Procalcitonin ratio and on-demand relaparotomy for septic peritonitis: validation of the focus index (FI).

PURPOSE: Secondary peritonitis remains challenging to manage and some recent evidence suggests that on-demand relaparotomy is more appropriate than planned relaparotomy. This study was designed to validate the predictive power of postoperative procalcitonin (PCT) changes in relation to elimination of the septic abdominal focus. METHODS: In this prospective trial, postoperative PCT serum levels were monitored in 234 surgical patients with secondary peritonitis. The PCT ratio on postoperative days (PODs) 1 and 2 (focus index; FI) was calculated and correlated with the success of the operation. RESULTS: A cutoff value of 1.1 was calculated for the FI. Values below 1.1 indicated insufficient elimination of the focus and values above 1.1 correlated with effective treatment. The optimal time for first PCT sampling was found to be 12-24 h after the index operation. After the respective data cleanup, successful elimination of the intraabdominal focus could be confirmed, with a sensitivity of 93 % and a specificity of 71 %. CONCLUSIONS: The FI is a single parameter-based reliable predictor of successful surgical eradication and strengthens the on-demand relaparotomy concept as the method of choice to treat secondary peritonitis.

The impact of neural invasion severity in gastrointestinal malignancies: a clinicopathological study.

OBJECTIVES: Because neural invasion (NI) is still inconsistently reported and not well characterized within gastrointestinal malignancies (GIMs), our aim was to determine the exact prevalence and severity of NI and to elucidate the true impact of NI on patient's prognosis. BACKGROUND: The union internationale contre le cancer (UICC) recently added NI as a novel parameter in the current TNM classification. However, there are only a few existing studies with specific focus on NI, so that the distinct role of NI in GIMs is still uncertain. MATERIALS AND METHODS: NI was characterized in approximately 16,000 hematoxylin and eosin tissue sections from 2050 patients with adenocarcinoma of the esophagogastric junction (AEG)-I-III, squamous cell carcinoma (SCC) of the esophagus, gastric cancer (GC), colon cancer (CC), rectal cancer (RC), cholangiocellular cancer (CCC), hepatocellular cancer (HCC), and pancreatic cancer (PC). NI prevalence and severity was determined and related to patient's prognosis and survival. RESULTS: NI prevalence largely varied between HCC/6%, CC/28%, RC/34%, AEG-I/36% and AEG-II/36%, SCC/37%, GC/38%, CCC/58%, and AEG-III/65% to PC/100%. NI severity score was uppermost in PC (24.9±1.9) and lowest in AEG-I (0.8±0.3). Multivariable analyses including age, sex, TNM stage, and grading revealed that the prevalence of NI was significantly associated with diminished survival in AEG-II/III, GC, and RC. However, increasing NI severity impaired survival in AEG-II/III and PC only. CONCLUSIONS: NI prevalence and NI severity strongly vary within GIMs. Determination of NI severity in GIMs is a more precise tool than solely recording the presence of NI and revealed dismal prognostic impact on patients with AEG-II/III and PC. Evidently, NI is not a concomitant side feature in GIMs and, therefore, deserves special attention for improved patient stratification and individualized therapy after surgery.

Secondary gastrectomy for stage IV gastroesophageal adenocarcinoma after induction-chemotherapy.

PURPOSE: With improved chemotherapeutic regimens, metastasized gastric cancer may show a good response rendering an initially unresectable tumor resectable. We performed a retrospective analysis on the outcome of stage IV gastric cancer patients treated by chemotherapy followed by oncologic resection in a western institution. METHODS: From August 1988 to December 2010, a total number of 1,817 patients underwent surgery for gastric cancer at the Department of Surgery, Technical University of Munich. A retrospective analysis of our prospective gastric cancer database identified 58 patients with stage IV gastric cancer having undergone induction chemotherapy followed by surgery in an individualized treatment concept. After induction chemotherapy usually consisting of 2 cycles of PLF (cisplatin, 5-fluorouracil, leucovorin), resection was performed with or without removal of metastases in patients without disease progression. Patients were followed up until death or loss to follow up. RESULTS: The three most common metastatic locations were liver (27.6 %), distant lymph nodes (22.4 %), and peritoneum (19.0 %). Of patients, 13.8 % had metastases in more than one location. Thirty-day mortality was 5.2 %, 90-day mortality was 13.8 %, while overall postoperative morbidity accounted for 24 %. In 19 (32.8 %) patients, a complete resection without any macroscopic tumor residues was achieved. In 39 (67.2 %) patients, tumors could not be completely removed with either local residual disease or residual disease at distant sites. Overall median survival was 20 months, while patients without residual tumor survived significantly longer (72 months) than patients with residual disease (12 months, p = 0.001). CONCLUSION: Secondary surgery of metastasized gastric cancer may be justified in selected cases without progression under induction chemotherapy. An achievable complete removal of the primary tumor and metastases appears the main selection criterion for patients benefitting from this approach.

