[4D electromagnetic navigation bronchoscopy for the diagnosis of peripheral pulmonary nodules - An overview and preliminary clinical results]. / 4D-Elektromagnetische Navigationsbronchoskopie zur Diagnostik peripherer Rundherde.

BACKGROUND: The diagnostic of peripheral pulmonary nodules (PPN) is a particular challenge in interventional bronchology, which is why navigation systems such as electromagnetic navigation (ENB) are increasingly being used. The 4D-ENB represents the most current development of the ENB. It utilizes inspiratory and expiratory CT scans for mapping and thus helps compensate for respiratory movements-induced CT-to-body divergence. The aim of this work was to present the first clinical data and experiences using the 4D-ENB method for diagnosis of PPNs. METHODS: We retrospectively describe the results of the first nine consecutive patient cases diagnosed at Klinikum Braunschweig using 4D-ENB in a unimodal diagnostic procedure. RESULTS: Of the first 9 PPNs examined by 4D-ENB, navigation and puncture of the lesion was successful in 8 patients (89%). Diagnostic biopsy was could be carried out in six out of nine patients (67%). There were no significant procedure-related complications. CONCLUSION: Our preliminary data suggest that 4D-ENB is a promising new alternative for the diagnosis of PPNs. To further improve diagnostic yield, 4D-END, which lacks real-time visualization, should be embedded in a multimodal diagnostic procedure with rEBUS and/or fluoroscopy.

SGLT1/2 inhibition improves glycemic control and multi-organ protection in type 1 diabetes.

Sodium glucose cotransporters (SGLTs) are transport proteins that are expressed throughout the body. Inhibition of SGLTs is a relatively novel therapeutic strategy to improve glycemic control and has been shown to promote cardiorenal benefits. Dual SGLT1/2 inhibitors (SGLT1/2i) such as sotagliflozin target both SGLT1 and 2 proteins. Sotagliflozin or vehicle was administered to diabetic Akimba mice for 8 weeks at a dose of 25 mg/kg/day. Urine glucose levels, water consumption, and body weight were measured weekly. Serum, kidney, pancreas, and brain tissue were harvested under terminal anesthesia. Tissues were assessed using immunohistochemistry or ELISA techniques. Treatment with sotagliflozin promoted multiple metabolic benefits in diabetic Akimba mice resulting in decreased blood glucose and improved polydipsia. Sotagliflozin also prevented mortalities associated with diabetes. Our data suggests that there is the possibility that combined SGLT1/2i may be superior to SGLT2i in controlling glucose homeostasis and provides protection of multiple organs affected by diabetes.

A Phase II Study of Nab-Paclitaxel and Gemcitabine as First-Line Therapy in Patients with Cholangiocarcinoma Ineligible for Cisplatin-Based Chemotherapy (NACHO).

INTRODUCTION: Gemcitabine and cisplatin is the standard first-line systemic treatment in patients with advanced cholangiocarcinoma (CCA). However, a substantial number of patients do not qualify for cisplatin due to comorbidities or poor performance status. The phase II pilot study NACHO evaluated the efficacy of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) given on days 1, 8, and 15 every 4 weeks as first-line therapy in patients with advanced CCA ineligible for cisplatin-based chemotherapy. METHODS: Patients with any comorbidity precluding cisplatin therapy, such as renal impairment, impaired hearing, increased risk or history for thromboembolic events, intolerance of extensive hydration, or significant cardiovascular disease were eligible. Primary endpoint was overall response rate (ORR) per RECIST 1.1. Secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and patient reported outcome. RESULTS: From December 2016 to July 2017, 10 patients were prospectively enrolled and treated. The ORR with nab-paclitaxel/gemcitabine was 50%, the disease control rate (DCR) was 90%. Median PFS was 5.7 months (95% CI: 5.3-6.1), and median OS was 7.8 months (95% CI: 5.4-10.2). In total, 13 SAEs were documented without any new safety signals. There were 14 grade 3-4 treatment-related adverse events (TRAEs) in 10 patients of the ITT population. Exploratory subgroup analyses including known prognostic markers were performed. CONCLUSIONS: The NACHO trial supports safety and efficacy of nab-paclitaxel and gemcitabine in patients with advanced CCA ineligible for cisplatin-based therapy and should be further evaluated in a larger prospective trial.

