Positron Emission Tomography Detection of Distant Metastatic or Synchronous Disease in Patients with Locally Advanced Rectal Cancer Receiving Preoperative Chemoradiation

Background Patients with locally advanced rectal cancer may present with synchronous distant metastases. Choice of optimal treatment—neoadjuvant chemoradiation versus systemic chemotherapy alone—depends on accurate assessment of distant disease. We prospectively evaluated the ability of [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) to detect distant disease in patients with locally advanced rectal cancer who were otherwise eligible for combined modality therapy (CMT). Methods Ninety-three patients with locally advanced rectal cancer underwent whole-body [¹⁸F]FDG PET scanning 2–3 weeks before starting CMT. Sites other than the rectum, mesorectum, or the area along the inferior mesenteric artery were considered distant and were divided into nine groups: neck, lung, mediastinal lymph node (LN), abdomen, liver, colon, pelvis, peripheral LN, and soft tissue. Two nuclear medicine physicians blinded to clinical information used PET images and a five-point scale (0–4) to determine certainty of disease. A score greater than 3 was considered malignant. Confirmation was based on tissue diagnosis, surgical exploration, and subsequent imaging. Results At a median follow-up of 34 months, the overall accuracy, sensitivity, and specificity of PET in detecting distant disease were 93.7%, 77.8%, and 98.7% respectively. Greatest accuracy was demonstrated in detection of liver (accuracy = 99.9%, sensitivity = 100%, specificity = 98.8%) and lung (accuracy = 99.9%, sensitivity = 80%, specificity = 100%) disease; PET detected 11/12 confirmed malignant sites in liver and lung. A total of 10 patients were confirmed to have M1 stage disease. All 10 were correctly staged by pre-CMT PET; abdominopelvic computed tomography (CT) scans accurately detected nine of them. Conclusion Baseline PET in patients with locally advanced rectal cancer reliably detects metastatic disease in liver and lung. PET may play a significant role in defining extent of distant disease in selected cases, thus impacting the choice of neoadjuvant therapy. An erratum to this article can be found at     

Expression of apoptosis-related genes and proteins in experimental chronic renal scarring

Apoptosis has been proposed to play an important role in the progression of renal scarring. The mechanisms that determine whether a cell enters the apoptotic program are complex. Bax and Bcl-2 are recognized modulators of this event; their relative levels determine the fate of cells. A role for apoptosis in the progression of renal scarring in the remnant kidneys of rats submitted to subtotal nephrectomy (SNx) has been described. This study investigated the expression (protein and mRNA) of Bax and Bcl-2 in remnant kidneys between day 7 and day 120 post-SNx. Northern blot analysis showed that bax mRNA was increased in remnant kidneys from day 7 (150% of control; P: < 0.05), whereas bcl-2 mRNA was decreased from day 15 (23% of control; P: < 0.05) resulting in a 14-fold increase in the ratio of bax to bcl-2 mRNA by day 120. Western blot analysis showed similar changes in Bax and Bcl-2 protein in remnant kidneys, resulting in a 147-fold increase in the ratio of Bax to Bcl-2 on day 120. Immunohistochemistry showed increases in Bax to be located predominantly in tubules in SNx kidneys. Interestingly, Bcl-2 immunostaining increased in some epithelial cells within atrophic tubules despite the overall decrease in Bcl-2 protein and mRNA. The overall renal apoptotic cells correlated closely with the ratio of bax to bcl-2 at both the mRNA and protein levels (r = 0.594 and 0.308, respectively; P: < 0.05). Furthermore, tubular apoptosis correlated positively with the mRNA level of bax (r = 0.471; P: < 0.01) and negatively with the mRNA and protein levels of bcl-2 (r = -0.443 and -0.607, respectively; P: < 0.01). The increase in the ratio of the death inducer (Bax) to the death repressor (Bcl-2) at the mRNA and protein levels may control the apoptosis associated with the progression of tubular atrophy and chronic renal fibrosis within remnant rat kidneys. These observations may have prognostic and therapeutic implications in chronic renal failure.     