Arterial Resection for Pancreatic Cancer: Feasibility and Current Standing in a High-Volume Center.

Background: Arterial resection (AR) during pancreatectomy for curative R0 resection of pancreatic ductal adenocarcinoma (PDAC) remains a controversial procedure with high morbidity. Objective: To investigate the feasibility and oncological outcomes of pancreatectomy combined with AR at a high-volume center for pancreatic surgery. Methods: We retrospectively analyzed our experience in PDAC patients, who underwent pancreatic resection with AR and/or venous resection (VR) between 2007 and 2021. Results: In total 259 PDAC patients with borderline resectable (n = 138) or locally advanced (n = 121) PDAC underwent vascular resection during tumor resection. From these, 23 patients had AR (n = 4 due to intraoperative injury, n = 19 due to suspected arterial infiltration). However, 12 out of 23 patients (52.2%) underwent simultaneous VR including 1 case with intraoperative arterial injury. In comparison, 11 patients (47.8%) underwent AR only including 3 intraoperative arterial injury patients. Although the operation time and bleeding rate of patients with AR were respectively longer and higher than in VR, no significant difference was detected in postoperative complications between VR and AR (P = 0.11). The final histopathological findings of PDAC patients were similar, including M stage, regional lymph node metastases, and R0 margin resection. The mortality of the entire cohort was 6.2% (16/259), with a tendency to increase mortality in the AR cohort, yet without statistical significance (VR: 5% vs AR: 21.1%; P = 0.05). Although 19 (82.6%) patients had PDAC in the final histopathology, only 6 were confirmed to have infiltrated arteria. The microscopic distribution of PDAC in these infiltrated arterial walls on hematoxylin-eosin staining was classified into 3 patterns. Strikingly, the perivascular nerves frequently exhibited perineural invasion. Conclusions: AR can be performed in high-volume centers for pancreatic surgery with an acceptable morbidity, which is comparable to that of VR. However, the likelihood of arterial infiltration seems to be rather overestimated, and as such, AR might be avoidable or replaced by less invasive techniques such as divestment during PDAC surgery.

Drain use in pancreatic surgery: Results from an international survey among experts in the field.

BACKGROUND: Drain use in pancreatic surgery remains controversial. This survey sought to evaluate habits, experiences, and opinions of experts in the field on the use of drains to provide interesting insights for pancreatic surgeons worldwide. METHODS: An online survey designed via Google Forms was sent in December 2020 to experienced surgeons of the International Study Group for Pancreatic Surgery. RESULTS: Forty-two surgeons (42/63, 67%) completed the survey. During their career, 74% (31/42) performed personally >500 pancreatic resections; of these, 9 (21%) >1,500. Sixty-nine percent of the respondents (29/42) declared to always use drains during pancreatic resections and 17% (7/42) in >50% of the operations. For these participants, the use of drains does not increase but reduces the risk of pancreatic fistula and other complications, and more importantly, helps to detect them earlier and manage them better. By contrast, 2 surgeons (5%) declared to never apply drains, whereas other 4 (10%) use drains only in selective cases, deeming that drains increase the risk of infection and other complications. When applied, drains are managed very heterogeneously as for the type of drains, enzyme testing, and removal schedules. Four participants declared to practice continuous irrigation. Twenty-two surgeons (55%) remove drains routinely within the third postoperative day, other 11 (27.5%) only in selected cases, whereas 7 (17.5%) normally keep drains longer. CONCLUSION: Despite plenty of publications on this topic, drain management in pancreatic surgery remains very heterogeneous. Safety and the surgeon´s personal experience seem to play a determining role.

Bacterial content of the human pancreatic duct: An observational study.