Clinical Outcome and Treatment Sequences of Patients with Advanced Pancreatic Cancer Treated with Contemporary Chemotherapy Protocols.

INTRODUCTION: Systemic therapy is firmly established in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Clinical efficacy is still modest and options are limited. Combination therapy protocols such as FOLFIRINOX and gemcitabine/nab-paclitaxel (Gem/NP) define standard-of-care. Patients may receive a sequence of both regimens as first- and second-line palliative treatment. However, there is no guidance regarding a preferred order. METHODS: This is a retrospective analysis of clinical characteristics, treatment trajectories, and outcomes of patients with advanced PDAC treated at the West German Cancer Center Essen from 2014 to 2020 to inform treatment decisions with respect to predictive factors, impact of chemotherapy regimen sequence, and maintenance treatment. RESULTS: We identified 170 patients with available follow-up. Of those, 160 (94.1%) patients received palliative CTX for primary metastatic, locally advanced, or recurrent PDAC. Median progression-free survival (PFS) upon first palliative chemotherapy was 4.1 (3.1-5.9) months. First-line FOLFIRINOX was associated with superior PFS (median 6.3 months) and OS (9.7 months, HR 0.7, p = 0.03) as compared to Gem/NP or other regimens (PFS 3.0, OS 6.9 months). However, OS benefit of first-line FOLFIRINOX was lost in patients who received at least two treatment lines (median OS 12.1 vs. 13.1 months, p = 0.43). A landmark analysis of patients with clinical benefit (defined as CR/PR/SD for at least 20 weeks) upon first-line therapy revealed improved OS (HR 0.53, p = 0.02) for patients receiving continued deescalated maintenance therapy. Second-line regimens resulted in similar PFS (overall log-rank p = 0.92, median PFS upon second-line therapy 2.3 [1.8-2.9], per-regimen median between 1.8 and 3.9 months). A previously established systemic inflammation score proved to be strongly prognostic and allowed identification of a patient subgroup with dismal prognosis (OS 2.9 vs. 11.4 months, HR 5.23, p < 0.001), independent of other prognostic factors and with no relevant interaction with the choice of first-line regimen. CONCLUSION: In this real-world population of PDAC patients treated with contemporary combination chemotherapies, a positive impact of first-line FOLFIRINOX was only observed when no second or further line treatment was administered. Intensity-reduced maintenance therapy may lead to superior survival.

Identification of a new prognostic score for patients with high-grade metastatic GEP-NEN treated with palliative chemotherapy.

PURPOSE: High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN G3) are rare and heterogeneous malignancies with poor prognosis. Aim of this study was to develop prognosticators identifying those patients that derive the most benefit from currently available systemic therapies. METHODS: This retrospective analysis included 78 patients with metastatic GEP-NEN G3. For patients with imaging data available (n = 52), the overall response rate (ORR) and disease control rate (DCR) were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). A Cox proportional hazard model was used to analyze the prognostic value of selected clinical and blood-based biomarkers. The impact of palliative chemotherapy regimens on time-to-treatment-failure (TTF) and overall survival (OS) was assessed. RESULTS: Median OS of the study cohort was 9.0 months (95% CI 7.0-11.1). The majority of patients received first-line treatment with platinum plus etoposide (83.3%). The ORR and DCR of the RECIST-evaluable subgroup were 34.6% and 76.9%. Median TTF upon first-line treatment was 4.9 months (95% CI 3.4-6.4). Multivariate analysis identified the Eastern Cooperative Oncology Group performance status (ECOG PS), lactate dehydrogenase (LDH) and absolute lymphocyte count as independent prognostic factors. A prognostic score based on these parameters discriminated patients with favorable and unfavorable outcomes. CONCLUSION: Outcomes of patients with GEP-NEN G3 are still limited. A new prognostic score identifying those patients benefitting from current platinum/etoposide-based chemotherapy protocols may help as stratification factor in future trial design.

Deep learning-based assessment of body composition and liver tumour burden for survival modelling in advanced colorectal cancer.

