Does prehabilitation before esophagectomy improve postoperative outcomes? A systematic review and meta-analysis.

Esophagectomy for esophageal cancer is associated with high morbidity. It remains unclear whether prehabilitation, a strategy aimed at optimizing patients' physical and mental functioning prior to surgery, improves postoperative outcomes. A systematic review and meta-analysis was conducted to evaluate the effect of prehabilitation on post-operative outcomes after esophagectomy. Data sources included Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and PEDro, with information from 1 January 2000 to 5 August 2023. The analysis included randomized controlled trials and observational studies that compared prehabilitation interventions to standard care prior to esophagectomy. A random effects model was used to generate a pooled estimate for pairwise meta-analysis, meta-analysis of proportions, and meta-analysis of means. A total of 1803 patients were included with 584 in randomized controlled trials (RCTs) and 1219 in observational studies. In the randomized evidence, there were no significant differences between prehabilitation and control in the odds of postoperative pneumonia (15.0 vs. 18.9%, odds ratio (OR) 1.06 [95% confidence interval (CI): 0.66;1.72]) or pulmonary complications (14 vs. 25.6%, OR 0.68 [95% CI: 0.32;1.45]). In the observational data, there was a reduction in both postoperative pneumonia (22.5 vs. 32.9%, OR 0.48 [95% CI: 0.28;0.83]) and pulmonary complications (26.1 vs. 52.3%, OR 0.35 [95% CI: 0.17;0.75]) with prehabilitation. Hospital and intensive care unit length of stay (days), operative mortality, and severe complications (Clavien-Dindo ≥ 3) did not differ between groups in both the randomized data and observational data. Prehabilitation demonstrated reductions in postoperative pneumonia and pulmonary complications in observational studies, but not RCTs. The overall certainty of these findings is limited by the low quality of the available evidence.

Management of severe asymmetric pectus excavatum complicating aortic repair in a patient with Marfan's syndrome.

We describe the case of a 28-year old man with Marfan's syndrome and severe pectus excavatum who required an aortic root replacement for an ascending aortic aneurysm. There was a near-vertical angulation of the sternum that presented challenges with opening and exposure of the heart during aortic surgery. Furthermore, removal of the sternal retractor after aortic repair resulted in sudden loss of cardiac output. A Ravitch procedure was then performed to successfully close the chest without further cardiovascular compromise. We propose that patients with a severe pectus excavatum and mediastinal displacement seen on preoperative CT scanning should be considered for simultaneous, elective repair.

Thoracoscopic Nuss procedure for young adults with pectus excavatum: excellent midterm results and patient satisfaction.

BACKGROUND: Chest wall remodeling by substernal placement of a Nuss bar is the treatment of choice for children with pectus excavatum; however, it has not yet gained widespread acceptance in adults. We demonstrate that thoracoscopic Nuss bar insertion in young adults is safe and leads to excellent results. METHODS: Adult patients who underwent thoracoscopic Nuss bar insertion at one institution between 2006 and 2012 were identified. Data on demographics, postoperative outcomes, quality of life, and cosmetic satisfaction was collected. A validated single-step quality of life survey was administered to patients. Student's t test and the Wilcoxon rank sum test were used for statistical analysis. RESULTS: Seventy-three patients (65 male, 8 female) with a median age of 20 years (range, 16 to 51) were included. The median follow-up was 44.6 months (range, 36.9 to 73.26). Most patients (59 of 73, 81%) had one bar placed. The median length of hospital stay was 5 days (range, 3 to 9) and the median duration of epidural anesthesia was 3 days (range, 0 to 7). There were 4 reoperations (5.5%) in the immediate postoperative period: 2 for bar displacement and 2 for poor cosmesis. All reoperations were performed thoracoscopically. Other postoperative complications included pneumothorax (3 of 73, 4.1%) and ileus (1 of 73, 1.3%). Fifty-one patients participated in a quality-of-life survey (73% response rate). The mean self-esteem score improved from 4.6 of 10 preoperatively to 6.5 of 10 postoperatively (p=0.002). The social impact of the pectus deformity became less significant (mean preoperative score 3.6, mean postoperative score 2.8, p=0.02). The severity of initial postoperative pain was much improved on follow-up. The vast majority of patients (41 of 51, 80%) were satisfied with the cosmetic result, and 96% (49 of 51) would opt to have the surgery again. CONCLUSIONS: For young adults who wish to correct their pectus deformity, a thoracoscopic Nuss procedure is safe and results in a high rate of patient satisfaction, significant improvement in self-image, and excellent midterm cosmetic results.

Plk4 is required for cytokinesis and maintenance of chromosomal stability.

