtypes. In this review, we discuss all these developments which allow breast radiation therapy to enter the era of personalisation of treatments in oncology.

Genomic surveillance for hypervirulence and multi-drug resistance in invasive Klebsiella pneumoniae from South and Southeast Asia.

BACKGROUND: Klebsiella pneumoniae is a leading cause of bloodstream infection (BSI). Strains producing extended-spectrum beta-lactamases (ESBLs) or carbapenemases are considered global priority pathogens for which new treatment and prevention strategies are urgently required, due to severely limited therapeutic options. South and Southeast Asia are major hubs for antimicrobial-resistant (AMR) K. pneumoniae and also for the characteristically antimicrobial-sensitive, community-acquired "hypervirulent" strains. The emergence of hypervirulent AMR strains and lack of data on exopolysaccharide diversity pose a challenge for K. pneumoniae BSI control strategies worldwide. METHODS: We conducted a retrospective genomic epidemiology study of 365 BSI K. pneumoniae from seven major healthcare facilities across South and Southeast Asia, extracting clinically relevant information (AMR, virulence, K and O antigen loci) using Kleborate, a K. pneumoniae-specific genomic typing tool. RESULTS: K. pneumoniae BSI isolates were highly diverse, comprising 120 multi-locus sequence types (STs) and 63 K-loci. ESBL and carbapenemase gene frequencies were 47% and 17%, respectively. The aerobactin synthesis locus (iuc), associated with hypervirulence, was detected in 28% of isolates. Importantly, 7% of isolates harboured iuc plus ESBL and/or carbapenemase genes. The latter represent genotypic AMR-virulence convergence, which is generally considered a rare phenomenon but was particularly common among South Asian BSI (17%). Of greatest concern, we identified seven novel plasmids carrying both iuc and AMR genes, raising the prospect of co-transfer of these phenotypes among K. pneumoniae. CONCLUSIONS: K. pneumoniae BSI in South and Southeast Asia are caused by different STs from those predominating in other regions, and with higher frequency of acquired virulence determinants. K. pneumoniae carrying both iuc and AMR genes were also detected at higher rates than have been reported elsewhere. The study demonstrates how genomics-based surveillance-reporting full molecular profiles including STs, AMR, virulence and serotype locus information-can help standardise comparisons between sites and identify regional differences in pathogen populations.

Cyclic vomiting syndrome is a prevalent and under-recognized condition in the gastroenterology outpatient clinic.

BACKGROUND: Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder (FGID) characterized by intermittent episodes of nausea and vomiting. Our aim was to report its prevalence and associated features. METHODS: Data concerning demographics, symptoms, and psychiatric comorbidity were collected. Symptoms compatible with CVS were classified as per Rome III criteria. We recorded whether a diagnosis of CVS was considered in patients after negative investigation. We compared demographics and association with other FGIDs in patients with and without CVS. KEY RESULTS: 920 of 1002 patients provided data. Of the 920 patients, 112 (12.2%) had symptoms compatible with CVS. Thirteen (11.6%) of these had an organic cause for their symptoms, but 99 patients (88.4%) were deemed to have CVS (prevalence=10.8%). Organic causes for symptoms compatible with CVS included gastroparesis, large hiatus hernia, achalasia, and small bowel obstruction. Only 39.4% of patients with CVS were asked about vomiting symptoms at their initial consultation, and a diagnosis of CVS was considered in only four (4.0%) of the 99 patients. CVS was associated with younger age, tobacco smoking, never having married, psychiatric comorbidity, and presence of symptoms compatible with other FGIDs (P≤.01). CONCLUSIONS AND INFERENCES: Prevalence of CVS in this outpatient gastroenterology adult population was 10.8%. Identified associations included younger age, tobacco smoking, psychiatric comorbidity, and symptoms compatible with other FGIDs. The condition was considered as a possible diagnosis in <5% of patients who met the diagnostic criteria.

Derivation and validation of a diagnostic test for irritable bowel syndrome using latent class analysis.