BACKGROUND: Personalized therapy planning remains a significant challenge in advanced colorectal cancer care, despite extensive research on prognostic and predictive markers. A strong correlation of sarcopenia or overall body composition and survival has been described. Here, we explore whether automated assessment of body composition and liver metastases from standard of care CT images can add to clinical parameters in personalized survival risk prognostication. METHODS: We retrospectively analysed clinical imaging data from 85 patients (50.6% female, mean age 58.9 SD 12.2 years) with colorectal cancer and synchronous liver metastases. Pretrained deep learning models were used to assess body composition and liver metastasis geometry from abdominal CT images before the initiation of systemic treatment. Abdominal muscle-to-bone ratio (MBR) was calculated by dividing abdominal muscle volume by abdominal bone volume. MBR was compared with body mass index (BMI), abdominal muscle volume, and abdominal muscle volume divided by height squared. Differences in overall survival based on body composition and liver metastasis parameters were compared using Kaplan-Meier survival curves. Results were correlated with clinical and biomarker data to develop a machine learning model for survival risk prognostication. RESULTS: The MBR, unlike abdominal muscle volume or BMI, was significantly associated with overall survival (HR 0.39, 95% CI: 0.19-0.80, P = 0.009). The MBR (P = 0.022), liver metastasis surface area (P = 0.01) and primary tumour sidedness (P = 0.007) were independently associated with overall survival in multivariate analysis. Body composition parameters did not correlate with KRAS mutational status or primary tumour sidedness. A prediction model based on MBR, liver metastasis surface area and primary tumour sidedness achieved a concordance index of 0.69. CONCLUSIONS: Automated segmentation enables to extract prognostic parameters from routine imaging data for personalized survival modelling in advanced colorectal cancer patients.

Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression.

Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.

Biweekly Cetuximab Plus FOLFOX6 as First-Line Therapy in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The CEBIFOX Trial.

BACKGROUND: The multicenter, single-arm, phase II study CEBIFOX evaluated the efficacy of a biweekly cetuximab administration in combination with FOLFOX6 as first-line therapy in KRAS (exon 2) wild-type (wt) metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients received FOLFOX6 with cetuximab (500 mg/m2) every second week. Primary endpoint was objective response rate (ORR), among others secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), and patient-reported outcome (PRO). The impact on the treatment efficacy was evaluated in explorative subgroup analyses, including extended molecular profiling and primary tumor location. RESULTS: In total, 57 were included in the intention-to-treat (ITT) analyses. New RAS mutations were detected in 14.0% by post hoc next-generation sequencing analysis in 43 patients. The ORR in the all RASwt population was 70.3% with a median PFS and OS of 10.9 (95% confidence interval [CI], 9.0-12.9) and 33.8 (95% CI, 21.1-45.5) months. Grade 3-5 adverse events occurred in 66.7% of the ITT, without significant impact on the PRO. Patients with right-sided primary tumors had a reduced ORR (54.5%), and median PFS and OS (10.1 and 23.8 months). BRAF mutations were detected in 11.3%. These patients had a significantly lower ORR, and median PFS and OS. Patients with RASwt/BRAFwt tumors had a notably high median PFS and OS of 14.3 and 38.9 months. CONCLUSIONS: This study supports the efficacy and safety of biweekly cetuximab given in combination with FOLFOX6 in patients with RASwt/BRAFwt mCRC with left-sided primary tumor. CEBIFOX is the first trial reporting the complete dataset, including extended molecular profiling and tumor location of a biweekly administered cetuximab/FOLFOX6 in mCRC. Clinical trial number: NCT01051167.

Impact of RAS mutation subtype on clinical outcome-a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer.

