Results from pelvic exenteration for locally advanced colorectal cancer with lymph node metastases

PURPOSE: We examined the survival benefit of pelvic exenteration for locally advanced colorectal cancer with lymph node metastases, because this issue remains controversial. METHODS: Medical records of 50 patients who underwent curative pelvic exenteration for colorectal cancer were reviewed retrospectively. Nodal metastases were examined by the clearing method in 29 patients and by the conventional manual method in 21 patients. RESULTS: Invasion to contiguous pelvic organs was present in 40 patients (80 percent) and absent in 10 patients (20 percent). Node metastases were present in 33 patients (66 percent). Operative morbidity and mortality rates were 22 percent (11 patients) and 6 percent (3 patients), respectively. Respective five-year survival rates were 60 and 80 percent in the groups with and without organ invasion (no significant difference). Five-year survival rates in patients with nodal metastases was 54.6 percent but was significantly higher, 82.4 percent, in patients without nodal metastases. Five-year survival in 28 patients with both organ invasion and nodal metastases was 53.6 percent. CONCLUSIONS: Long-term survival was afforded by pelvic exenteration for locally advanced colorectal cancer with nodal metastases.     

Distribution of metastatic lymph nodes in colorectal cancer by the modified clearing method

PURPOSE: The aim of this study was to clarify the distribution of lymph node metastasis in colorectal cancer. We also examined the relationship between the primary tumor (T) and the regional node (N) categories of the TNM (primary tumor, regional nodes, metastasis) classification. METHOD: Lymph nodes of surgical specimens in 311 consecutive patients with colorectal cancer were studied using the modified clearing method. RESULTS: Lymph node metastasis was seen in 59.2 percent of the total cases. The upward metastasis rate was 30.7 percent. In the longitudinal spread, most of the lymph node metastasis was seen within 10 cm. On the oral side in rectal cancer, there was no metastasis beyond 4 cm. The lateral metastasis rate in rectal cancer was 8.8 percent and in the lower rectum, the rate of cancer within 6 cm from the anal verge or beyond pT3 was much higher. CONCLUSION: In the TNM classification, there was no significant difference between colon and rectal cancer except pT1 with rectal cancer. In the lower rectal cancer within 6 cm from the anal verge or beyond pT3, there is a high risk of lateral metastasis, and lateral lymph node dissection or radiation therapy should be performed.     

CHA2DS2-VASc score is a useful-predictor of not prognosis but coronary-arteriosclerosis in chronic atrial-fibrillation compared with CHADS2 score: A two-center study of 320-slice CT,part 2

Background

The aim of this study is to predict the risk of coronary-arteriosclerosis and prognosis in subjects with chronic-atrial-fibrillation (CAF) using the CHADS2 and CHA2DS2-VASc scores by 320-slice-CT and invasive-coronary-angiography (ICA) in a two-center-study.

Methods

53 CAF subjects who underwent 320-slice-CT and ICA within 6-months (43 male; 69 ± 9 years; CHADS2 score 2.2 ± 1.3; CHA2DS2-VASc score 3.5 ± 1.6) in the two-institutes were analyzed. CT and ICA data were transferred to the analysis-center and were analyzed by cardiologists.

Results

Agatston-calcium-score and frequencies of the presence of various-kinds of plaques and > 50% and > 75% coronary artery stenosis were significantly higher in the subjects with CHA2DS2-VASc score ≥ 3 compared with those with score < 3. However there were no-significant differences in the Agatston-calcium-score and frequencies of the presence of various-kinds of plaques and > 50% and > 75% coronary artery stenosis evaluated by 320-slice CT between the subjects with CHADS2 score ≥ 2 and < 2. Frequency of > 50% coronary artery stenosis by ICA was significantly higher in the subjects with CHA2DS2-VASc score ≥ 3 compared with those with score < 3. However, there were no-significant differences in the frequencies of > 50% and > 75% coronary artery stenosis by ICA between the subjects with CHADS2 score ≥ 2 and < 2. During a mean of 15.9 months, composite rate of cardiac death and heart failure did not differ between subjects with CHADS2 score ≥ 2 and score < 2 and between subjects with CHA2DS2-VASc score ≥ 3 and score < 3.

Conclusions

The CHA2DS2-VASc score is a useful predictor of not prognosis but coronary-arteriosclerosis in subjects with CAF compared with CHADS2 score in this two-center-study.     