BACKGROUND: The accuracy of symptom-based diagnostic criteria for irritable bowel syndrome (IBS) is modest. AIMS: To derive and validate a new test that utilises latent class analysis. METHODS: Symptom, colonoscopy, and histology data were collected from 1981 patients and 360 patients in two cohorts referred to secondary care for investigation of their gastrointestinal symptoms in Canada and the UK, respectively. Latent class analysis was used to identify naturally occurring clusters in patient-reported symptoms in the Canadian dataset, and the latent class model derived from this was then applied to the UK dataset in order to validate it. Sensitivity, specificity, and positive and negative likelihood ratios (LRs) were calculated for the latent class models. RESULTS: In the Canadian cohort, the model had a sensitivity of 44.7% (95% CI 40.0-50.0) and a specificity of 85.3% (95% CI 83.4-87.0). Positive and negative LRs were 3.03 (95% CI 2.57-3.56) and 0.65 (95% CI 0.59-0.71) respectively. A maximum positive LR of 3.93 was achieved following construction of a receiver operating characteristic curve. The performance in the UK cohort was similar, with a sensitivity and specificity of 52.5% (95% CI 42.2-62.7) and 84.3% (95% CI 79.3-88.6), respectively. Positive and negative LRs were 3.35 (95% CI 2.38-4.70) and 0.56 (95% CI 0.45-0.68), respectively, with a maximum positive LR of 4.15. CONCLUSIONS: A diagnostic test for IBS, utilising patient-reported symptoms incorporated into a latent class model, performs as accurately as symptom-based criteria. It has potential for improvement via addition of clinical markers, such as coeliac serology and faecal calprotectin.

Systematic review with meta-analysis: the effect of tobacco smoking on the natural history of ulcerative colitis.

BACKGROUND: Tobacco smoking is associated with a reduced risk of developing ulcerative colitis (UC). A high proportion of UC patients perceive a benefit in disease outcomes secondary to smoking. However, the effects of smoking on the natural history of UC are uncertain. AIM: To conduct a systematic review and meta-analysis of the effects of tobacco smoking on the natural history of UC. METHODS: A search of MEDLINE, EMBASE and EMBASE classic was carried out (up to December 2015) to identify observational studies reporting data on smoking and rates of colectomy, flare of disease activity, proximal disease extension, and development of pouchitis following panproctocolectomy and ileal pouch-anal anastomosis in patients with UC. Dichotomous data were pooled to obtain odds ratios (ORs), with 95% confidence intervals (CIs). RESULTS: The search identified 16 eligible studies: five (2615 patients) studying colectomy; four (620 patients) reporting on flare of disease activity; four (687 patients) examining proximal disease extension and three (355 patients) assessing development of pouchitis. Compared with nonsmokers, the odds of colectomy (OR = 0.89; 95% CI 0.62-1.26), flare of disease activity (OR = 1.26; 95% CI 0.65-2.44), proximal extension of disease (OR = 0.57; 95% CI 0.20-1.66) or the development of pouchitis (OR = 0.57; 95% CI 0.21-1.53) were not significantly lower in smokers. CONCLUSIONS: Smoking may not improve the natural history of ulcerative colitis. Given the health benefits of smoking cessation and the lack of clear benefit in ulcerative colitis, smoking cessation advice should be incorporated into guidance on the management of ulcerative colitis.

Systematic review with meta-analysis: the adverse effects of tobacco smoking on the natural history of Crohn's disease.

BACKGROUND: Tobacco smoking is a well-established risk factor for the development of Crohn's disease, and this may lead to a more complicated disease course. However, recent evidence suggests that many patients with Crohn's disease are unaware of this fact. AIM: To perform a systematic review and meta-analysis of the effects of smoking on disease course in Crohn's disease. METHODS: A search of MEDLINE, EMBASE and EMBASE classic was carried out (up to July 2015) to identify observational studies reporting data on smoking and rates of surgery or flares of disease activity in patients with Crohn's disease. Dichotomous data were pooled to obtain odds ratios (ORs) for flares of disease activity or need for surgery, with 95% confidence intervals (CIs). RESULTS: The search identified 33 eligible studies. Compared with nonsmokers, smokers had increased odds of flare of disease activity (OR, 1.56; 95% CI, 1.21-2.01), flare after surgery (OR, 1.97; 95% CI, 1.36-2.85), need for first surgery (OR, 1.68; 95% CI, 1.33-2.12) and need for second surgery (OR, 2.17; 95% CI, 1.63-2.89). The odds of these outcomes among ex-smokers diminished upon smoking cessation, with ORs comparable to those among nonsmokers and, in the case of flare or second surgery, significantly lower than smokers. CONCLUSIONS: Smokers with Crohn's disease have a more complicated disease course than nonsmokers, and quitting smoking may ameliorate this. Patients should be reminded of the detrimental effects of smoking on the course of their disease, and smoking cessation advice should be provided to reduce disease burden and costs in these patients.