Background: Pancreatic fistula/PF is a challenging surgical complication. We could recently show that intestinal bacteria such as Enterobacterales colonize the PF fluid even after a "sterile" operation like distal pancreatectomy/DP. Therefore, we explored the bacterial flora of the human pancreatic duct in a patient collective undergoing pancreatic surgery. Methods: In this observational study, upon transection of the pancreas during surgery, a swab was inserted into the main duct, and the micro-organismal content was correlated with clinical characteristics. Results: Between February 2017 and February 2020, an intraoperative swab from the pancreatic duct was obtained from a total of 54 patients who underwent pancreatico-duodenectomy/PD or DP. The swabs were sterile in 39 cases (72.2%), detected intestinal bacteria in 10 cases (18.5%), and other bacteria in 5 cases (9.3%). There was no correlation of the micro-organismal content of the pancreatic duct swab with bacteria detected in the PF fluid or bile. Preoperative ERCP was associated with a higher frequency of bacterial colonization of the pancreatic duct (33.3% vs. 6.7%, p = 0.005). There was no correlation of the pancreatic duct swabs with postoperative complications. Discussion: The human main pancreatic duct is usually sterile, and its bacterial colonization does not correlate with the occurrence of PF. Therefore, the mechanisms leading to infection of PF warrant in-depth, mechanistic investigation.

Cytochrome P450 activity mirrors nitric oxide levels in postoperative sepsis: predictive indicators of lethal outcome.

BACKGROUND: The development of liver failure significantly influences prognosis during the course of major septic complications. Although the underlying cause for septic liver failure is still unclear, research using animal models has demonstrated that an increased nitric oxide (NO) synthesis compromises detoxification processes in the liver. METHODS: In the present study, serum NO levels were measured by high-performance liquid chromatography (HPLC) and aminopyrine breath test (ABT) scores, reflecting the in vivo activity of cytochrome P450-dependent liver enzymes, were investigated in 42 patients (23 who survived sepsis [survivors]/19 patients who ultimately died of sepsis [nonsurvivors]) suffering from major septic complications after abdominal surgery. Additionally, TNF-alpha serum levels, serving as indicators for major systemic inflammation, were monitored using enzyme-linked immunosorbent assay (ELISA). RESULTS: The increased serum NO levels that were found during sepsis correlated with the severity of the septic course. Compared with preoperative values of 42.77 +/- 5.84 mM, nitrite/nitrate levels reached 72.88 +/- 10.16 mM in early sepsis. An increased NO synthesis also was accompanied by a rise in serum TNF-alpha levels. Monitoring of liver function by ABT allowed an early differentiation between transient sepsis and sepsis with a lethal outcome (P=.006). In contrast, cytochrome P450 activity as measured by the ABT was significantly diminished in septic patients (0.45 +/- 0.02 [% dose x kgBW per (mmol CO2)-1] before sepsis onset/0.16 +/- 0.01 [% dose x kgBW per (mmol CO2)-1] in sepsis). Like the NO and TNF-alpha levels, ABT scores showed a difference between transient sepsis and sepsis with a lethal outcome. Serum NO levels were inversely correlated with ABT scores (P=.022) and positively correlated with TNF-alpha levels (P=0.015) in the late phase of sepsis. Serum TNF-alpha levels and ABT scores were inversely correlated in the early (P=.027), as well as in the late (P=.015) phases of sepsis. CONCLUSIONS: This study supports the hypothesis that septic liver failure is linked to the induction of NO synthesis in major systemic inflammation. Therefore, the ABT provides a clinically useful tool for predicting the outcome in the early stages of sepsis. This may aid in the decision-making process when early surgical intervention is considered.

Adjuvant and/or neoadjuvant therapy for gastric cancer? A perspective review.

Surgery is still the only curative therapy for locoregional gastric cancer. Hereby it is important to achieve negative margins (R0 resection) and to perform an adequate lymph-node dissection (D2 lymphadenectomy). Unfortunately most cases of gastric cancer are diagnosed in a locally advanced tumor stage. The poor prognosis of patients with these tumors is due to the frequent recurrences after primary resection in curative intent. This observation led to the development of (neo)adjuvant treatment concepts. Beginning with the end of the 1980s, more and more patients with locally advanced tumors were subjected to a preoperative, perioperative, or postoperative treatment in order to improve the prognosis after curative resection. However, in different regions of the world, different regiments are preferred. While adjuvant chemotherapy is the established treatment in Asia, adjuvant chemoradiotherapy is favored in the USA and perioperative chemotherapy is considered the treatment of choice in Europe. However, recently a certain convergence of the different philosophies is to be observed. This article covers the relevant studies dealing with neoadjuvant and adjuvant treatment concepts and gives an overview on the latest developments in this field.