Mutated RAS onco-proteins are key drivers across many cancers. The distribution of somatic RAS mutations varies between cancer entities. Retrospective analyses have associated some RAS mutations with distinct clinical outcomes. However, the clinical impact of the full spectrum of RAS mutations in their disease contextuality remains to be defined. To improve upon this situation, we studied genomically and clinically annotated, prospectively recruited cohorts of patients with RAS-mutated metastatic lung cancer and colorectal cancer. Mutational spectra were compared with predictions derived from analyzing the mutagenic impact at the genome level for each entity. Interestingly, we found concordance of predicted signatures with those actually observed in our patients. Thus, composition of the functionally active RAS mutational subtypes is primarily determined by the mutagenic context. Most RAS mutations seemed dominant oncogenic drivers with entity-dependent clinical outcomes. RAS comutations were enriched in tumors harboring class 2/3 BRAF mutations, highlighting the functional dependency of some mutated BRAF isoforms on RAS. With our dataset, we established a probabilistic model for cross-entity comparison of the prognostic impact of specific RAS mutational subtypes. The resulting prognostic clusters showed largely consistent clinical categorizations in both entities. This suggests mutant subtype-specific functional properties leading to similar clinical effects. A notable exception is KRAS G12C, which imparted an adverse prognosis only in colorectal cancer. Our findings provide a framework for risk stratification of specific RAS mutations across several cancer entities, which is required to guide the analysis of clinical findings in patients treated with direct RAS inhibitors or agents targeting downstream pathways.

Phosphorylation of p70 Ribosomal Protein S6 Kinase ß-1 is an Independent Prognostic Parameter in Metastatic Colorectal Cancer.

BACKGROUND: Deregulation of signal transduction pathways plays a critical role in oncogenesis of colorectal cancer (CRC) and directly affects sensitivity to targeted therapies. Against this background we developed a comprehensive biomarker profiling program including markers of downstream signaling to study their association with clinical outcomes. PATIENTS AND METHODS: A prospectively studied cohort of 160 patients with metastatic CRC was included. Standard diagnostic workup included mutational analyses of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-Raf murine sarcoma viral oncogene homolog B (BRAF). In addition, markers of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mammalian target of rapamycin pathway activation (phosphorylation of extracellular signal-regulated kinase [ERK], AKT, and p70 ribosomal protein S6 kinase ß-1 [p70S6K]) were studied using standardized immunohistochemistry. RESULTS: There was a significant correlation between markers of ERK and AKT activation in the full cohort. In addition, phosphorylation of p70S6K correlated strongly with ERK and AKT phosphorylation and primary tumor localization in the right colon. Subgroup analyses specified these correlations to patients with all-RAS wild type tumors. In contrast, tumors harboring RAS mutations predominantly exhibited ERK phosphorylation. Interestingly, patients with CRC showing high p70S6K phosphorylation (highest quartile) had a significantly inferior overall survival (hazard ratio [HR], 2.4; P = .002) irrespective of RAS mutational status. This effect remained significant in multivariate analysis (P = .002). A patient subgroup characterized by high p70S6K phosphorylation and right-sided primary tumors had a particularly poor prognosis with a dramatically inferior overall survival (HR, 5.2; P < .001). Patients with right-sided primary tumor and low p70S6K phosphorylation had responses to anti-epidermal growth factor receptor antibody-based therapies and overall survival similar to patients with left-sided primary tumors. CONCLUSION: High phosphorylation of p70S6K is a novel, independent biomarker for poor prognosis, in particular in patients with right-sided primary tumors.

Feasibility of preemptive biomarker profiling for personalised early clinical drug development at a Comprehensive Cancer Center.

PURPOSE: Multiple investigational drugs are currently explored in cancer patient populations defined by specific biomarkers. This demands a new process of patient selection for clinical trials. PATIENTS AND METHODS: Starting January 1, 2012, preemptive biomarker profiling was offered at the West German Cancer Center to all patients with advanced non-small-cell lung (NSCLC) or colorectal cancer (CRC), who met generic study inclusion criteria. Tumour specimens were subjected to prespecified profiling algorithms to detect 'actionable biomarkers' by amplicon sequencing, in situ hybridisation and immunohistochemistry. The clinical course was closely monitored to offer trial participation whenever applicable. RESULTS: Within 12 months, 267 patients (188 NSCLC, 79 CRC) were profiled. Estimated additional cost for biomarker profiling was 219615.51 EUR excluding histopathology workup and administration. The most prevalent biomarkers in pulmonary adenocarcinoma were KRAS mutations (29%), loss of PTEN expression (18%), EGFR mutations (9%), HER2 amplification (5%) and BRAF mutations (3%), while the prevalence of ALK translocations and PIK3CA mutations was extremely low. In pulmonary squamous cell carcinoma FGFR1 amplifications were found in 15%, PTEN expression was lost in 20% and DDR2 was mutated in a single case. KRAS mutations (41%) predominated in CRC, followed by loss of PTEN expression (16%), PIK3CA (5%) and BRAF (5%) mutations. So far 13 patients (5%) have entered biomarker-stratified clinical trials. Therapeutic decisions for approved drugs were guided in another 45 patients (17%). CONCLUSION: Preemptive biomarker profiling can be implemented into the diagnostic algorithm of a large Comprehensive Cancer Center. Substantial investments in diagnostics and administration are required.