Evaluation of biofouling for implantable micro dialysis system.

Implantable artificial kidney can drastically improve the quality of life of the renal disease patients. In previous study, our group has developed a multi-layered micro dialysis device which is composed of micro stainless steel channels and nano-porous polyethersulfone (PES) membranes. The device conducts hemofiltration without dialysis fluids, which is advantageous in miniaturization. We investigated the water-permeability of the PES membrane through in vivo experiments using rat model of renal disease for 5 hours and verified the effectiveness of the device. We investigated the permeability of PES membrane via in vitro experiments for 24 days. Biofouling on the PES membrane was found and caused deterioration of dialysis performance of the membrane. In this research, we investigated the biofouling such as thrombus, coagulation and protein adhesion on the sidewall of the micro fluidic channels. We investigated the micro fluidic channel geometry and surface condition associated with the processing methods. Conducting in vitro experiment for 7 days, biofouling was found to be mainly caused by the surface conditions. The mirror surface formed by electrolytic etching could substantially prevent biofouling.

Development of implantable hemodialysis system using PES membranes with high water-permeability.

This paper presents development of high water-permeable dialysis membranes. We proposed the system that does not use dialysis fluid for the implantable micro dialysis treatment and development of such membranes is crucial. We developed micro dialysis system composed by nanoporous membranes and microfluidic channels in our prior work. The membranes were made of nanoporous polyethersulfone (PES), which was not water-permeable. By not using dialysate, our device can be simplified because the pumps and storage tanks for the dialysis fluid are not necessary. This treatment is termed as hemofiltration. We measured the water permeability of PES membrane with respect to the concentrations of the PES, the additives, and the solvents in the casting solution. We could find the membranes with sufficiently high water permeability through in vitro experiments using a syringe pomp and whole cow blood, and the membrane had enough mechanical strength. We conducted experiments with multi-layered device in in vitro and in vivo using rats, where the system was connected to the vein and artery. We successfully collected the filtrate beyond target line, which was set by a medical doctor, without any leakage of blood from the device. The results verified that the filtration device can be scaled-up by increasing a number of the layer. We connected the device to a rat for 5h. It was verified the device maintained almost constant water permeability beyond our target line.

Histopathologic prognostic factors in stage IIb cervical carcinoma treated with radical hysterectomy and pelvic-node dissection - an analysis with mathematical statistics.

Of 107 patients with stage IIb cervical cancer who underwent laparotomy, 82 (77%) could be treated with radical hysterectomy (RAH) and pelvic-node dissection (PND). The remaining 25 patients were unsuitable for radical surgery because of para-aortic lymph node metastases, direct cancer invasion into the bladder muscle, and/or fixed enlarged pelvic lymph nodes (PLN): Such patients were treated with radiation therapy after laparotomy. Fifty-nine of RAH patients were given postoperative pelvic radiation because they had PLN metastases, parametrial invasion, and/or full thickness cervical stromal invasion. The overall 5-year survival of the patients undergoing RAH was significantly better than that of those who could not be treated with RAH (P < 0.001). In the RAH patients, parametrial invasion, which clinically defines stage IIb, was found only in 45%. Univariate analysis of histopathologic prognostic factors revealed that PLN metastasis, parametrial invasion, adenocarcinoma, and lymph-vascular space invasion significantly affected survival of the RAH patients (P < 0.05). Multivariate analysis using Cox's proportional hazards regression model, however, selected only PLN metastasis as a strong prognostic factor (P < 0.001). Concerning PLN metastasis patients with two or more positive nodal groups vs. 49%, P < 0.0001). The logistic regression analysis revealed that tumor diameter, parametrial invasion and lymph-vascular space invasion were independently correlated with PLN metastases in two or more nodal groups. The present data suggest that (i) the patients with massive pelvic extension of cancer cannot be cured by radiation therapy alone, (ii) the strong determinant of the prognosis of the patients undergoing RAH and PND is PLN metastasis. Therefore, for these patients with poor prognosic factors, other treatment modalities should be considered. From the present study it seems that planning RAH and PND for patients with stage IIb disease might make it possible to select poor prognostic subgroups, who have extra cervical extension or PLN metastases in two or more groups, and be useful in individualizing treatment.