Successful renal transplantation after intimal dissection of the renal artery secondary to trauma.

BACKGROUND: Organ shortage increasingly forces surgeons to consider the use of marginal organs. METHODS: The authors report a case in which a kidney with traumatic dissection of the renal artery and marginal perfusion by means of collaterals was successfully transplanted into a 63-year-old patient. A computed tomographic scan of the donor showed a marginally perfused left kidney, suggestive of renal artery dissection. After surgical reconstruction of the renal artery, transplantation followed the usual course. RESULTS: The organ started clearing shortly after the operation and was homogeneously perfused in a postoperative scan. Creatinine and blood urea nitrogen levels dropped to normal values within a couple of days after the transplantation. During 1 year of follow-up, organ function was always excellent and retention parameters were within the normal range. CONCLUSIONS: This case illustrates that marginally perfused kidneys can be successfully used for transplantation in certain cases.

Mixed antagonist response and sepsis severity-dependent dysbalance of pro- and anti-inflammatory responses at the onset of postoperative sepsis.

It has been postulated that an early systemic inflammatory response syndrome (SIRS) and a subsequent compensatory anti-inflammatory response syndrome (CARS) occur sequentially in sepsis. Co-existence of both is referred to as mixed antagonist response syndrome (MARS). Pro- and anti-inflammatory cytokine production was investigated in patients with postoperative sepsis, a murine peritonitis model and in vitro to further delineate the interaction of hyper- and hypo-inflammation in sepsis. IL-6 and IL-10 were measured in serum samples from 80 patients on d1 and d2 of postoperative sepsis and were similarly determined at various time points after induction of septic peritonitis in mice. Cytokine production of RAW264 macrophages was stimulated in vitro using TLR agonists. IL-6 and IL-10 were measured in supernatants. All cytokine measurements were performed by ELISA. In patients, the initial phase of the immune response to sepsis was characterized by a concomitant elevation of serum IL-6 and IL-10 levels. IL-10 levels were correlated with IL-6 levels in an exponential manner (p<0.001), which could be confirmed in a mouse model of septic peritonitis. In vitro experiments revealed that the observed exponential correlation may occur as function of TLR signaling intensity. Early postoperative sepsis seems to be characterized by a primary MARS. Sepsis severity was positively correlated with a disproportionate elevation of the anti-inflammatory response relative to the pro-inflammatory response, a pattern reminiscent of TLR-driven responses. Detailed characterization of immune responses in sepsis may help to direct standard therapies and to develop effective immunomodulatory strategies.

Combined immunosuppressive and antibiotic therapy improves bacterial clearance and survival of polymicrobial septic peritonitis.

Effective immunosuppressive therapy is essential to prevent transplant rejection but renders patients vulnerable to opportunistic infections. The present study investigates the effects of common immunosuppressive drugs on the course of septic peritonitis in an experimental mouse model. We show that treatment with a combination of tacrolimus, mycophenolate mofetil, and methylprednisolone resulted in highly elevated lethality of septic peritonitis. When immunosuppressive drugs were combined with antibiotic therapy, however, mice were almost completely protected. The combination of mycophenolate mofetil and methylprednisolone was shown to be required and sufficient to improve outcome of septic peritonitis in the presence of antibiotic therapy. Combined immunosuppressive and antibiotic therapy, but not antibiotic therapy alone, resulted in enhanced bacterial clearance. These beneficial effects were linked to an elevated expression of activation markers and an increased production of reactive oxygen metabolites by peritoneal neutrophils and correlated with a reduced messenger RNA expression of the inhibitory cytokine IL-22. In contrast, systemic or peritoneal levels of IL-10, IL-12, TNF-alpha, keratinocyte chemoattractant, and monocyte chemoattractant protein 1, and splenic messenger RNA levels of IFN-gamma were not influenced by the immunosuppressive therapy. These results therefore suggest that combined immunosuppressive and antibiotic therapy may improve bacterial clearance and survival of septic peritonitis by a mechanism that involves enhanced activation and antimicrobial activity of neutrophils and reduced production of IL-22.

Procalcitonin ratio indicates successful surgical treatment of abdominal sepsis.