Two-stage recovery of amphibian assemblages following selective logging of tropical forests.

There is a lack of quantitative information on the effectiveness of selective-logging practices in ameliorating effects of logging on faunal communities. We conducted a large-scale replicated field study in 3 selectively logged moist semideciduous forests in West Africa at varying times after timber extraction to assess post logging effects on amphibian assemblages. Specifically, we assessed whether the diversity, abundance, and assemblage composition of amphibians changed over time for forest-dependent species and those tolerant of forest disturbance. In 2009, we sampled amphibians in 3 forests (total of 48 study plots, each 2 ha) in southwestern Ghana. In each forest, we established plots in undisturbed forest, recently logged forest, and forest logged 10 and 20 years previously. Logging intensity was constant across sites with 3 trees/ha removed. Recently logged forests supported substantially more species than unlogged forests. This was due to an influx of disturbance-tolerant species after logging. Simultaneously Simpson's index decreased, with increased in dominance of a few species. As time since logging increased richness of disturbance-tolerant species decreased until 10 years after logging when their composition was indistinguishable from unlogged forests. Simpson's index increased with time since logging and was indistinguishable from unlogged forest 20 years after logging. Forest specialists decreased after logging and recovered slowly. However, after 20 years amphibian assemblages had returned to a state indistinguishable from that of undisturbed forest in both abundance and composition. These results demonstrate that even with low-intensity logging (≤3 trees/ha) a minimum 20-year rotation of logging is required for effective conservation of amphibian assemblages in moist semideciduous forests. Furthermore, remnant patches of intact forests retained in the landscape and the presence of permanent brooks may aid in the effective recovery of amphibian assemblages.

Neuroinflammatory processes in Alzheimer's disease.

Generation of neurotoxic amyloid beta peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer's disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction, may actively contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzyme systems are expressed and released by microglia, astrocytes and neurons in the AD brain. Degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may facilitate the occurrence of inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate amyloid precursor protein processing by various means and therefore can establish a vicious cycle. Despite the fact that some aspects of inflammation may even be protective for bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal anti-inflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. While, the precise molecular mechanism underlying this effect is still unknown, a number of possible mechanisms including cyclooxygenase 2 or gamma-secretase inhibition and activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection.

Controlled reperfusion using a simplified perfusion system preserves function after acute and persistent limb ischemia: a preliminary study.

OBJECTIVE: Reperfusion of the limb after acute and persistent ischemia is associated with high rates of morbidity and mortality despite complete revascularization. Although reperfusion is a prerequisite for maintaining limb function, it may in itself cause further injury. There is experimental evidence that modification of the initial reperfusion modalities can minimize this reperfusion injury. We hypothesized that controlled reperfusion using a simple blood bag perfusion system reduces reperfusion injury and facilitates the return of normal function. METHODS: Fifteen consecutive patients (mean age, 80.5 +/- 5.0 years) with severe, acute lower-limb ischemia were allocated to two treatment arms in this prospective, controlled observational study. Group I (n = 8) underwent surgical embolectomy alone, and group II (n = 7) underwent surgical embolectomy plus controlled reperfusion using a simplified perfusion system. Indication for controlled reperfusion was made by the responsible surgeon. Controlled reperfusion consisted of a 30-minute infusion of a crystalloid reperfusion solution that was mixed with oxygenated blood (the blood:reperfusion solution ratio was 6:1) distal to the occlusion. Duration of ischemia, postoperative amputation rate, motor function of the ischemic limb, and pre- and postoperative serum creatine kinase levels were assessed. RESULTS: The duration of ischemia was 10.7 +/- 1.1 hours in group I and 19 +/- 5.2 hours in group II (P < .05). The site of the arterial occlusion was the iliac artery in nine patients and the common femoral artery in six patients. Full recovery was achieved in six of seven patients in group II and in only two of eight patients in group I (P < .05). There were three in-hospital deaths in group I, and two patients underwent major amputations. No in-hospital deaths or major amputations occurred in group II. CONCLUSION: The results from this preliminary study strongly suggest the hypothesis that the results of conventional embolectomy for acute, severe lower-limb ischemia can be improved by controlled reperfusion. To prove our preliminary findings, a large randomized, prospective, controlled, multicenter trial, the Controlled Reperfusion of the Acutely Ischemic Limb trial (CRAIL-Trial) is currently being conducted to prove our preliminary findings.

Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: five-year safety and efficacy results.

PURPOSE: Although complete resection (R0) of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC) patients amenable to curative therapy, only approximately one third survive for 5 years. The objective of this phase II study was to evaluate the safety and efficacy of radioimmunotherapy (RAIT) after salvage resection of LM. PATIENTS AND METHODS: Twenty-three patients who underwent surgery for LM of CRC received a dose of 40 to 60 mCi/m2 of 131I-labetuzumab, which is a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival (DFS; n = 19), and overall survival (OS; n = 19) were determined. RESULTS: With a median follow-up of 64 months, the median OS time from the first liver resection for RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time was 18.0 months (95% CI, 11.0 to 31.0 months). The 5-year survival rate was 51.3%. RAIT benefited patients independently of bilobar involvement, size and number of LM, and resection margins. The major adverse effect was transient myelosuppression, resulting mostly in grade < or = 3 neutropenia and/or thrombocytopenia. CONCLUSION: Because both the median OS and 5-year survival rates seem to be improved with adjuvant RAIT after complete LM resection in CRC, compared with historical and contemporaneous controls not receiving RAIT, these results justify further evaluation of this modality in a multicenter, randomized trial.

Liver repopulation after hepatocellular transplantation: integration and interaction of transplanted hepatocytes in the host.

The mechanisms of donor hepatocyte integration into recipient liver are not fully understood. We investigated mechanisms of both the integration and interaction of transplanted hepatocytes with host liver cells as well as the repopulation of the host organ following intraportal transplantation. Mature hepatocytes were injected into the portal vein of dipeptidylpeptidase IV (DPPIV)-deficient rats pretreated with retrorsine and subjected to 30% partial hepatectomy to ensure selective donor growth. The degree of integration and proliferation was studied by colocalizing transplanted cells (DPPIV positive) with connexin 32, MMP-2, and OX-43 (multilayer immunofluorescence imaging). FACS analysis was established to assess the extent of repopulation quantitatively. Transplanted hepatocytes reached the distal portal spaces and sinusoids within 1 h after injection. A small proportion of cells succeeded in traversing the endothelial barrier through mechanical disruption in both locations. Transplanted hepatocytes lost their membrane-bound gap junctions (connexin 32) during this process. Successful integration of the donor cells required up to 5 days, heralded by gap junction reconstitution and the specific basolateral membrane expression of DPPIV. MMP-2 degraded the extracellular matrix in close proximity to donor cells, providing space for cell division. FACS analysis revealed that more than 37% of the liver was repopulated by cells derived from donors at 2 months after transplantation. Our data demonstrate a high degree of donor cell repopulation of the host organ and provide valuable insight into the specific mechanisms of donor cell integration. Connexin 32 expression in transplanted hepatocytes may serve as an indicator of their effective incorporation and communication within the recipient liver. FACS analysis reveals an accurate method to determine quantitatively the extent of liver repopulation.

Reduced sympathoneural responses to the cold pressor test in individuals with essential hypertension and in those genetically predisposed to hypertension. No support for the "pressor reactor" hypothesis of hypertension development.