Right bundle branch block without overt heart disease predicts higher risk of pacemaker implantation: The study of atomic-bomb survivors

Background

We investigated the clinical course of complete right bundle branch block (RBBB) or RBBB with axis deviation (AD) in terms of subsequent pacemaker implantation for high-degree atrioventricular (AV) block or sick sinus syndrome (SSS).

Methods and results

Among the 16,170 atomic-bomb survivors in our biennial health examination between July 1967 and December 2010, we detected 520 newly-acquired RBBB subjects with no organic heart disease, and selected 1038 age- (at RBBB diagnosis) and sex-matched subjects without RBBB to serve as comparison subjects. Multivariate Cox regression analysis was used to estimate the hazard ratios (HRs) for the risk of pacemaker implantation due to all causes, AV block or SSS between RBBB and comparison subjects and between RBBB subjects with and without AD. The risk of pacemaker implantation for RBBB was 4.79 (95% confidence interval [CI] 1.89–12.58; P = 0.001), 3.77 (95% CI, 1.09–13.07; P = 0.036), and 6.28 (95% CI, 1.24–31.73, P = 0.026) when implantation was for all causes, AV block and SSS, respectively. RBBB subjects with AD had a higher risk for all-cause pacemaker implantation than subjects without AD (HR, 3.03; 95% CI, 1.00–9.13, P = 0.049). RBBB subjects with AD were younger than subjects without AD at the time of RBBB diagnosis (59.4 ± 7.6 vs 74.4 ± 3.1 years old, P = 0.019), and their progression from diagnosis to pacemaker implantation took longer (15.1 ± 6.6 vs 6.4 ± 3.0 years, P = 0.032).

Conclusions

RBBB, especially with AD, progresses to AV block and SSS that requires pacemaker implantation; the mechanisms by which the conduction defect progresses differ among patients with and without AD.     

Immunolocalization of murine type VI 3β-hydroxysteroid dehydrogenase in the adrenal gland,testis, skin,and placenta

The enzyme 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD) is essential for the biosynthesis of all active steroid hormones, such as those secreted from the adrenal gland, testis, ovary, skin and placenta. The 3β-HSD enzymes exist in multiple isoforms in humans and rodents. To date, six different isoforms have been identified in the mouse, and these isoforms are speculated to play different roles in different tissues. We previously showed that the murine type VI 3β-HSD isoform (Hsd3b6) is expressed specifically in the aldosterone-producing zona glomerulosa cells within the adrenal gland and that its overexpression causes abnormally increased aldosterone synthesis, revealing a crucial (or rate-limiting) role of this enzyme in steroidogenesis. However, potential contributions of this enzyme to the steroid hormone synthesis outside the adrenal glands are poorly understood. This paucity of knowledge is partly because of the lack of isoform-specific antibody that can be used for immunohistochemistry. Here, we report the development and characterization of specific antibody to Hsd3b6 and show the results of immunohistochemistry for the adrenal gland, testis, ovary, skin and placenta. As expected, Hsd3b6 immunoreactivities within the adrenal gland were essentially confined to the zona glomerulosa cells, where aldosterone is produced. By contrast, no immunopositive cells were observed in the zona fasciculata, which is where corticosterone is produced. In the gonads, while the ovaries did not show any detectable immunoreactivity to Hsd3b6, the testes displayed intense immunoreactivities within the interstitial Leydig cells, where testosterone is produced. In the skin, positive immunoreactivities to Hsd3b6 were only seen in the sebaceous glands, suggesting a specific role of this enzyme in sebaceous function. Moreover, in the placenta, Hsd3b6 was specifically found in the giant trophoblast cells surrounding the embryonic cavity, which suggests a role for this enzyme in local progesterone production that is required for proper embryonic implantation and/or maintenance of pregnancy. Taken together, our data revealed that Hsd3b6 is localized in multiple specific tissues and cell types, perhaps thereby involved in biosynthesis of a number of tissue-specific steroid hormones with different physiological roles.     

Beneficial effect of coronary artery bypass grafting as assessed by quantitative gated single-photon emission computed tomography.

