Cortisol Levels During First Admission Day Are Associated With Clinical Outcomes in Surgical Critically Ill Patients.

IMPORTANCE: To explore the correlation between cortisol levels during first admission day and clinical outcomes. OBJECTIVES: Although most patients exhibit a surge in cortisol levels in response to stress, some suffer from critical illness-related corticosteroid insufficiency (CIRCI). Literature remains inconclusive as to which of these patients are at greater risk of poor outcomes. DESIGN: A retrospective study. SETTING: A surgical ICU (SICU) in a tertiary medical center. PARTICIPANTS: Critically ill patients admitted to the SICU who were not treated with steroids. MAIN OUTCOMES AND MEASURES: Levels of cortisol taken within 24 hours of admission (day 1 [D1] cortisol) in 1412 eligible patients were collected and analyzed. Results were categorized into four groups: low (0-10 µg/dL), normal (10-25 µg/dL), high (25-50 µg/dL), and very high (above 50 µg/dL) cortisol levels. Primary endpoint was 90-day mortality. Secondary endpoints were the need for organ support (use of vasopressors and mechanical ventilation [MV]), ICU length of stay (LOS), and duration of MV. RESULTS: The majority of patients (63%) had high or very high D1 cortisol levels, whereas 7.6% had low levels and thus could be diagnosed with CIRCI. There were statistically significant differences in 90-day mortality between the four groups and very high levels were found to be an independent risk factor for mortality, primarily in patients with Sequential Organ Failure Assessment (SOFA) less than or equal to 3 or SOFA greater than or equal to 7. Higher cortisol levels were associated with all secondary endpoints. CIRCI was associated with favorable outcomes. CONCLUSIONS AND RELEVANCE: In critically ill surgical patients D1 cortisol levels above 50 mcg/dL were associated with mortality, need for organ support, longer ICU LOS, and duration of MV, whereas low levels correlated with good clinical outcomes even though untreated. D1 cortisol level greater than 50 mcg/dL can help discriminate nonsurvivors from survivors when SOFA less than or equal to 3 or SOFA greater than or equal to 7.

Two-hour indirect calorimetry measurement as a predictor of 24-hour energy expenditure in critically ill surgical patients: A longitudinal study.

BACKGROUND: Measuring energy expenditure (EE) by indirect calorimetry (IC) has become the gold standard tool for critically ill patients to define energy targets and tailor nutrition. Debate remains as to the optimal duration of measurements or the optimal time of day in which to perform IC. METHODS: In this retrospective longitudinal study, we analyzed results of daily continuous IC in 270 mechanically ventilated, critically ill patients admitted to the surgical intensive care unit in a tertiary medical center and compared measurements performed at different hours of the day. RESULTS: A total of 51,448 IC hours was recorded, with an average 24-h EE of 1523 ± 443 kcal/day. Night shift (00:00-8:00) was found to have significantly lower EE measurements (mean, 1499 ± 439 kcal/day) than afternoon (16:00-00:00; mean, 1526 ± 435 kcal/day) and morning (8:00-16:00; mean, 1539 ± 462 kcal/day) measurements (P < 0.001 for all). The bi-hourly time frame that most closely resembled the daily mean was 18:00-19:59, with a mean of 1521 ± 433 kcal/day. Daily EE measurements of the continuous IC at days 3-7 of admission showed a trend toward a daily increase in 24-h EE, but the difference was not statistically significant (P = 0.081). CONCLUSIONS: Periodic measurements of EE can differ slightly when performed at various hours of the day, but the error range is small and may not necessarily have a clinical impact. When continuous IC is not available, a 2-h EE measurement between 18:00 and 19:59 can serve as a reasonable alternative.