Endometrial carcinoma in women aged 40 years or younger: a Japanese experience.

We report on the clinical and pathologic findings in 17 cases of endometrial carcinoma in Japanese women aged 40 years or younger. Age of the patients ranged from 16 to 40 years, with a median of 35 years. Nine of 17 tumors (52.9%) were stage I or II (FIGO 1988) but 8 (47.1%) were stage III. Four of the 8 patients with stage III disease had pelvic lymph node metastases and one also had para-aortic lymph node metastasis. One patient had metastasis to the ovary and peritoneal cytology was positive in 4 patients. Histologically, 13 of these 17 patients had endometrioid adenocarcinoma, 3 had adenoacanthoma and 1 had an undifferentiated carcinoma. Ten were well differentiated tumors (G1), 3 were moderately differentiated tumors (G2), and 4 were poorly differentiated tumors (G3). Nine of 17 (52.9%) showed deep myometrial invasion (more than a half of the myometrium) and 5 of 17 (29.4%) demonstrated lymphatic/vascular space invasion. Pelvic and para-aortic lymph node metastases were seen in 4 of 15 (26.7%) and 1 of 15 (6.7%), respectively. Two of these 17 patients died of disease in a relatively short follow-up period. In our experience there is no difference in the survival rates between patients aged 40 years or younger and those over 40 years.

A cheap technical solution for cranioplasty treatments.

Skull defects are treated by cranioplasty techniques, which are required to protect underlying brain, correct major aesthetic deformities, or both. This research is a part of our research project in ASEAN countries to investigate (i) the methods for design and manufacturing of cranioplasty implants, and (ii) the feasible technical solutions of minimizing the implant cost based on available production and biomaterial technologies in the region. In this paper, solutions for design and manufacturing of standardized implant templates (SDT) are presented. SDT are made based on the reverse engineering and rapid tooling techniques. With the use of SDT, surgeons have flexible options in preparing the implant both pre and intra operatively, and the operation time is minimized. In addition, the skills required to prepare an implant from SDT are not highly required. The cost for cranioplasty treatments by using SDT is acceptable for ASEAN region.

A FRET analysis to unravel the role of cholesterol in Rac1 and PI 3-kinase activation in the InlB/Met signalling pathway.

The signalling pathway for the hepatocyte growth factor receptor, Met/HGF-R, is hijacked by the bacterial surface protein InlB to induce Listeria monocytogenes entry into non-phagocytic cells. We previously showed that Listeria invades host cells by interacting with specialized microdomains of the host plasma membrane called lipid rafts. In this study, we analysed in living cells signalling events that are crucial for Listeria entry using a fluorescence resonance energy transfer-based microscopic method. Phosphoinositide (PI) 3-kinase activity and Rac1 signalling induced by Listeria interacting with epithelial cells were monitored as well as signalling induced by soluble InlB and the Met natural ligand HGF. We found that InlB and HGF induced similar kinetics of PI 3-kinase and Rac1 activation. PI 3-kinase activation was upstream and independent of Rac1 activation. Cholesterol-depletion experiments were performed to address the role of lipid rafts in Met signalling. The amount of 3'-phosphoinositides produced by PI 3-kinase was not affected by cholesterol depletion, while their membrane dynamic was cholesterol-dependent. Rac1 activation, downstream from PI 3-kinase, was cholesterol-dependent suggesting that the spatial distribution of 3'-phosphoinositides within membrane microdomains is critical for Rac1 activation and consequently for F-actin assembly at bacterial entry site.