BACKGROUND: On-demand relaparotomy has been associated with a slightly decreased mortality compared to planned relaparotomy in the surgical treatment of secondary peritonitis. On-demand relaparotomy must be performed without delay to detect progressing sepsis early, before the onset of multiorgan failure. The aim of the study was to evaluate procalcitonin (PCT) as a parameter for early detection of progressing sepsis after operative treatment of the infective source. METHODS: In 104 consecutive patients with secondary peritonitis, PCT serum levels were monitored on postoperative days 1 and 2 after initial operative elimination of the septic focus. The PCT ratio between postoperative days 1 and 2 was calculated and correlated to the success of the initial intervention. The latter was considered inadequate if relaparotomies were necessary to eliminate the intraabdominal infection. RESULTS: Using classification and regression tree analysis, a cutoff could be calculated at 1.03 for the PCT ratio of postoperative day 1 to day 2. Lesser values indicated unsuccessful elimination of the septic source, whereas values above 1.03 represented successful operative treatment of the septic focus. Unsuccessful treatment of the septic process could be detected with a specificity of 63% and a sensitivity of 95%. CONCLUSION: The PCT ratio appears to be a valuable aid in deciding if further relaparotomies are necessary after initial operative treatment of an intraabdominal septic focus.

Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER.

Communication between the nervous and immune systems involves the release of neuropeptides, such as calcitonin gene-related peptide (CGRP), from sensory nerves during inflammation. CGRP may inhibit the activities of both innate and adaptive immune cells, but the molecular pathways underlying this function are largely unknown. In this study, we identify CGRP as a potent inhibitor of TLR-stimulated production of inflammatory mediators, such as TNF-alpha and CCL4, by murine dendritic cells. Inhibition of TLR responses was independent of IL-10 and did not involve perturbation of canonical TLR signaling, including activation of MAPK and NF-kappaB. Instead, the inhibitory activity of CGRP was mediated by the cAMP/protein kinase A pathway leading to rapid up-regulation of the transcriptional repressor, inducible cAMP early repressor (ICER). Ectopically expressed ICER directly repressed the LPS-stimulated activity of a synthetic Tnf promoter, as well as TNF-alpha protein production driven by the endogenous promoter. Inhibition of dendritic cell gene expression by CGRP was associated with the presence of a composite cAMP response element/kappaB promoter element. In a murine model of endotoxemia, CGRP markedly attenuated serum TNF-alpha levels, and this effect was associated with the up-regulation of ICER. Together, these results establish a novel pathway for the negative regulation of TLR responses through the nervous system that critically involves induction of the transcriptional repressor ICER by the neuropeptide CGRP.

Predicting individual survival after gastric cancer resection: validation of a U.S.-derived nomogram at a single high-volume center in Europe.

OBJECTIVE: Validation of a U.S.-derived nomogram for individual prediction of disease-specific gastric cancer survival at a European institution. SUMMARY BACKGROUND DATA: One major issue of modern cancer treatment is the individualization of therapy. For gastric cancer, Kattan et al, at Memorial Sloan-Kettering Cancer Center, New York, NY, developed a nomogram, allowing to predict individual patient risk of tumor-related death after R0 resection from basic patient-related variables. The validity of the nomogram has not yet been shown in patients from other institutions. The accuracy of the nomogram when applied to patients after having undergone R0 gastric cancer resection at a European high-volume center was investigated. METHODS: Clinical data from patients who underwent R0 gastric cancer resection at Klinikum rechts der Isar, Technical University of Munich, Germany and fitted the respective derivation criteria were used for external validation (n = 862). Nomogram predictions for 60- and 108-month disease-specific survival were calculated for each patient and compared with actual survival. The concordance index was used as an accuracy measure. RESULTS: The bootstrap-corrected concordance index was 0.77 and was superior when compared with the predictive ability of International Union Against Cancer tumor stage (P < 0.008). Nomogram calibration was excellent for 60-month disease-specific survival. Nomogram predictions showed the trend to underestimate survival in stage II/III disease of the MRI patients. CONCLUSIONS: The use of the nomogram created by Kattan et al is not only confined to the institution where it was created, but it can be adopted by other institutions with similar surgical strategies.

Esophageal replacement by Lexer's esophagoplasty: adenocarcinoma as late complication.

The most successful method for esophageal reconstruction in the early 20th century was the jejunodermatoesophagoplasty after Lexer, involving the presternal formation of a skin tube for passage reconstruction. A 59-year-old patient presented to our hospital with adenocarcinoma at the dermatojejunostomy 47 years after undergoing a Lexer procedure. The neoesophagus was removed, and the passage was reconstructed by a retrosternal colonic interposition. Although squamous cell carcinoma is known as a late complication of dermatoesophagoplasties, this is a reported case of adenocarcinoma formation.