Long-term outcomes of elderly patients with peritoneal metastases of colorectal origin after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) were reportedly safe for the elderly. However, long-term survival data in this subgroup of patients are scarce. Our aim was to evaluate the peri-operative and long-term outcomes of CRS + HIPEC in colorectal peritoneal metastases (CRC-PM) in patients ≥70 years of age. MATERIAL AND METHODS: We retrospectively analyzed our combined institutional databases for patients who underwent CRS + HIPEC for CRC-PM. Clinical and pathological characteristics, as well as overall survival (OS) and progression-free survival (PFS) were compared between the groups. Tumor extent was measured by the peritoneal carcinomatosis index (PCI) and completeness of cytoreduction by the CCR score. Major morbidity was defined according to Clavien-Dindo classification. RESULTS: The dataset of 159 patients included 33 elderly and 126 non-elderly patients. Clinical characteristics between the groups differed only in medical comorbidities (Charlson comorbidity index 10 vs. 7, P < 0.001) and delivery of post-HIPEC adjuvant treatment (12.5% vs. 43.8%, P = 0.004). Overall PCI and CCR0 rates were similar between the groups, as were length of stay and major morbidity and mortality rates. Long-term outcomes in the elderly group were lower than those of the non-elderly (median OS: 21.8 vs. 40.5 months, P < 0.001; median PFS: 6 vs. 8 months, P = 0.02, respectively). CONCLUSIONS: CRS + HIPEC in selected elderly patients can be safe in terms of postoperative morbidity and mortality. However, despite the same surgical extents and radicality, their long-term outcomes are inferior, possibly due to under-usage of systemic chemotherapy.

Gastric Cancer-Derived Extracellular Vesicles (EVs) Promote Angiogenesis via Angiopoietin-2.

Angiogenesis is an important control point of gastric cancer (GC) progression and metastasis. Angiopoietin-2 (ANG2) is a key driver of tumor angiogenesis and metastasis, and it has been identified in primary GC tissues. Extracellular vesicles (EVs) play an important role in mediating intercellular communication through the transfer of proteins between cells. However, the expression of ANG2 in GC-EVs has never been reported. Here, we characterized the EV-mediated crosstalk between GC and endothelial cells (ECs), with particular focus on the role of ANG2. We first demonstrate that ANG2 is expressed in GC primary and metastatic tissues. We then isolated EVs from two different GC cell lines and showed that these EVs enhance EC proliferation, migration, invasion, and tube formation in vitro and in vivo. Using an angiogenesis protein array, we showed that GC-EVs contain high levels of proangiogenic proteins, including ANG2. Lastly, using Lenti viral ANG2-shRNA, we demonstrated that the proangiogenic effects of the GC-EVs were mediated by ANG2 through the activation of the PI3K/Akt signal transduction pathway. Our data suggest a new mechanism via which GC cells induce angiogenesis. This knowledge may be utilized to develop new therapies in gastric cancer.

Lymph Node Metastases from Visceral Peritoneal Colorectal Metastases are Associated with Systemic Recurrence.

BACKGROUND: Visceral peritoneal colorectal metastases (VPCMs) may further metastasize to lymph nodes that drain those organs. The rate of lymph node metastases (LNMs) from VPCMs and their clinical and prognostic significance are unknown. METHODS: This study retrospectively analyzed the authors' institutional databases of 160 patients with peritoneal colorectal metastases who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Patients with LNM-VPCM (n = 12) were identified by pathologic reports, and both their short- and long-term outcomes were compared with those of patients without LNM-VPCM. RESULTS: The clinical presentation and primary tumor pathologic characteristics did not differ between the two groups. The patients with LNM-VPCM had a higher tumor burden (measured by the peritoneal carcinomatosis index [PCI]) and visible remnant disease compared with those who had no LNM-VPI (10 vs 5.5 [p = 0.03] vs 33.3% vs 6.8% [p = 0.007], respectively). The postoperative outcomes also were comparable. The patients with LNM-VPCM had a shorter overall survival (OS) than those without LNM-VPCM (median OS, 22.5 months; 95% confidence interval [CI], 15.1-29.9 months vs 40.1 months; 95% CI, 38.1-42 months; p = 0.02). However, only tumor grade and PCI were predictors of OS in the multivariate analysis (hazard ratio [HR], 2.33 [p = 0.001]; 1.77 [p = 0.03], respectively). The study showed that LNM-VPCM was associated with systemic but not peritoneal recurrence compared with non-LNM-VPCM (81.8% vs 51.6% for systemic recurrence, respectively; p = 0.05). CONCLUSION: The small distinct group of patients defined by LNM-VPCM were prone to systemic recurrence. Given its correlation with systemic recurrence, LNM-VPCM may indicate the need for adjuvant treatment.

