Optimizing Colorectal Cancer Care in Older Patients

Colorectal cancer is a disease affecting mainly older people, a fact that is becoming more apparent with the global population aging. However, this patient group is more likely to be subjected to suboptimal treatment due to a number of factors, but most commonly as a result of the physician’s weakness to recognize those fit for the full spectrum of cancer therapy. In this regard, clinical screening tests, such as the Comprehensive Geriatric Assessment, can be invaluable in guiding treatment decisions. Fluoropyrimidine-based adjuvant chemotherapy clearly confers a survival advantage in older individuals with node-positive disease; however, the benefit from the administration of oxaliplatin-based regimens is less clear. Palliative chemotherapy also has an important role in managing metastatic disease, and with the use of novel targeted agents it can potentially prolong survival and improve quality of life. The management of rectal cancer in this population can present a challenge, since it appears that the optimal treatment of chemoradiation followed by total mesorectal excision can be applied in select few. Indeed, the morbidity and mortality rates in older people treated with these combined modalities can be too high, guiding many physicians to opt for more conservative approaches, directed at providing palliation and local control, especially in those with limited life expectancy. In conclusion, in order to provide the best care in an older colorectal cancer patient, we need to individualize our approach, selecting the right patient for the right treatment.     

Successful Fusion of the Proximal Tibiofibular Joint with Osteogenic Protein-1 (OP-1) Augmentation

Proximal tibiofibular joint (PTFJ) instability is rare, but when encountered can be difficult to manage. Previously reported forms of treatment, including cast immobilization, soft tissue repairs and reconstructions, and fibular head resection have met with limited success. Another option is PTFJ arthrodesis—however, fusion can be difficult and ankle pain after surgery is not uncommon. In this report, we present a novel surgical technique used to treat PTFJ instability. It is a form of PTFJ arthrodesis that utilizes the osteoinductive agent recombinant human osteogenic protein (rhOP-1) to help achieve fusion, in conjunction with a fibular osteotomy to unload the PTFJ and to preserve normal rotator mobility of the distal fibula during ankle motion. We have used this technique in two patients with successful results; one of whom required revision after two previous failed attempts at PTFJ fusion and the other who had a previous diagnosis of underlying collagen disorder. Their case studies are presented in detail in this report.     

The clinical evaluation of the CADence device in the acoustic detection of coronary artery disease

The noninvasive detection of turbulent coronary flow may enable diagnosis of significant coronary artery disease (CAD) using novel sensor and analytic technology. Eligible patients (n?=?1013) with chest pain and CAD risk factors undergoing nuclear stress testing were studied using the CADence (AUM Cardiovascular Inc., Northfield MN) acoustic detection (AD) system. The trial was designed to demonstrate non-inferiority of AD for diagnostic accuracy in detecting significant CAD as compared to an objective performance criteria (sensitivity 83% and specificity 80%, with 15% non-inferiority margins) for nuclear stress testing. AD analysis was blinded to clinical, core lab-adjudicated angiographic, and nuclear data. The presence of significant CAD was determined by computed tomographic (CCTA) or invasive angiography. A total of 1013 subjects without prior coronary revascularization or Q-wave myocardial infarction were enrolled. Primary analysis was performed on subjects with complete angiographic and AD data (n?=?763) including 111 subjects (15%) with severe CAD based on CCTA (n?=?34) and invasive angiography (n?=?77). The sensitivity and specificity of AD were 78% (p?=?0.012 for non-inferiority) and 35% (p?<?0.001 for failure to demonstrate non-inferiority), respectively. AD results had a high 91% negative predictive value for the presence of significant CAD. AD testing failed to demonstrate non-inferior diagnostic accuracy as compared to the historical performance of a nuclear stress OPC due to low specificity. AD sensitivity was non-inferior in detecting significant CAD with a high negative predictive value supporting a potential value in excluding CAD.     

