Spontaneous Coronary Artery Dissection: Review of Possible Pathophysiological Risk Factors.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS) that typically affects the younger and healthier female population without the typical ACS risk factors such as hypertension, diabetes, or hyperlipidemia. The clinical presentation of SCAD can be diverse and the diagnosis is typically by coronary angiography but also can require advanced imaging such as intravascular ultrasound or optical coherence tomography. Past studies have shown the atypical patient characteristics of SCAD patients among ACS patients. The main challenge is that the exact pathophysiology of SCAD is unknown. Potential pathophysiological risk factors are discussed including fibromuscular dysplasia, other arteriopathies, pregnancy and female sex hormone changes, migraines, inflammatory conditions, and stress. The current understanding of these risk factors along with potential pathophysiological mechanisms are discussed. There still remain many areas of additional investigation in understanding this rare cause of ACS.

Coronavirus Disease 2019 and Cardiometabolic Disease.

Cardiometabolic disease describes a combination of metabolic abnormalities that increases the risk of type 2 diabetes and cardiovascular diseases, including pathological changes such as insulin resistance, hyperglycemia, dyslipidemia, abdominal obesity, and hypertension, and environmental risk factors such as smoking, sedentary lifestyle, poor diet, and poverty. As the number of coronavirus disease 2019 (COVID-19) patients continues to rise, type 2 diabetes, cardiovascular disease, hypertension, and obesity, all components of, or sequelae of cardiometabolic disease, were identified among others as key risk factors associated with increased mortality in these patients. Numerous studies have been done to further elucidate this relationship between COVID-19 and cardiometabolic disease. Cardiometabolic disease is associated with both increased susceptibility to COVID-19 and worse outcomes of COVID-19, including intensive care, mechanical ventilation, and death. The proinflammatory state of cardiometabolic disease specifically obesity, has been associated with a worse prognosis in COVID-19 patients. There has been no evidence to suggest that antihypertensives and antidiabetic medications should be discontinued in COVID-19 patients but these patients should be closely monitored to ensure that their blood pressure and blood glucose levels are stable. Assessment of vaccination efficacy in cardiometabolic disease patients is also discussed.

Tumor immune microenvironment of primary colorectal adenocarcinomas metastasizing to the liver or lungs.

BACKGROUND: Because of the heterogeneity of metastatic colorectal cancer (mCRC), a genome-wide analysis was performed to characterize the tumor immune microenvironment (TIME). METHODS: RNA-seq analysis of 62 primary CRCs without and 63 with systemic metastasis (SM- and SM+ groups) was conducted, and the data were used in a training set after adjustment by propensity score matching. Samples were further subdivided into those with hepatic metastasis (CHM subgroup), pulmonary metastasis (CPM subgroup), or concurrent CHM and CPM (concurrent group). Validation was done by quantitative reverse-transcription polymerase chain reaction using another 40 primary CRC samples. RESULTS: Compared with the CHM or CPM subgroups, the concurrent group showed upregulated in inflammatory or immune processes, cytokine secretion, and myeloid leukocyte migration. Nine candidate genes were selected: SM-specific IDO1, JAM3, and PDE2A; CHM- or CPM-specific BIRC7; CPM-specific HISI1H2BK, and both SM-specific and CHM- or CPM-specific EPHB6, LPL, THBD, and PPBP. In a validation set of primary CRCs, JAM3 and IDO1 (p = 0.044 and p = 0.036, respectively) were confirmed to show significant upregulation and downregulation, respectively, in the SM+ group, whereas HIST1H2BK (p = 0.017) was significantly upregulated in the CPM subgroup. CONCLUSIONS: Our findings indicate that a host-suppressive TIME is established in the primary tumor of mCRC and identify immune-related site-specific markers of mCRC.

Mechanotechnical faults and particular issues of anastomotic complications following robot-assisted anterior resection in 968 rectal cancer patients.