Severe Postoperative Complications are Associated with Impaired Survival in Primary but not in Recurrent Retroperitoneal Sarcoma.

BACKGROUND: Retroperitoneal sarcoma (RPS) surgery entails multivisceral resection, which may cause postoperative complications. We assessed the effects of complications on survival to identify their predisposing factors in primary (PRPS) and recurrent (RRPS) RPS. METHODS: We retrospectively analyzed our institutional database. Severe postoperative complications (SC) were defined as Clavien-Dindo classification ≥ 3. Predisposing factors for complications were investigated, as was their effect on long-term outcomes. RESULTS: In total, 154 RPS resections (78 PRPS and 76 RRPS) performed between January 2008 and December 2018 were included. Neoadjuvant chemotherapy and multifocal tumors were more common in RRPS than PRPS (34.2% vs. 11.3%, P = 0.001 and 42.1% vs. 10.3%, P < 0.001, respectively). Although surgical extent in RRPS was limited compared with PRPS (weighted organ score 1 vs. 2, P = 0.01; transfusion requirement 23.6% vs. 35.8%, P = 0.04), SC and mortality rates were comparable. SC rates were 30.1% and 35.5% for PRPS and RRPS, respectively. NACT rate tended to be higher in PRPS patients with SC (20.8% vs. 7.4%, P = 0.09), whereas weighted organ score and transfusion requirement were increased in RRPS patients with SC (2 vs. 1, P = 0.01; 40.7% vs. 14.3%, P = 0.009, respectively). PRPS patients with SC had decreased overall survival (35 months, 95% confidence interval [CI] 12.2-57.7) compared with those without SC (90 months, 95% CI 71.4-108.5, P = 0.01). CONCLUSIONS: Postoperative complications are associated with impaired outcomes in PRPS but not in RRPS. The negative effects of complications on outcomes should be factored to perioperative management.

Innate inflammatory markers for predicting survival in retroperitoneal sarcoma.

INTRODUCTION: Existing prognostic tools for retroperitoneal sarcomas (RPS) utilize parameters that can be accurately determined only postoperatively. This study evaluated the application of the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) levels for predicting prognosis in primary RPS. MATERIALS AND METHODS: We retrospectively analyzed our database of patients with primary RPS operated between 2008 and 2018. The NLR was calculated from preoperative blood tests and its association with outcomes was determined. RESULTS: The NLR values of 78 suitable patients were analyzed. Patients were classified in the NLR-high group if the NLR was ≥2.1. High-grade tumors were more common in the NLR-high group (71.6% vs 48%, P = .02). NLR-high patients had impaired overall survival (OS) and progression-free survival (PFS) compared to NLR-low patients (median OS not reached vs 74 months 95% confidence interval [CI]: 21.6-126.4, P = .03; median PFS not reached vs 48 months 95% CI: 6.5-98.6, P = .06, respectively). Multivariate analysis showed statistical significance only for PFS but not for OS (hazard ratio [HR] = 4.1, P = .03; HR = 2.3, P = .3). Patients with low CRP levels had improved OS and PFS. CONCLUSIONS: The NLR may serve as a preoperative, easily derived marker for prognosis in RPS. Serum biomarkers may prove useful in these large and spatially heterogeneous tumors.