BACKGROUND: The aim of this study was to examine the influences of genetic predisposition to hypertension and of age on the sympathetic nervous system response to the cold pressor test (CPT). METHODS: A total of 32 young subjects (aged 27 +/- 2 years) were studied: 11 normotensive subjects without a family history of hypertension (FH), 14 normotensive subjects with a strong family history of hypertension (FH+), and eight hypertensive subjects. In addition, 21 older subjects (aged 53 +/- 2 years) were studied: 13 hypertensive and eight normotensive subjects. Blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during a 2-min period of a CPT. RESULTS: Both young and older hypertensive subjects had higher resting MSNA than did the normotensive ones (47 +/- 7 v 29 +/- 4 bursts per 100 heartbeats (P < .05) and 66 +/- 4 v 40 +/- 7 bursts per 100 heartbeats (P < .01), respectively). The CPT resulted in HR increases of similar magnitude in all groups of patients. The FH+ group displayed slightly less increase in systolic BP than that of the FH- group (P < .05). The MSNA increased to a far greater degree in FH- (103%) than in FH+ (32%) and in young hypertensive patients (12%) (P < .05). Similarly, MSNA change with the CPT was greater in older normotensive subjects than in older hypertensive patients (61% v 12%, P < .05). CONCLUSIONS: Our results show that a CPT induces sympathetic responses that are subnormal in hypertensive patients and those with a family history of hypertension, highlighting the importance of genetic factors in determining the sympathetic nervous reactivity to CPT.

Significance of isolated tumor cells in lymph nodes among gastric cancer patients.

PURPOSE: To determine the frequency and prognostic impact of isolated tumor cells (ITC) in regional lymph nodes judged to be tumor free in conventional histopathology among gastric cancer patients. METHODS: Among 161 patients who underwent gastrectomy and D2-lymphadenectomy, 56 were staged pN0(35%). Archival paraffin blocks of 1148 resected regional lymph nodes of those pN0 patients were reevaluated for ITC using monoclonal antibody Ber-EP4. Patients with and without ITC were compared with regard to the distribution of various clinicopathological factors. Prognostic impact of ITC was tested in uni- and multivariate analysis. RESULTS: Of 56 pN0 patients, 33 (59%) exhibited single Ber-Ep4 immunoreactive cells or small cell clusters in at least one lymph node. The occurrence of ITC was not dependent on other clinicopathological factors. ITC impaired patients' prognoses significantly in uni- as well as multivariate analyses [estimated 5-year survival rate: 82% for pN0((i-))vs 58% for pN0((i+))(p = 0.059) and 15% for pN1/2 (p = 0.0005 and p < 0.0001, respectively)]. CONCLUSION: ITC are a frequent event in apparently tumor-free lymph nodes of gastric cancer patients and are overlooked by conventional histopathology. They are encountered even in limited stages of disease and impair patients' prognoses. This should be borne in mind when advocating local resection for early gastric cancer.

Pylorus preservation has no impact on delayed gastric emptying after pancreatic head resection.

OBJECTIVES: Delayed gastric emptying (DGE) has been specifically attributed to pylorus-preserving pancreaticoduodenectomy (PPPD). As PPPD has been shown to be comparable with the classic Kausch-Whipple pancreaticoduodenectomy (KWPD) in terms of oncological radicality, DGE has advanced to be the leading argument for hemigastrectomy in PD. METHODS: A prospective, nonrandomized comparison of patients undergoing PPPD (n = 113), KWPD (n = 19), and duodenum-preserving, pancreatic head resection (DPPHR, n = 18) for various diseases was performed. First, groups were analyzed with regard to structural similarity; then, they were compared with special emphasis on DGE and other postoperative complications. Finally, further prognostic factors were sought that had an impact on DGE. RESULTS: The PPPD group was comparable with the KWPD group, but not to the DPPHR population. The in-clinic course after DPPHR compared favorably with PPPD as well as KWPD, and, here, no DGE occurred. The overall morbidity rates of PPPD and KWPD were comparable; 1 patient died in hospital (mortality rate, 0.7%). The gastric tube after PPPD and KWPD could be withdrawn at a median of 2 and 3 days, respectively, a liquid diet was started after 4 and 5 days, respectively, and a full diet was tolerated after 10 days each (n.s.). DGE was distributed evenly among PPPD (12%) and KWPD patients (21%, n.s.), and it was noted almost exclusively when other postoperative complications were present (P < 0.0001). No further prognostic factors influencing DGE could be identified. CONCLUSION: Pylorus preservation does not increase the frequency of DGE. DGE almost exclusively occurs as a consequence of other postoperative complications. Therefore, DGE should not be used as an argument to advocate hemigastrectomy in PPPD.