BACKGROUND: As most risk factors for anastomotic complications (AC) in rectal cancer patients appear to be noncorrectable, it is needed to find the correctable causes. Additionally, the outcomes of indocyanine-green fluorescence imaging (IFI) and robot-stapled anastomosis have yet been undetermined. METHODS: This study retrospectively analyzed 968 consecutive patients with rectal cancer, who underwent curative robot-assisted anterior resections between 2010 and 2018. IFI parameters and stapling features in the surgical records were reviewed, and reconfirmed. RESULTS: AC occurred in 54 patients (5.6%), 34 (3.5%) with anastomotic leakage (AL) and 24 (2.5%) with anastomotic stenosis (AS). Mechanotechnical faults including defective stapling configurations, including angles lesser than or equal to 150° and outer deviation (more than half from the center of the circle) of linear staples, between the two linear staples were independently associated with AL (P < .001 each). IFI significantly reduced AL rate (2.5% vs 5.3%, P = .029) and AS rate (2% vs 18.8%, P = .006), respectively. Robot linear stapling enabled to maintain the obtuse angle during consecutive staplings and reduced console time. AL and AS were independent risk factors for disease-free survival (P = .02) and local recurrence (P = .03), respectively. CONCLUSIONS: AC were associated with some correctable causes, namely, mechanotechnical errors and lack of use of IFI.

Increased nicotinamide adenine dinucleotide pool promotes colon cancer progression by suppressing reactive oxygen species level.

Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD+ ) and a reduced form (NADH). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD+ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD+ /NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD+ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two-photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT-mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.

Resection after preoperative chemotherapy versus synchronous liver resection of colorectal cancer liver metastases: A propensity score matching analysis.

This study aimed to determine the prognostic effects of preoperative chemotherapy for colorectal cancer liver metastasis (CLM).We retrospectively evaluated 2 groups of patients between January 2006 and August 2012. A total of 53 patients who had ≥3 hepatic metastases underwent resection after preoperative chemotherapy (preoperative chemotherapy group), whereas 96 patients who had ≥3 hepatic metastases underwent resection with a curative intent before chemotherapy for CLM (primary resection group). A propensity score (PS) model was used to compare the both groups.The 3-year disease-free survival (DFS) rates were 31.7% and 20.4% in the preoperative chemotherapy and primary resection groups, respectively (log-rank = 0.015). Analyzing 32 PS matched pairs, we found that the DFS rate was significantly higher in the preoperative chemotherapy group than in the primary resection group (3-year DFS rates were 34.2% and 16.8%, respectively [log-rank = 0.019]). Preoperative chemotherapy group patients had better DFSs than primary resection group patients in various multivariate analyses, including crude, multivariable, average treatment effect with inverse probability of treatment weighting model and PS matching.Responses to chemotherapy are as important as achieving complete resection in cases of multiple hepatic metastases. Preoperative chemotherapy may therefore be preferentially considered for patients who experience difficulty undergoing complete resection for multiple hepatic metastases.

Outcomes of ultra-low anterior resection combined with or without intersphincteric resection in lower rectal cancer patients.

PURPOSE: We evaluated the current practice of ultra-low anterior resection (uLAR) in patients with lower rectal cancer and compared uLARs using mostly transabdominal approach with or without intersphincteric resection (ISR). METHODS: A total of 624 consecutive lower rectal cancer patients undergoing curative uLAR were prospectively enrolled as ISR+ vs. ISR- groups (329 vs. 295 patients) between 2005 and 2012. The ISR+ group additionally received levator-sphincter reinforcement after distal resection. RESULTS: The circumferential resection margin (CRM) + rate (≤1 mm) was 2.1 % in the two groups. Postoperative ileus occurred more in the ISR- group than in the ISR+ group (p = 0.02). Substantial erectile dysfunction occurred 1.8 times more frequently in the ISR- group than in the ISR+ group (32 vs. 18.1 %; p = 0.01) among male patients at 2 years postoperatively. The urge to defecate volume and maximal tolerance volume, closely correlated with maximal squeezing pressure and/or mean resting pressure, did not differ between patients with and without chemoradiotherapy until 24 months postoperatively. Nevertheless, the urge to defecate volume was lesser in the ISR- group than in the ISR+ group at 24 months postoperatively (p = 0.022). For 301 patients in which >5 years had elapsed postoperatively, the mean 5-year local recurrence rate was 4.3 %, and the 5-year disease-free and overall survival rates were 78.9 and 92 %, respectively, without differences between the two groups. CONCLUSIONS: Compared with uLAR without ISR, the transabdominal ISR with levator-sphincter reinforcement provides a safe resection plane with competent CRM, concurrently reduces substantial complications, and marginally promotes recovery of neorectal function.

Epigenetic regulation of KLHL34 predictive of pathologic response to preoperative chemoradiation therapy in rectal cancer patients.