Aneuploidy is a characteristic feature of established cancers and can promote tumor development. Aneuploidy may arise directly, through unequal distribution of chromosomes into daughter cells, or indirectly, through a tetraploid intermediate. The polo family kinase Plk4/Sak is required for late mitotic progression and is haploinsufficient for tumor suppression in mice. Here we show that loss of heterozygosity (LOH) occurs at the Plk4 locus in 50% of human hepatocellular carcinomas (HCC) and is present even in preneoplastic cirrhotic liver nodules. LOH at Plk4 is associated with reduced Plk4 expression in HCC tumors but not with mutations in the remaining allele. Plk4(+/-) murine embryonic fibroblasts (MEFs) at early passage show a high incidence of multinucleation, supernumerary centrosomes, and a near-tetraploid karyotype. Underlying these phenotypes is a high rate of primary cytokinesis failure, associated with aberrant actomyosin ring formation, reduced RhoA activation, and failure to localize the RhoA guanine nucleotide exchange factor Ect2 to the spindle midbody. We further show that Plk4 normally localizes to the midbody and binds to and phosphorylates Ect2 in vitro. With serial passaging Plk4(+/-) MEFs rapidly immortalize, acquiring an increasing burden of nonclonal and clonal gross chromosomal irregularities, and form tumors in vivo. Our results indicate that haploid levels of Plk4 disrupt RhoGTPase function during cytokinesis, resulting in aneuploidy and tumorigenesis, thus implicating early LOH at Plk4 as one of the drivers of human hepatocellular carcinogenesis. These findings represent an advance in our understanding of genetic predisposition to HCC, which continues to increase in incidence globally and particularly in North America.

Results of an aggressive approach to resection of locally recurrent rectal cancer.

BACKGROUND: The value of resection for locally recurrent rectal cancer (LRRC) remains controversial. We analyzed outcomes of an aggressive approach to resection of LRRC. METHODS: We conducted a retrospective chart review of 52 consecutive patients who underwent resection of LRRC from September 1997 through August 2005. Overall and disease-free survival (OS, DFS) curves were constructed by the Kaplan-Meier method, and compared by log-rank analysis. Median follow-up time was 29 months (range 3-72). RESULTS: Thirty-one patients (60%) were male. Median age was 60 years (range 36-88). Forty-six of the 52 patients were resected with curative intent, while 6 had known distant metastases at the time of resection. All 52 patients underwent grossly complete resection of local disease, and 41 (79%) had microscopically clear resection margins. An en bloc sacrectomy was performed in 28 (54%) patients. Postoperative mortality was nil; significant complications developed in 42% of patients. The complication rate was higher in patients with sacrectomy than without (50 vs. 33%, P = 0.017, Chi square). For the entire cohort of 52 patients, median OS and DFS were 40 and 24 months, respectively. Survival was equivalent in patients with and without sacrectomy. In the 46 patients who had resection with curative intent, 4-year OS was 48%. Median OS in the six patients with distant metastases at the time of resection was 21 months. OS was predicted by the presence of metastases (P = 0.01), and margin status (P < 0.0001). DFS was predicted by margin status (P = 0.0001). CONCLUSIONS: In this series of patients who underwent resection of LRRC, microscopic margin status was the most significant predictor of OS and DFS. Requirement for en bloc sacrectomy was not associated with inferior survival. Carefully selected patients with distant metastases may benefit from resection of LRRC.

Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis.

The polo-like kinase Plk4 (also called Sak) is required for late mitotic progression, cell survival and postgastrulation embryonic development. Here we identified a phenotype resulting from Plk4 haploinsufficiency in Plk4 heterozygous cells and mice. Plk4+/- embryonic fibroblasts had increased centrosomal amplification, multipolar spindle formation and aneuploidy compared with wild-type cells. The incidence of spontaneous liver and lung cancers was approximately 15 times high in elderly Plk4+/- mice than in Plk4+/+ littermates. Using the in vivo model of partial hepatectomy to induce synchronous cell cycle entry, we determined that the precise regulation of cyclins D1, E and B1 and of Cdk1 was impaired in Plk4+/- regenerating liver, and p53 activation and p21 and BubR1 expression were suppressed. These defects were associated with progressive cell cycle delays, increased spindle irregularities and accelerated hepatocellular carcinogenesis in Plk4+/- mice. Loss of heterozygosity occurs frequently (approximately 60%) at polymorphic markers adjacent to the PLK4 locus in human hepatoma. Reduced Plk4 gene dosage increases the probability of mitotic errors and cancer development.

Sak/Plk4 and mitotic fidelity.

Sak/Plk4 differs from other polo-like kinases in having only a single polo box, which assumes a novel dimer fold that localizes to the nucleolus, centrosomes and the cleavage furrow. Sak expression increases gradually in S through M phase, and Sak is destroyed by APC/C dependent proteolysis. Sak-deficient mouse embryos arrest at E7.5 and display an increased incidence of apoptosis and anaphase arrest. Sak(+/-) mice are haploinsufficient for tumor suppression, with spontaneous tumors developing primarily in the liver with advanced age. During liver regeneration following partial hepatectomy, Sak(+/-) hepatocytes display a delay in reaching the first M phase, multipolar spindles, disorganized tissue morphology and loss of acuity for cyclin B1 expression. Similarly, Sak(+/-) MEF cells proliferate slowly, and show a high incidence of centrosome hyper-amplification. We suggest that Sak provides feedback to cell cycle regulators, and thereby precision to the switch-like transitions of centrosome duplication and exit-from-mitosis. Sak binds to p53, and studies are underway to provide a molecular context for the Sak-p53 interaction. Animal models of haploinsufficiency and more comprehensive models of cell cycle regulation should contribute to improvements in cancer risk assessment and novel therapies.