Intraobserver and interobserver variation in the histopathological assessment of liver allograft rejection. The Liver Transplantation Database (LTD) Investigators

A study to determine the reproducibility of histopathological findings and diagnoses of rejection was carried out on a series of 42 liver allograft needle biopsy specimens by five pathologists practicing at four liver transplant centers. Pathologists from each of the four centers read each slide independently on two different occasions and were asked to assess 12 histopathological features and render a diagnosis. For all histological variables, the intrarater agreement was higher than the interrater agreement. Moderate to excellent agreement occurred among the pathologists about all histological variables thought to be important in establishing the diagnosis of acute rejection (i.e., portal tract inflammation, subendothelial inflammation and bile duct damage). Other variables such as lobular disarray, bile duct proliferation and particularly arteritis, however, were only fairly or poorly reproducible. Surprisingly, the diagnosis of acute rejection was more reproducible than the individual histopathological findings that were thought to be the basis for the diagnosis. The agreement for the diagnosis of chronic rejection, however, varied according to observer. We noted that relatively inexperienced observers within this group had some difficulties agreeing with more experienced observers in establishing a diagnosis of chronic rejection. These findings demonstrate that the histopathological diagnosis of acute cellular liver allograft rejection is highly reproducible within a group of experienced pathologists and that this diagnosis can be pooled in a common data base with confidence.     

Intestinal bacterial translocation and tight junction structure in acute porcine pancreatitis

Background/Aims: To examine whether intestinal bacterial translocation occurs early in acute mild and severe pancreatitis and whether the intestinal expression of tight junction proteins (claudins-2, -3, -4, -5, -7), apoptosis or proliferation would explain the possible translocation. Methodology: Fifteen pigs were randomized to controls (n=5) or to develop mild edematous pancreatitis (n=5, saline infusion to pancreatic duct) or severe necrotic pancreatitis (n=5, taurocholic acid infusion). Translocation was studied by measuring bacterial cultures from portal vein blood and mesenteric lymph nodes. Immunohistochemical expression of the tight junction proteins, apoptosis rate (TUNEL) and Ki-67 were analyzed quantitatively from the epithelium of the jejunum and colon. Results: There was no bacterial translocation during the 6 hours followup, nor changes in the expression of tight junction proteins claudins-2 and -5 in jejunum or colon. Saturation and proportional area of claudin-3 staining decreased in the colon, as did claudins-4 and -7 staining in the jejunum of the necrotic pancreatitis group. Increased apoptosis was found in all samples from controls and the edematous pancreatitis group but not in jejunum in the necrotic pancreatitis group. Ki-67 activity tended to increase in the upper half of the villus in edematous and necrotic pancreatitis. There were no changes in the basic histology. Conclusions: The major finding of this study was that bacterial translocation from the gut is not present at the beginning of acute pancreatitis. Tight junction proteins claudin-2 and -5 do not become altered in the early stages of pancreatitis. Claudin-3 decreases in the colon and claudins-4 and -7 in the jejunum in necrotic pancreatitis. Laparotomy itself causes increased apoptosis in the colon and the jejunum.     

Amélioration de la perfusion des organes vitaux par la valve d’impédance inspiratoire et le concept de pompe respiratoire : rationnel physiologique et application clinique

Objective

In this article, we review the effects of the respiratory pump to improve vital organ perfusion by the use of an inspiratory threshold device.

Data sources

Medline and MeSH database.

Study selection

All papers with a level of proof of I to III have been used.

Data extraction

The analysis of the papers has focused on the physiological modifications induced by intrathoracic pressure regulation.

Data synthesis

Primary function of breathing is to provide gas exchange. Studies of the mechanisms involved in animals and humans provide the physiological underpinnings for “the other side of breathing”: to increase circulation to the heart and brain. We describe studies that focus on the fundamental relationship between the generation of negative intrathoracic pressure during inspiration through a low-level of resistance created by an impedance threshold device and the physiologic effects of a respiratory pump. A decrease in intrathoracic pressure during inspiration through a fixed resistance resulting in an intrathoracic pressure of −7 cmH₂O has multiple physiological benefits including: enhanced venous return, cardiac stroke volume and aortic blood pressure; lower intracranial pressure; resetting of the cardiac baroreflex; elevated cerebral blood flow oscillations and increased tissue blood flow/pressure gradient.

Conclusion

The clinical and animal studies support the use of the intrathoracic pump to treat different clinical conditions: hemorrhagic shock, orthostatic hypotension, septic shock, and cardiac arrest.     

