Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival

Background:

Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity.

Methods:

The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)–BRCA pathway, ATM–ATR pathway and enzymatic activation of MMC. Functionality of the FA–BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20).

Results:

High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA–BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04).

Conclusions:

Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.     

Ischemic Burden Reduction and Long-Term Clinical Outcomes After Chronic Total Occlusion Percutaneous Coronary Intervention

ObjectivesThe authors sought to evaluate the impact of ischemic burden reduction after chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on long-term prognosis and cardiac symptom relief.BackgroundThe clinical benefit of CTO PCI is questioned.MethodsIn a high-volume CTO PCI center, 212 patients prospectively underwent quantitative [¹⁵O]H₂O positron emission tomography perfusion imaging before and three months after successful CTO PCI between 2013-2019. Perfusion defects (PD) (in segments) and hyperemic myocardial blood flow (hMBF) (in ml · min^?1 · g^?1) allocated to CTO areas were related to prognostic outcomes using unadjusted (Kaplan-Meier curves, log-rank test) and risk-adjusted (multivariable Cox regression) analyses. The prognostic endpoint was a composite of all-cause death and nonfatal myocardial infarction.ResultsAfter a median [interquartile range] of 2.8 years [1.8 to 4.3 years], event-free survival was superior in patients with ≥3 versus <3 segment PD reduction (p < 0.01; risk-adjusted p = 0.04; hazard ratio [HR]: 0.34 [95% confidence interval (CI): 0.13 to 0.93]) and with hMBF increase above (Δ≥1.11 ml · min^?1 · g^?1) versus below the population median (p < 0.01; risk-adjusted p < 0.01; HR: 0.16 [95% CI: 0.05 to 0.54]) after CTO PCI. Furthermore, event-free survival was superior in patients without versus any residual PD (p < 0.01; risk-adjusted p = 0.02; HR: 0.22 [95% CI: 0.06 to 0.76]) or with a residual hMBF level >2.3 versus ≤2.3 ml · min^?1 · g^?1 (p < 0.01; risk-adjusted p = 0.03; HR: 0.25 [95% CI: 0.07 to 0.91]) at follow-up positron emission tomography. Patients with residual hMBF >2.3 ml · min^?1 · g^?1 were more frequently free of angina and dyspnea on exertion at long-term follow-up (p = 0.04).ConclusionsPatients with extensive ischemic burden reduction and no residual ischemia after CTO PCI had lower rates of all-cause death and nonfatal myocardial infarction. Long-term cardiac symptom relief was associated with normalization of hMBF levels after CTO PCI.     

Changing patterns of cocaine use and hiv risks in the south of Brazil

For well over a decade, researchers in Porto Alegre, Brazil, have been documenting the extent of the AIDS epidemic in the region, with a specific focus on the linkages between drug use and HIV seropositivity. Virtually all of the studies conducted during those years found injection drug use (IDU) to be the major vector for HIV seropositivity in this population. However, recent research found that the number of IDUs had declined significantly. Qualitative interviews and focus groups suggested many reasons for this decline: (1) many had died, because they had never heard of AIDS or HIV, and were unaware of how HIV is transmitted. As a result, they had become infected through the sharing of injection paraphernalia. (2) The quality of street cocaine had declined, making injection difficult. (3) Because of a fear of AIDS, some shifted to the smoking of crack, which had become a newly availability commodity in the street culture. Within this context, this article describes the qualitative data describing the decline of cocaine injecting and the corresponding emergence of crack use in Porto Alegre, Brazil, and related HIV risks.     

Experimental model to induce obesity in rats

The etiology of obesity is multifactorial and is becoming a problem of public health, due to its increased prevalence and the consequent repercussion of its comorbidities on the health of the population. The great similarity and homology between the genomes of rodents and humans make these animal models a major tool to study conditions affecting humans, which can be simulated in rats. Obesity can be induced in animals by neuroendocrine, dietary or genetic changes. The most widely used models to induce obesity in rats are a lesion of the ventromedial hypothalamic nucleus (VMH) by administering monosodium glutamate or a direct electrical lesion, ovariectomy, feeding on hypercaloric diets and genetic manipulation for obesity.     

CSE1L, DIDO1 and RBM39 in colorectal adenoma to carcinoma progression

Background

Gain of chromosome 20q is an important factor in the progression from colorectal adenomas to carcinomas. Genes that drive 20q gain are expected to show correlation of mRNA and protein expression levels with 20q DNA copy number status while functionally influencing cancer processes. CSE1L, DIDO1 and RBM39 are located on the 20q amplicon and affect processes such as cell viability and anchorage-independent growth in colorectal cancer. This study aimed to investigate whether CSE1L, DIDO1 and RBM39 may drive 20q amplification.

Methods

Protein expression levels were examined by immunohistochemical evaluation of tissue microarrays containing a series of colorectal adenoma and carcinoma samples, which were characterized by genome-wide (microarray-based) DNA and mRNA profiling.

Results

CSE1L, DIDO1 and RBM39 mRNA expression levels correlated with chromosome 20q DNA copy number status. CSE1L protein expression was not associated with 20q gain, although its expression was increased in carcinomas compared to adenomas. DIDO1 and RBM39 protein expression was quite strong in the majority of tumors irrespective of 20q DNA copy number status.

Conclusion

The lack of correlation between protein expression levels and 20q DNA copy number status implies that CSE1L, DIDO1 and RBM39 are merely passengers rather than drivers of chromosome 20q gain in colorectal adenoma-to-carcinoma progression.     

Childhood trauma, impulsivity, and executive functioning in crack cocaine users

BackgroundThe use of crack cocaine is a major public health concern in Brazil and internationally. Recent data suggest that childhood trauma is associated with worse outcomes among cocaine users. This study had the objective of evaluating the relationship of childhood trauma with executive functioning and impulsivity in outpatients with crack cocaine use disorders.MethodsThis is a cross-sectional study of 84 consecutive outpatients with a primary crack cocaine use disorder who sought treatment in Porto Alegre, Brazil. Childhood trauma was evaluated with the Childhood Trauma Questionnaire; executive functioning, with the Wisconsin Card Sorting Test; and impulsivity, with the Barratt Impulsivity Scale.ResultsChildhood trauma was strongly associated with executive dysfunction and impulsivity, even when controlled for possible confounders.ConclusionsChildhood trauma may be associated with executive dysfunction and impulsivity in crack cocaine users. The full impact of trauma needs to be further investigated in longitudinal studies.     

The effects of replacing a portion of endurance training by explosive strength training on performance in trained cyclists

To investigate the effects of replacing a portion of endurance training by strength training on exercise performance, 14 competitive cyclists were divided into an experimental (E; n=6) and a control (C; n=8) group. Both groups received a training program of 9 weeks. The total training volume for both groups was the same [E: 8.8 (1.1) h/week; C: 8.9 (1.7) h/week], but 37% of training for E consisted of explosive-type strength training, whilst C received endurance training only. Simulated time trial performance (TT), short-term performance (STP), maximal workload ( ) and gross (GE) and delta efficiency (DE) were measured before, after 4 weeks and at the end of the training program (9 weeks). No significant group-by-training effects for the markers of endurance performance (TT and ) were found after 9 weeks, although after 4 weeks, these markers had only increased (P<0.05) in E. STP decreased (P<0.05) in C, whereas no changes were observed in E. For DE, a significant group-by-training interaction (P<0.05) was found, and for GE the group-by-training interaction was not significant. It is concluded that replacing a portion of endurance training by explosive strength training prevents a decrease in STP without compromising gains in endurance performance of trained cyclists. Electronic Publication