T-Helper 1 Immune Response in Metastatic Lymph Nodes of Pancreatic Ductal Adenocarcinoma: A Marker For Prolonged Survival.

BACKGROUND: Although lymph node (LN) metastases is considered a grave prognostic sign in pancreatic ductal adenocarcinoma (PDAC), patients with positive lymph nodes (PLN) constitute a heterogeneous group. Our purpose was to identify morphological and immune parameters in the primary tumor and in PLN of resected PDAC patients, which could further stratify these patients to different subgroups. METHODS: We retrospectively evaluated histological and immunohistochemical characteristics of 66 patients with PDAC who were operated at our institution. These were subsequently correlated to clinical outcome. RESULTS: Mean patient age and number of LN harvested was 65.5 ± 10.3 and 12.3 ± 6.5 years, respectively. Tumor size (T stage) and perineural invasion had no effect on clinical outcome. High-grade tumor was associated with decreased survival [overall survival (OS) = 19.6 ± 2.7 months for poorly differentiated PDAC vs. 31.2 ± 4 for well and moderately differentiated, p = 0.03]. Patients with ≥ 8 PLN had significantly worse outcome (OS = 7.3 ± 0.8 months for PLN ≥ 8 vs. OS = 30.1 ± 3.2 months for PLN < 8, p < 0.0001). T helper (Th) 1 immune response was measured both by its effector cells (CD8+) and expression of its main transcription factor, T-bet. CD8+ high patients had significantly increased OS compared with CD8+ low (OS = 36.8 ± 5.3 months for CD8 + high vs. OS = 24.3 ± 3.5 for CD8 + low, p = 0.03) Similarly, Th1 predominant immune response measured by T-bet expression was associated with improved OS compared with non-Th1 (OS = 32.8 ± 3.2 vs. OS = 19.5 ± 2.9, p < 0.0001). CONCLUSIONS: Our data indicate an association between Th1-type immune response and increased survival. Future research is needed to exploit Th1 immune response as a biological marker for immunotherapy.

Visceral Fat Content Correlates with Retroperitoneal Soft Tissue Sarcoma (STS) Local Recurrence and Survival.

BACKGROUND: Our aim was to evaluate the association between visceral fat content with soft tissue sarcoma (STS) local recurrence and survival. METHODS: One hundred and one computed tomography imaging studies of primary STS patients who had complete macroscopic resection at our institution between 2002 and 2012 were reviewed, and retroperitoneal and circumferential fat contents were measured. Correlations between imaging findings and clinical data were analyzed. RESULTS: Fifty-seven STS tumors (56.4%) were retroperitoneal; of them, 65% were high grade, median size was 15 cm (range 3-49), and the most common histological subtype was high grade liposarcoma (31.6%). Median follow-up length for the entire cohort was 64 months (range 6-95). High visceral fat (VF) content≥15 versus <15 mm was identified as a risk factor for retroperitoneal STS local recurrence; 65.1 versus 26.7%, respectively (p=0.04); VF content did not correlate with distant metastasis. Median overall survival (OS) length of patients with VF≥15 versus <15 mm was 57 months (range 2-144) versus not reached, respectively (p=0.007). Multivariable analysis identified VF≥15 mm as an independent risk factor for decreased OS (HR: 4.2, 95% CI 1.07-16.67). In contrast, circumferential fat content did not correlate with retroperitoneal STS patient outcomes. CONCLUSION: High VF content is an independent adverse prognosticator associated with significantly higher rates of retroperitoneal STS local recurrence and decreased patients survival. Local tumor biology may be affected by the presence of adipose cells. Further clinical and molecular research is needed to establish this premise.

Pancreaticoduodenectomy in elderly adults: is it justified in terms of mortality, long-term morbidity, and quality of life?