PURPOSE: Prediction of individual responsiveness to preoperative chemoradiation therapy (CRT) is urgently needed in patients with poorly responsive locally advanced rectal cancer (LARC). METHODS AND MATERIALS: Candidate methylation genes associated with radiosensitivity were identified using a 3-step process. In the first step, genome-wide screening of methylation genes was performed in correlation with histopathologic tumor regression grade in 45 patients with LARC. In the second step, the methylation status of selected sites was analyzed by pyrosequencing in 67 LARC patients, including 24 patients analyzed in the first step. Finally, colorectal cancer cell clones with stable KLHL34 knockdown were generated and tested for cellular sensitivity to radiation. RESULTS: Genome-wide screening identified 7 hypermethylated CpG sites (DZIP1 cg24107021, DZIP1 cg26886381, ZEB1 cg04430381, DKK3 cg041006961, STL cg00991794, KLHL34 cg01828474, and ARHGAP6 cg07828380) associated with preoperative CRT responses. Radiosensitivity in patients with hypermethylated KLHL34 cg14232291 was confirmed by pyrosequencing in additional cohorts. Knockdown of KLHL34 significantly reduced colony formation (KLHL34 sh#1: 20.1%, P=.0001 and KLHL34 sh#2: 15.8%, P=.0002), increased the cytotoxicity (KLHL34 sh#1: 14.8%, P=.019 and KLHL34 sh#2: 17.9%, P=.007) in LoVo cells, and increased radiation-induced caspase-3 activity and the sub-G1 population of cells. CONCLUSIONS: The methylation status of KLHL34 cg14232291 may be a predictive candidate of sensitivity to preoperative CRT, although further validation is needed in large cohorts using various cell types.

A comparison of the technical and oncologic validity between robot-assisted and conventional open abdominoperineal resection.

PURPOSE: This study was to ascertain whether a robot-assisted (RA) approach to APR might facilitate a cylindrical APR by enabling a deeper pelvic dissection during an abdominal approach, concurrently comparing the feasibility and short-term oncologic outcomes. METHODS: Forty-eight consecutive patients with lower rectal cancer who had undergone curative APR (21 RA vs. 27 open) were prospectively enrolled. The short-term operative outcomes and oncologic feasibility were evaluated and compared. A levator muscle excision was performed concomitantly with the abdominal procedure in the RA group and with the perineal procedure in the open group. RESULTS: No patients in the RA group experienced intraoperative perforation or required conversion to open APR. Overall, a cylindrical APR was performed in 72 % of patients, and subtotal excision of the levator muscle, i.e., either one or both sides of the puborectalis and pubococcygeus muscles, was more likely in the RA group (P = 0.019). A positive CRM was exclusively identified in four open APR patients. The mean number of retrieved lymph nodes was greater in the RA group (20 vs. 16, P = 0.035). There was no difference in perineal morbidity between the two groups (P = 0.445). CONCLUSIONS: The RA approach facilitates an efficient excision in the pelvic region than open APR during the abdominal procedure. The RA approach also demonstrated a trend toward improved oncologic outcomes with equivalent postoperative morbidities than with the open approach.

Completely abdominal intersphincteric resection for lower rectal cancer: feasibility and comparison of robot-assisted and open surgery.

BACKGROUND: Most previous studies of intersphincteric resection (ISR) adopted a two-stage procedure involving abdominal and transanal approaches. We performed completely abdominal ISR via open and a robot-assisted (RA) approaches as treatments for lower rectal cancer (LRC). The RA approach might enable deep dissection and facilitate ISR in patients with restrictive pelvic anatomy. METHODS: A consecutive cohort of 222 LRC patients who underwent completely abdominal ISR (RA ISR, n = 108; open ISR, n = 114) was enrolled prospectively, and their short-term outcomes were evaluated. RESULTS: In a multivariate analysis, ISR was performed more frequently in the RA than in the open group (82.6 vs. 67.9 %, p = 0.008). The number of harvested lymph nodes was >12 in both groups. A positive distal resection margin was not observed in either group, and a positive circumferential resection margin was found in one patient in the RA group. Overall morbidity did not differ between the groups. Moderate to severe sexual dysfunction occurred 2.7-fold more frequently in the open group (p = 0.023) among male patients ≤65 years. Mean Wexner's fecal incontinence scores at postoperative months 6 and 12 were greater in the open group than in the RA group (p < 0.05). CONCLUSIONS: Completely abdominal ISR may be feasible in the treatment of LRC, based on a short-term study. Furthermore, RA ISR had equivalent oncological outcomes and slightly improved functional recovery relative to open ISR.