Dynamics of anti‐human leukocyte antigen antibodies after renal transplantation and their impact on graft outcome

The purpose of this study was to sequentially monitor anti‐HLA antibodies and correlate the results with antibody‐mediated rejection (AMR), graft survival (GS), and graft function (GF). We collected sera from 111 kidney transplant recipients on transplant days 0, 7, 14, 30, 60, 90, 180, and 360 and analyzed PRA levels by ELISA. DSAs were analyzed by single‐antigen beads in rejecting kidneys. At pre‐transplant, 79.3% of the patients were non‐sensitized (PRA = 0%) and 20.7% were sensitized (PRA > 1%). After transplant, patients were grouped by PRA profile: no anti‐HLA antibodies pre‐ or post‐transplant (group HLApre?/post?; n = 80); de novo anti‐HLA antibodies post‐transplant (group HLApre?/post+; n = 8); sensitized pre‐transplant/increased PRA post‐transplant (group HLApre+/post↑; n = 9); and sensitized pre‐transplant/decreased PRA post‐transplant (group HLApre+/post↓; n = 14). De novo anti‐HLA antibodies were detected at 7–180 d. In sensitized patients, PRA levels changed within the first 30 d post‐transplant. Incidence of AMR was higher in HLApre?/post+ and HLApre+/post↑ than in HLApre?/post?, and HLApre+/post↓ (p < 0.001) groups. One‐yr death‐censored GS was 36% in group HLApre+/post↑, compared with 98%, 88% and 100% in groups HLApre?/post?, HLApre?/post+, and HLApre+/post↓, respectively (p < 0.001). Excluding first‐year graft losses, GF and GS were similar among the groups. In conclusion, post‐transplant antibody monitoring can identify recipients at higher risk of AMR.     

Short-duration virtual reality simulation training positively impacts performance during laparoscopic colectomy in animal model: results of a single-blinded randomized trial

Background

Several studies have demonstrated skills transfer after virtual reality (VR) simulation training in laparoscopic surgery. However, the impact of VR simulation training on transfer of skills related to laparoscopic colectomy remains not investigated. The present study aimed at determining the impact of VR simulation warm-up on performance during laparoscopic colectomy in the porcine model.

Methods

Fourteen residents naive to laparoscopic colectomy as surgeons were randomly assigned in block to two groups. Seven trainees completed a 2-h VR simulator training in the laparoscopic sigmoid colectomy module (study group). The remaining seven surgeons (control group) underwent no intervention. On the same day, all participants performed a sigmoid colectomy with anastomosis on a pig. All operations were video recorded. Two board-certified expert colorectal surgeons independently assessed performance during the colectomy on the swine. Examiners were blinded to group assignment. The two examiners used a previously validated clinical instrument specific to laparoscopic colectomy. The primary outcome was the generic and specific skills score values.

Results

Surgeons undergoing short-duration training on the VR simulator performed significantly better during laparoscopic colectomy on the pig regarding general and specific technical skills evaluation. The average score of generic skills was 17.2 (16.5–18) for the control group and 20.1 (16.5–22) for the study group (p = 0.002). The specific skills average score for the control group was 20.2 (19–21.5) and 24.2 (21–27.5) for the study group (p = 0.001). There was acceptable concordance (Kendall’s W) regarding the video assessment of generic (W = 0.78) and specific skills (W = 0.84) between the two examiners.

Conclusions

A single short-duration VR simulator practice positively impacted surgeons’ generic and specific skills performance required to accomplish laparoscopic colectomy in the swine model.     

A novel approach for the treatment of pelvic abscess: transrectal endoscopic drainage facilitated by transanal endoscopic microsurgery access

Background

Postoperative pelvic abscesses in patients submitted to colorectal surgery are challenging. The surgical approach may be too risky, and image-guided drainage often is difficult due to the complex anatomy of the pelvis. This article describes novel access for drainage of a pelvic collection using a minimally invasive natural orifice approach.