OBJECTIVES: To evaluate long-term morbidity, mortality, and quality of life (QoL) after pancreaticoduodenectomy (PD) in elderly adults. DESIGN: Retrospective cohort study. SETTING: Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. PARTICIPANTS: One hundred and sixty-eight individuals aged 70 and older who underwent PD between 1995 and 2010. MEASUREMENTS: A prospective pancreatic surgery database was analyzed for postoperative morbidity; mortality; intensive care unit (ICU), hospital, and rehabilitation facility stay; and readmissions after surgery. QoL was assessed using a validated questionnaire completed 3, 6, and 12 months after surgery. RESULTS: Seventy-two percent of the participants had an American Society of Anesthesiologists score of 3 or greater. There was no intraoperative death. Thirty- and 60-day postoperative mortality rates were 5.9% and 6.5%, respectively. Median ICU stay was 2 days, and median hospital stay was 22 days. Sixty-four participants (37.5%) were discharged to a rehabilitation facility. The first-year readmission rate was 31%. One- and 2-year overall survival rates were 58% and 36%, respectively. Global QoL scores 3 and 12 months after surgery were 68% and 73%, respectively. Scores were lower yet comparable with those of matched individuals undergoing laparoscopic cholecystectomy. CONCLUSION: Most elderly adults with pancreatic cancer survive longer than 1 year after PD; 36% survive longer than 2 years. These individuals are likely to have acceptable long-term morbidity and overall good QoL, corresponding with their age.

Sarcomas of the breast.

Sarcomas of the breast are a rare group of heterogeneous mesenchymal tumors accounting for less than 1% of all breast malignancies. Owing to the rarity of the disease, current knowledge is mostly based on numerous case reports and relatively small retrospective series; unlike epithelial breast cancer, there is no high level evidence to support a standard of care for primary and/or adjuvant therapy. To overcome this relative shortage of data, most therapeutic strategies for breast sarcoma are extrapolated from current treatment for soft tissue sarcoma in other locations, mainly of the extremities and thoracic wall. In general, the therapeutic approach to sarcoma of the breast should be based on a multidisciplinary strategy including surgery, radiation to improve local control and systemic chemotherapy in selected patients. This review discusses the results of the key larger retrospective studies including data on incidence, etiology, presentation, diagnosis, management and prognosis of this challenging rare disease entity.

Pancreatic cancer: surgery is a feasible therapeutic option for elderly patients.

BACKGROUND: Compromised physiological reserve, comorbidities, and the natural history of pancreatic cancer may deny pancreatic resection from elderly patients. We evaluated outcomes of elderly patients amenable to pancreatic surgery. METHODS: The medical records of all patients who underwent pancreatic resection at our institution (1995-2007) were retrospectively reviewed. Patient, tumor, and outcomes characteristics in elderly patients aged ≥ 70 years were compared to a younger cohort (<70 y). RESULTS: Of 460 patients who had surgery for pancreatic neoplasm, 166 (36%) aged ≥ 70 y. Compared to patients < 70 y (n = 294), elderly patients had more associated comorbidities; 72% vs. 43% (p = 0.01) and a higher rate of malignant pathologies; 73% vs. 59% (p = 0.002). Operative time and blood products consumption were comparable; however, elderly patients had more post-operative complications (41% vs. 29%; p = 0.01), longer hospital stay (26.2 vs. 19.7 days; p < 0.0001), and a higher incidence of peri-operative mortality (5.4% vs. 1.4%; p = 0.01). Multivariable analysis identified age ≥ 70 y as an independent predictor of shorter disease-specific survival (DSS) among patients who had surgery for pancreatic adenocarcinoma (n = 224). Median DSS for patients aged ≥ 70 y vs. < 70 y were 15 months (SE: 1.6) vs. 20 months (SE: 3.4), respectively (p = 0.05). One, two, and 5-Y DSS rates for the cohort of elderly patients were 58%, 36% and 23%, respectively. CONCLUSIONS: Properly selected elderly patients can undergo pancreatic resection with acceptable post-operative morbidity and mortality rates. Long term survival is achievable even in the presence of adenocarcinoma and therefore surgery should be seriously considered in these patients.