Efficacy of light-emitting diode photomodulation in reducing erythema after fractional carbon dioxide laser resurfacing: a pilot study.

BACKGROUND: The most common side effects of fractional carbon dioxide (CO2 ) laser resurfacing are erythema and edema of the treated skin. Light-emitting diode (LED) devices have been shown to stimulate fibroblast activity and hasten wound healing. The current study was designed to evaluate the efficacy of such LED devices in treating post-laser therapy erythema. OBJECTIVES: To evaluate the clinical efficacy of LED photomodulation in reducing erythema resulting from ablative fractional CO2 laser resurfacing. MATERIALS AND METHODS: Randomly selected facial halves of 10 Korean subjects (Fitzpatrick skin type III-IV) were treated using a 635-nm wavelength LED array immediately after full-face fractional laser skin resurfacing. Each participant was subsequently treated with LED daily for the following 7 days. Clinical photographs, subjective physician assessment, and chromometer erythema index were used to track the results, with clinical improvement assessed using a 5-point grading scale. RESULTS: The postlaser erythema resolved faster on the experimental side than the control side, with improvements noted according to physician assessment and chromometer erythema index. Statistically significant improvements between the two sides were first noted on day 4. CONCLUSION: Treatment using a 635-nm-wavelength LED array decreases the intensity and duration of post-fractional CO2 laser treatment erythema.

Abdominoperineal resection and low anterior resection: comparison of long-term oncologic outcome in matched patients with lower rectal cancer.

PURPOSE: The current study aimed to compare the oncologic outcome and pattern of metastasis after abdominoperineal resection (APR) and low anterior resection (LAR) treating lower rectal cancer. METHODS: A total of 804 patients undergoing curative resection (R0) were enrolled prospectively. The APR and LAR groups (n = 402, respectively) were matched for gender, age, and stage, for a retrospectively comparative analysis. RESULTS: In a multivariate analysis with potential variables, APR itself was not a risk factor for increased local recurrence (LR) or reduced survival (P = 0.243-0.994). Circumferential resection margin (CRM) involvement as an operation-related risk was 1.6-fold more frequent in the APR group and was significantly associated with LR and systemic recurrence (OR, 2.487-4.017; P < 0.01). Circumferential margin positivity (CRM+) was concurrently correlated with advanced stage, larger tumor (long diameter, >4 cm), and longer sagittal midpelvic diameter (>10 cm) in a multivariate analysis (P < 0.001-0.05). The site of metastasis did not differ between the two groups, with the exception of lung metastasis which was more frequent in the APR group (APR vs. LAR: 15.9 vs. 10 %, P = 0.015). In the APR group, CRM+ and the presence of an infiltrating tumor were correlated with disease-free survival (hazard ratio (HR), 1.644 and 1.654, respectively), whereas elevated serum carcinoembryonic antigen and LVI+ were correlated with overall survival (HR, 1.57 and 1.671, respectively), in a multivariate analysis with potential variables (P < 0.05). CONCLUSIONS: When performed with appropriate skill to achieve R0 resection, APR can be used safely without impairing oncological outcome, although sphincter-preserving surgery should remain the preferred option.

Novel chemosensitive single-nucleotide polymorphism markers to targeted regimens in metastatic colorectal cancer.

PURPOSE: Methods for predicting individual responsiveness to targeted chemotherapy are urgently needed, considering the frequent resistance and extremely high cost. EXPERIMENTAL DESIGN: A chemosensitive single-nucleotide polymorphism (SNP) discovery schema is presented that utilizes (i) genome-wide SNP screening with a human SNP array and an in vitro chemosensitivity assay in 118 colorectal cancers, (ii) clinical association analysis in the other 98 patients who had received chemotherapy for metastatic cancer, and (iii) biological utility assessment using cell viability assays of transfected colorectal cancer (CRC) cells. RESULTS: Nine SNPs related to bevacizumab and cetuximab regimen sensitivity were chosen during screening. Overall responses for bevacizumab regimens revealed that patients carrying the TT genotype at ANXA11 rs1049550 or at least one G allele at LINS1 rs11247226 seemed greater chemosensitive than those carrying at least one C allele or the AA genotype, respectively (P < 0.05). For cetuximab regimens, patients carrying the GG genotype at DFNB31 rs2274159 or LIFR rs3729740 seemed greater chemosensitive than those carrying at least one A allele (P = 0.025 and P = 0.07). Cytotoxicity analyses showed that all RKO and HCT116 CRC clones transfected with the G allele at LIFR rs3729740 and the C allele at ISX rs361863 were more sensitive to cetuximab regimens than those with the A and T allele, respectively (P ≤ 0.001-0.024). CONCLUSIONS: Chemosensitive SNP markers were identified using a novel three-step process. The candidate marker LIFR rs3729740 and possibly ISX rs361863 will hopefully predict responsive patients to cetuximab regimens, although further validation is needed in large cohorts.