Methods

A 37?year-old man presented with sepsis due to a pelvic abscess during the second postoperative week after a Hartmann procedure due to perforated rectal cancer. Percutaneous drainage was determined by computed tomography to be unsuccessful, and another operation was considered to be hazardous. Because the pelvic fluid was very close to the rectal stump, transrectal drainage was planned. The rectal stump was opened using transanal endoscopic microsurgery (TEM) instruments. The endoscope was advanced through the TEM working channel and the rectal stump opening, accessing the abdominal cavity and pelvic collection.

Results

The pelvic collection was endoscopically drained and the local cavity washed with saline through the scope channel. A Foley catheter was placed in the rectal stump. The patient’s recovery after the procedure was successful, without the need for further intervention.

Conclusions

Transrectal endoscopic drainage may be an option for selected cases of pelvic fluid collection in patients submitted to Hartmann’s procedure. The technique allows not only fluid drainage but also visualization of the local cavity, cleavage of multiloculated abscesses, and saline irrigation if necessary. The use of TEM instrumentation allows safe access to the peritoneal cavity.     

Transforming growth factor-beta(1) in the kidney and urine of patients with glomerular disease and proteinuria.

BACKGROUND: Transforming growth factor-beta(1) (TGF-beta(1)) is the major fibrogenic growth factor implicated in the pathogenesis of renal scarring. Proteinuria is a poor prognostic feature for various types of glomerular disease and its toxic action may be related to the activation of tubular epithelial cells towards increased production of cytokines and chemoattractant peptides. In this work we studied the site of synthesis and expression profile of TGF-beta(1) in the renal tissue of patients with heavy proteinuria and examined the relation of this expression with the urinary excretion of TGF-beta(1). METHODS: Twenty-five patients with heavy proteinuria (8.4+/-3.0 g/24 h) were included in the study. All patients underwent a diagnostic kidney biopsy and were commenced on immunosuppressive therapy with corticosteroids and cyclosporin. The sites of synthesis and expression profile of TGF-beta(1) mRNA and protein in the kidney were examined by in situ hybridization and immunohistochemistry. Urinary and plasma TGF-beta(1) levels were determined by ELISA before the initiation of treatment and 6 months later and compared with those of normal subjects and of patients with IgA nephropathy and normal urinary protein excretion. RESULTS: The site of synthesis and expression of TGF-beta(1) in the renal tissue of patients with heavy proteinuria was mainly localized within the cytoplasm of tubular epithelial cells. Interstitial expression was also present but glomerular TGF-beta(1) expression was found only in patients with mesangial proliferation. Urinary TGF-beta(1) excretion was significantly higher in nephrotic patients compared with normal subjects and with patients with IgA nephropathy and normal urinary protein excretion (783+/-280 vs 310+/-140 and 375+/-90 ng/24 h, respectively; P<0.01). In patients with remission of proteinuria after immunosuppressive therapy, urinary TGF-beta(1) excretion was significantly reduced (from 749+/-290 to 495+/-130 ng/24 h; P<0.01), while in patients with persistent nephrotic syndrome, it remained elevated. CONCLUSIONS: The localization of TGF-beta(1) mRNA and protein within tubular epithelial cells, along with its increased urinary excretion in patients with nephrotic syndrome, suggest the activation of these cells by filtered protein towards increased TGF-beta(1) production.     

