Reduction of clinically manifest colorectal cancer by endoscopic screening: empirical evaluation and comparison of screening at various ages.

Endoscopic screening (sigmoidoscopy, colonoscopy) with removal of precancerous lesions can prevent a large proportion of colorectal cancers (CRCs). However, there is lack of data regarding optimal age, time intervals and numbers of screening examinations. We developed and applied modified techniques of epidemiological analysis to evaluate the impact of various endoscopy-based screening strategies on prevention of clinically manifest CRCs between the ages of 50 and 79 in a population-based case-control study (294 cases, 254 controls) conducted in Saarland, Germany. We found a strong potential for reduction of CRC occurrence even with a single screening endoscopy. The optimal age for a single screening endoscopy appears to be around 55 (estimated potential for prevention of cases between the ages of 55 and 79 in case of 100% compliance: 77% (95% confidence interval (CI) 46-90%)). A single screening endoscopy at age 50 would have a lower impact due to failure to prevent CRC at higher ages. Similarly, screening at ages 60 or older would have a lower impact because it would fail to prevent CRC at lower ages. Repeated offers of screening examinations could provide substantial additional benefit with the levels of compliance to be expected in practice, but they would have to be weighed against the increased risks and costs.     

Renal function and clinical outcome of patients with cancer-associated venous thromboembolism randomized to receive apixaban or dalteparin. Results from the Caravaggio trial

The effect of renal impairment (RI) on risk of bleeding and recurrent thrombosis in cancer patients treated with direct oral anticoagulants for venous thromboembolism (VTE) is undefined. We ran a prespecified analysis of the randomized Caravaggio study to evaluate the role of RI as a risk factor for bleeding or recurrence in patients treated with dalteparin or apixaban for cancer-associated VTE. RI was graded as moderate (creatinine clearance between 30-59 mL/minute; 275 patients) and mild (between 60-89 mL/minute; 444 patients). In the 1142 patients included in this analysis, the incidence of major bleeding was similar in patients with moderate vs. no or mild RI (HR 1.06-95% CI: 0.53-2.11), with no difference in the relative safety of apixaban and dalteparin. Recurrent VTE was not different in moderate vs. no or mild RI (HR=0.67, 95% CI: 0.38-1.20); in moderate RI, apixaban reduced recurrent VTE compared to dalteparin (HR=0.27, 95% CI: 0.08-0.96; P for interaction 0.1085). At multivariate analysis, no association was found between variation of renal function over time and major bleeding or recurrent VTE. Advanced or metastatic cancer was the only independent predictor of major bleeding (HR=2.84, 95% CI: 1.20-6.71), with no effect of treatment with apixaban or dalteparin. In our study, in cancer patients treated with apixaban or dalteparin, moderate RI was not associated with major bleeding or recurrent VTE. In patients with moderate renal failure, the safety profile of apixaban was confirmed with the potential for improved efficacy in comparison to dalteparin. ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT03045406","term_id":"NCT03045406"}}NCT03045406.     

Enjoyment as a preventive of depressive affect

Previous work suggests two mechanisms whereby finding enjoyment in life decreases the likelihood of depressive affect: (a) enjoyment counteracts depressive affect and (b) failure to find enjoyment is itself a stimulus for depressive affect. The present study, based on interviews with 2168 adults in two communities, yields findings which are consistent with the proposition that satisfaction with major life areas is a factor in finding enjoyment in life, thereby a factor in avoiding depressive affect and thereby a factor in avoiding psycho-physiologic problems. Thus the present study provides a measure of support for the proposition that finding enjoyment in life reduces the likelihood of depressive affect and for the corollary of this proposition, that social, psychological, and other factors in the enjoyment of life are thereby also factors in depressive affect and its consequences.     

Extracellular truncations of h beta c, the common signaling subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5, lead to ligand-independent activation

The hypothesis that extracellular truncation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony- stimulating factor, and IL-5 (h beta c) can lead to ligand-independent activation was tested by infecting factor-dependent hematopoietic cell lines with retroviruses encoding truncated forms of h beta c. A truncation, resembling that in v-Mpl, and retaining 45 h beta c-derived extracellular residues, led to constitutive activation in the murine myeloid cell line, FDC-P1. However, infection of cells with retrovirus encoding a more severely truncated receptor, retaining only 7 h beta c- derived extracellular residues, did not confer factor independence on these cells. These experiments show that truncation activates the receptor and define a 37-amino acid segment of h beta c (H395-A431) which contains two motifs conserved throughout the cytokine receptor superfamily (consensus Y/H XX R/Q VR and WSXWS), as essential for factor-independent signaling. The mechanism of activation was also investigated in less severe truncations. A receptor that retains the entire membrane-proximal domain (domain 4) also conferred factor independent growth on FDC-P1 cells; however, a retrovirus encoding a truncated form of h beta c having two intact membrane proximal domains did not have this ability, suggesting that domain 3 may have an inhibitory role in h beta c. The ability of these receptors to confer factor independence was cell specific as demonstrated by their inability to confer factor-independent growth when introduced into the murine IL-3-dependent pro-B cell line BaF-B03. These results are consistent with a model in which activation requires unmasking of an interactive receptor surface in domain 4 and association with a myeloid- specific receptor or accessory component. We suggest that in the absence of ligand intramolecular interactions prevent inappropriate signaling.     