In vitro evaluation of histone deacetylase inhibitors as combination agents for colorectal cancer.

BACKGROUND: Our primary aim was to evaluate the additive efficacy of histone deacetylase inhibitors (HDACIs) in established treatment regimens for colorectal cancer in concurrence with identifying the clinicopathological markers significantly associated with tumor responsiveness. PATIENTS AND METHODS: The chemosensitivities of 125 colorectal carcinomas to established regimens [FLOX (5-FU + leucovorin + oxaliplatin) and FLIRI (5-FU + leucovorin + irinotecan)], two biologically targeted drugs (avastin and erbitux), and two hydroxamic acid derivatives (vorinostat, SAHA(R), and a novel candidate, CG2) were comparatively evaluated using an in vitro tumor response assay. RESULTS: The response rates of tumors (inhibition rate > or =30%) were significantly greater for FLOX and combinations (55.2-68%) compared to FLIRI and combinations (44-63.2%) (p=0.001 to 0.048), except in the case of the CG2 combination. The additive effects of HDACIs on the respective established regimens were considerably greater for non-responsive tumors (64.3-80%) than responsive tumors (32.7-45%) (p< or =0.0001 to 0.008). A number of biological parameters, including less advanced tumors and p53 overexpression, were significantly associated with additive chemosensitivity to HDACIs in combination with FLOX and FLIRI in multivariate analyses (p< or =0.001 to 0.023). Expanding tumor growth, diffuse cytoplasmic carcinoembryonic antigen (CEA) expression and synchronous adenoma were associated with combination regimens with targeted drugs (p=0.013 to 0.032). CONCLUSION: Our findings show additive chemoresponsiveness of colorectal tumors to HDAC inhibitors in combination with established regimens. The significant parameters associated with combination regimens of targeted drugs and HDACIs may be applied as effective chemosensitive markers in future clinical trials.

Chemoresponsiveness associated with canonical molecular changes in colorectal adenocarcinomas.

BACKGROUND: The canonical molecular changes in colorectal tumorigenesis were assessed for correlation with response to chemotherapy, in order to identify candidate markers. PATIENTS AND METHODS: In total, 156 patients received adjuvant postoperative fluoropyrimidine-based chemotherapy and 32 patients received oxaliplatin- or irinotecan-based chemotherapy following palliative surgery or for metastatic or recurrent colorectal tumors. Representative molecular changes in tumor tissues, including adenomatous polyposis coli (APC) gene, wingless-type MMTV integration site family (Wnt), mismatch repair (MMR), RAF, transforming growth factor (TGF)-beta, bone morphogenetic protein, and p53, had been previously determined, with an additional 42 patients included in this analysis. RESULTS: The disease-free survival period (mean+/-SEM) was significantly longer after fluoropyrimidine-based adjuvant chemotherapy in tumors with TGF-beta2 expression (42+/-1.4 vs. 21+/-4.7 months; p=0.005) and D18S46 loss of heterozygosity or microsatellite instability (45.7+/-1.5 vs. 40.5+/-1.4 months; p=0.048). In the metastatic settings, the high disease-control rate of oxaliplatin and irinotecan regimens correlated significantly with wild-type APC and intact MMR, respectively, relative to mutant APC and defective MMR (p=0.013, respectively). Interestingly, specific molecular steps of tumorigenensis were closely associated with particular toxicities. CONCLUSION: A subset of molecular changes occurring during colorectal tumorigenesis showed significant associations with therapeutic responses and toxicities to chemotherapy regimens, suggesting that these changes may be candidate predictors of chemoresponsiveness with further validation.