Podocyte number in normotensive type 1 diabetic patients with albuminuria

We estimated glomerular cell number in 50 normotensive type 1 diabetic patients with raised albumin excretion rate (AER) and investigated any change after 3 years in a subgroup of 16 placebo-treated patients. Biopsies from 10 normal kidney donors were used as controls. Mesangial and endothelial cell number was increased in the 50 diabetic patients at the start of the study compared with control subjects. There was no difference in podocyte number. Glomerular volume was increased in diabetic patients, but surface area of glomerular basement membrane (GBM) underlying the podocytes did not differ between groups. AER correlated positively with mesangial cell number in microalbuminuric patients (r = 0.44, P = 0.012) and negatively with podocyte number in proteinuric patients (r = -0.48, P = 0.040). In the 16 placebo-treated patients, glomerular volume increased after 3 years owing to matrix accumulation and increased GBM surface area. Although overall cell number did not differ significantly from baseline, the decrease in podocyte number during follow-up correlated with AER at follow-up (r = -0.72, P = 0.002). In conclusion, cross-sectional analysis of podocyte number in type 1 diabetic patients with raised AER but normal blood pressure shows no significant reduction compared with nondiabetic control subjects. Longitudinal data provide evidence for an association between podocyte loss and AER, but whether cellular changes are a response to, a cause of, or concomitant with the progression of nephropathy remains uncertain.     

Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human kidney disease and is caused by germline mutations in PKD1 (85%) or PKD2 (15%). It has been estimated that around 1% of tubular cells give rise to cysts, and cell hyperproliferation has been noted to be a cardinal feature of cystic epithelium. Nevertheless, it is uncertain whether the increase in proliferative index observed is an early or late feature of the cystic ADPKD kidney. METHODS: Two Pkd2 mouse mutants (WS25 and WS183) have been recently generated as orthologous models of PKD2. To determine the effect of Pkd2 dosage on cell proliferation, cyst formation and renal fibrosis, we studied renal tissue from Pkd2(WS25/WS25) and Pkd2(+/-) mice by histological analysis. We also examined the proliferative index in archival nephrectomy tissue obtained from patients with ADPKD and normal controls. RESULTS: The proliferative index of non-cystic tubules in Pkd2 mutant mice as assessed by proliferating cell nuclear antigen and Ki67-positive nuclei was between 1-2%, values 5-10 times higher than control tissue. Similarly, the proliferative index of non-cystic tubules in human ADPKD kidneys was 40 times higher than corresponding controls. In Pkd2 mutant mice, significant correlations were found between the fibrosis score and the mean cyst area as well as with the proliferative index. Of significance, proliferating tubular cells were uniformly positive for polycystin-2 expression in Pkd2(+/-) kidney. CONCLUSION: These results suggest that an increase in cell proliferation is an early event preceding cyst formation and can result from haploinsufficiency at Pkd2. The possible pathogenic link between tubular cell proliferation, interstitial fibrosis and cyst formation is discussed.     

PTEN抑癌基因在乳腺癌组织中的表达及其与乳腺癌微小转移灶的关系

目的:研究PTEN抑癌基因在乳腺癌组织中的表达,探讨其与乳腺癌病人的外周血、骨髓及前哨淋巴结微小转移灶之间的关系。方法:选择53例乳腺癌病人的组织标本,用免疫组织化学方法检测原发肿瘤PTEN蛋白的表达;用定量RT鄄PCR法测定原发肿瘤PTENmRNA的表达。以免疫细胞化学法检测外周血和骨髓中的微小转移灶;HE染色和免疫组织化学法检测前哨淋巴结中的微小转移灶。结果:外周血、骨髓及前哨淋巴结中微小转移灶的检出率分别是24.5%,56.6%,26.4%和41.5%。乳腺癌组织中PTEN蛋白表达呈丢失者占35.8%,后者与外周血和骨髓微小转移灶间无显著关系,而与前哨淋巴结中的微小转移密切相关(P≤0.001)。PTENmRNA的表达与外周血、骨髓及前哨淋巴结中的微小转移灶之间均无显著相关性。结论:乳腺癌组织中PTEN蛋白表达的丢失与前哨淋巴结中的微小转移有密切关系,可作为预测其早期转移的重要指标。