Perioperative morbidity and renal function in young and elderly patients undergoing elective nephron‐sparing surgery or radical nephrectomy for renal tumours larger than 4 cm

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? The incidence of renal tumours is rising constantly. Patients in the 6th or 7th decade of life are mainly affected. Nephron‐sparing surgery (NSS) has become the gold standard for the treatment of patients presenting with renal tumors ≤4 cm and is recommended for cT1b lesions in experienced centers. Little is known about the functional outcome of elderly patients presenting with renal tumours larger than 4 cm and being treated by NSS in comparison to radical nephrectomy (RN). Here we could show that NSS can be performed safely with considerable perioperative morbidity and a better functional outcome according to renal function without lacking oncological control.

OBJECTIVE

To analyse renal function, perioperative morbidity and overall survival (OS) in patients aged <55 years compared with patients aged >65 years treated by radical nephrectomy (RN) or elective nephron‐sparing surgery (NSS) for renal tumours >4 cm.

PATIENTS AND METHODS

From our database, we identified 829 patients with renal tumours >4 cm treated by either RN (n= 641) or NSS (n= 188) at our institution between 1981 and 2007. After excluding patients with imperative indication and metastases, we identified retrospectively 81 patients aged <55 years (young patients) and 85 patients aged >65 years (elderly patients) treated for renal tumours >4 cm. In all, 36 and 33 patients underwent NSS and 45 and 52 patients underwent RN in the young and elderly group, respectively. Preoperative and periodically postoperative serum creatinin values were used to estimate glomerular filtration rate (GFR). Chronic kidney disease (CKD) was defined as GFR <60 mL/min/1.73 m². Clinical characteristics, complications and renal function were compared between age groups and surgical approaches, and OS was estimated using the Kaplan–Meier method.

RESULTS

The median (range) tumour size in young patients was larger compared with that of elderly patients, i.e. 6 (4.2–14.0) cm vs 5 (4.2–16.0) cm, with P < 0.001 considered to be statistically significant. The complication rates did not differ between the age groups (P= 0.656) or between NSS and RN in young (P= 0.095) or elderly patients (P= 0.277). Chronic kidney disease after RN or NSS occurred in 31.1% and 15.5% for young patients, respectively and in 50.9% and 24.2% in elderly patients, respectively, until last available follow‐up which was obtained after a median (range) of 5.69 (0.1–19.2) years for young patients and 5.48 (0.8–18.1) years for elderly patients. Overall survival did not significantly differ between NSS vs RN in young (P= 0.655) and elderly patients (P= 0.058).

CONCLUSION

Our findings suggest that performing NSS for tumours >4 cm when feasible in young and carefully selected elderly patients is more beneficial for maintaining long‐term renal function. Regardless of age, patients undergoing RN for renal tumours >4 cm developed more new onsets of CKD than patients treated by elective NSS. The complication rate did not differ between the age groups or between types of surgery.     

Prognosis of patients with recurrent laryngeal carcinoma

BACKGROUND: Although recurrent laryngeal carcinoma is a common clinical problem, the data regarding its natural history and prognostic factors are limited. The aim of the study was to describe the clinical course of patients with recurrent laryngeal carcinoma and determine the impact of various factors on their survival. METHODS: The medical files of 65 patients with recurrent laryngeal cancer treated at the Rabin Medical Center between 1975 and 1996 were reviewed. The possible risk factors for survival were analyzed using univariate and multivariate models. RESULTS: The estimated 2- and 5-year survival rates of the patient population were 67% and 56%, respectively. On univariate analysis, primary tumor site, T stage and nodal status, duration of disease-free interval, site of recurrence, and operability of recurrent tumor were all powerful prognostic factors for survival. On multivariate analysis, three variables retained statistical significance: primary tumor site (p < .001), site of recurrence (p < .001), and its operability (p = .005). CONCLUSIONS: We found several disease-related factors to be predictive of poor outcome in patients with recurrent laryngeal cancer. Our data emphasize the need for early detection not only of primary tumors but also of their recurrences.     

The development of the external urethral sphincter in humans

OBJECTIVE: To assess the hypothesis that during fetal development, the external urethral sphincter changes from a concentric sphincter of undifferentiated muscle fibres to a transient ring of striated muscle which regresses caudo-cranially in the posterior urethra during the first year of life, when the sphincter assumes its omega-shaped configuration. MATERIALS AND METHODS: The anatomy and development of the external urinary sphincter was assessed in human males and females during fetal life. Plastic-embedded sections (transverse, sagittal and frontal planes; 300-700 microm) of the pelvis of 31 females and 31 males (9 weeks of gestation to newborn) were stained with azure II/methylene blue/basic fuchsin and viewed at x 4-80. The sections of interest were taken from the bladder neck to the perineum. The sections of the membranous urethra were reconstructed three-dimensionally using a computer program. RESULTS: In both male and female an omega-shaped external sphincter was apparent in all specimens at > 10 weeks of gestation. In the early fetal period (ninth week), there was undifferentiated mesenchyme; in this period the mesenchyme was more dense in the anterior part and loose in the posterior part of the urethra. In females, there was a close connection between the urethra and the anterior wall of the vagina. CONCLUSION: The omega-shaped configuration of the external urethral sphincter was recognisable from 10 weeks of gestation in both sexes. There was no suggestion of a change from a cylindrical to an omega-shaped sphincter in the fetal period to birth. Also, a transient 'tail' posterior to the sphincter was not apparent. The rectovesical septum was well developed in neonates. There is no reason to assume that the development of the septum leads to an apoptosis of muscle cells in the posterior part of the external sphincter in males after birth. The anatomical development of the external sphincter does not explain transient outlet obstruction during fetal life. The function of the muscle may change during development because of neuronal maturation.