A validated model for predicting outcome after liver transplantation: implications on transplanting the extremely sick

Given the organ shortage, there is a need to optimize outcome after liver transplantation (LT). We defined posttransplant hospital length of stay >60 days (LOS > 60) as a surrogate of suboptimal outcome. In the first phase of the study, a ‘Study cohort’ (SC) of 643 patients was used to identify risk factors and construct a mathematical model to identify recipients with anticipated inferior results. In the second phase, a cohort of 417 patients was used for validation of the model [‘Validation Cohort’ (VC)]. In the SC, 65 patients (10.1%) had LOS > 60 days. One‐ and 3‐year patient/graft survival rates were 81.9%/76.1% and 73.4%/67.4%, respectively. Patient and graft survival rates of those with LOS >60 days were inferior (P < 0.0001), while transplant cost was greater [3.42 relative units (RU) vs. 1 RU, P < 0.0001]. In a multivariable analysis, pretransplant dialysis (P < 0.001), mechanical ventilation (P < 0.015), MELD (P < 0.003), and age (P < 0.009) were predictors of LOS > 60 days [ROC curve – 0.75 (95% CI 0.70, 0.81)]. In the VC, 53 patients (12.7%) were expected to have adverse outcome by the model. These patients had longer LOS (P < 0.0001), higher cost (<0.0001), and inferior patient and graft survival (P < 0.007).     

“Plasma Cell Hepatitis” in Liver Allografts: Identification and Characterization of an IgG4‐Rich Cohort

Plasma cell hepatitis (PCH), also known as “de novo autoimmune” hepatitis, is an increasingly recognized, but suboptimally named and poorly understood, category of late allograft dysfunction strongly resembling autoimmune hepatitis (AIH): They share plasma‐cell‐rich necro‐inflammatory activity on biopsy, autoantibodies and steroid responsiveness, but overlap with rejection is problematic. A retrospective study of clinical, serological, histopathological and IgG4 immunohistological features of PCH (n = 20) in liver allograft recipients, native liver AIH (n = 19) and plasma‐cell‐rich renal allograft rejection (n = 20) showed: (1) high frequency (44%) of HLA‐DR15; (2) less female predominance (p = 0.03) and (3) n = 9/20 PCH recipients showed >25 IgG4+ plasma cells/high‐power field (IgG4+ PCH) versus AIH (n = 1/19, p = 0.008) or plasma‐cell‐rich kidney rejection (n = 2/20, p = 0.03). The IgG4+ PCH (n = 9) subgroup showed lower alanine transaminase (ALT) (p < 0.01) and aspartate transaminase (AST) (p < 0.05) at index biopsy but (a) higher plasma cell number/percentage, (b) more aggressive‐appearing portal/periportal and perivenular necro‐inflammatory activity and (c) more severe portal/periportal fibrosis than IgG4? PCH (n = 11). Significant demographic, histopathologic and plasma cell phenotype differences between PCH and AIH suggest distinct pathogenic mechanisms for at least the IgG4+ PCH subgroup likely representing an overlap between allo‐ and auto‐immunity. IgG4+ PCH was associated with fibrosis, but also highly responsive to increased immunosuppression.

     

Proposed Diagnostic Criteria for Chronic Antibody‐Mediated Rejection in Liver Allografts

Donor‐specific alloantibodies (DSA) can cause acute antibody‐mediated rejection (AMR) in all solid organ allografts. However, long‐term outcome in patients with posttransplant DSA needs further study. We retrospectively evaluated prospectively collected paired serum, tissue, and data on 45 matched DSA? positive [DSA+; mean florescence intensity (MFI) ≥10 000] and ‐negative (DSA?) recipients of a primary liver‐only allograft from January 2000 to April 2009. Blinded histopathologic evaluation demonstrated that DSA+ versus DSA? patients were more likely to have subtle inflammation and unique patterns of fibrosis, despite normal or near‐normal liver function tests. Stepwise multivariable modeling developed a score (putatively named the chronic AMR [cAMR] score) that included interface activity, lobular inflammation, portal tract collagenization, portal venopathy, sinusoidal fibrosis, and hepatitis C virus status. The score was developed (c = 0.811) and cross‐validated (c = 0.704) to predict allograft failure. Two cutoffs were employed to optimize sensitivity and specificity (80% each); a value >27.5 predicted 50% 10‐year allograft failure. We propose chronic AMR as a potential new entity defined by (1) a high cAMR score, (2) DSA, and (3) elimination of other potential causes of a similar injury pattern. In conclusion, cAMR score calculation identified liver allograft recipients with DSA at highest risk for allograft loss, although independent validation is needed.