The development of quantitative gated single-photon emission computed tomography (SPECT) has enabled the assessment of left ventricular perfusion, function and wall thickness in a single examination. Accordingly, the present study used gated SPECT to assess the benefit of coronary artery bypass grafting (CABG) in patients with coronary artery disease; 47 of those patients were evaluated before and 5 months after CABG. As a result of coronary revascularization, a significant improvement was observed in global ejection fraction (50+/-12 --> 53+/-11%; p<0.05). In 107 revascularized territories, the average regional reversible defect score (0.8+/-0.5 --> 0.2 +/-0.3; p<0.0001), average regional perfusion score at rest (0.6+/-0.6 --> 0.3+/-0.4; p<0.0001), average regional wall motion score (0.9+/-0.7 --> 0.7+/-0.5; p<0.05), and end-diastolic wall thickness (8.1+/-1.3 --> 8.6+/-1.5 mm; p<0.0005) all improved significantly. Even in 34 non-revascularized territories, the average regional reversible defect score (0.5+/-0.7 --> 0.2+/-0.5; p<0.03), average regional wall motion score (0.8+/-1.1 --> 0.5 +/-1.0; p<0.03) and end-diastolic wall thickness (8.0+/-1.4 --> 9.1+/-2.0 mm; p<0.03) all improved significantly. These results indicate that improvement in myocardial ischemia, hibernation and left ventricular function with CABG can be assessed in detail with gated SPECT.     

Associations between Chest CT Abnormalities and Clinical Features in Patients with the Severe Fever with Thrombocytopenia Syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus. It involves multiple organ systems, including the lungs. However, the significance of the lung involvement in SFTS remains unclear. In the present study, we aimed to investigate the relationship between the clinical findings and abnormalities noted in the chest computed tomography (CT) of patients with SFTS. The medical records of 22 confirmed SFTS patients hospitalized in five hospitals in Nagasaki, Japan, between April 2013 and September 2019, were reviewed retrospectively. Interstitial septal thickening and ground-glass opacity (GGO) were the most common findings in 15 (68.1%) and 12 (54.5%) patients, respectively, and lung GGOs were associated with fatalities. The SFTS patients with a GGO pattern were elderly, had a disturbance of the conscious and tachycardia, and had higher c-reactive protein levels at admission (p = 0.009, 0.006, 0.002, and 0.038, respectively). These results suggested that the GGO pattern in patients with SFTS displayed disseminated inflammation in multiple organs and that cardiac stress was linked to higher mortality. Chest CT evaluations may be useful for hospitalized patients with SFTS to predict their severity and as early triage for the need of intensive care.     

Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking‐related disease risk. The heritability of the NMR is 60–80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30–35%. Rare variants (minor allele frequency <1%) are hypothesized to explain some of this missing heritability. We present two targeted sequencing studies where rare protein‐coding variants are functionally characterized in vivo, in silico, and in vitro to examine this hypothesis. In a smoking cessation trial, 1687 individuals were sequenced; characterization measures included the in vivo NMR, in vitro protein expression, and metabolic activity measured from recombinant proteins. In a human liver bank, 312 human liver samples were sequenced; measures included RNA expression, protein expression, and metabolic activity from extracted liver tissue. In total, 38 of 47 rare coding variants identified were novel; characterizations ranged from gain‐of‐function to loss‐of‐function. On a population level, the portion of NMR variation explained by the rare coding variants was small (~1%). However, upon incorporation, the accuracy of the wGRS was improved for individuals with rare protein‐coding variants (i.e., the residuals were reduced), and approximately one‐third of these individuals (12/39) were re‐assigned from normal to slow metabolizer status. Rare coding variants can alter an individual’s CYP2A6 activity; their integration into wGRSs through precise functional characterization is necessary to accurately assess clinical outcomes and achieve precision medicine for all. Investigation into noncoding variants is warranted to further explain the missing heritability in the NMR.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Common CYP2A6 variants (minor allele frequency >1%) explain 30–35% of the variation in CYP2A6 activity, despite high heritability estimates (60–80%) in the CYP2A6 activity biomarker measure. One hypothesis is that rare coding variants (minor allele frequency <1%) may explain a portion of the missing heritability from pharmacogenes, including CYP2A6.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What is the relative contribution of rare coding variants in explaining variation in CYP2A6 activity? How necessary is the incorporation of rare coding variants in predicting individual metabolic status, and consequent tailoring of treatment?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Rare coding variants may explain only a small fraction of the variation on a population level; however, their role may be important on an individual level, altering the predicted metabolic status in a third of the individuals with these rare coding variants.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Evaluating rare coding variants in pharmacogenes, such as CYP2A6, will be valuable in enhancing the investigation of CYP2A6’s influence on tobacco addiction and disease pathogenesis, by providing a more accurate reflection of the phenotypic metabolic status through improved genetic assessments.