Predictive modeling of frailty status in elderly abdominal surgery patients by preoperative quadriceps ultrasound testing.

OBJECTIVE: To develop a predictive model based on preoperative quadriceps ultrasound measurements to determine frailty status in elderly patients undergoing abdominal surgery. METHODS: The clinical data of 148 elderly patients who underwent abdominal surgery from July 2018 to June 2022 were retrospectively analyzed. The patients were assessed for frailty using the Fried Frailty Phenotype Assessment Scale after operation and divided into a no-frailty group (n=89) and a frailty group (n=59). The differences in the patient's clinical data, perioperative indexes, and imaging indexes were compared. The risk factors affecting the frailty status of elderly patients undergoing abdominal surgery were analyzed by logistic regression. The efficacy of the prediction model was evaluated by receiver operating characteristic (ROC) curve, with model validity confirmed through calibration curves and decision curve analysis (DCA). RESULTS: The proportion of patients with age ≥80 and BMI ≥23 kg/m2 in the frailty group was significantly higher than that in the no-frailty group (both P<0.01). The operation duration and postoperative hospital stay in the frail group were significantly longer the non-frail group, and the complication rate within postoperative 7 days was significantly higher than that in the non-frail group (all P<0.05). The cross-sectional area of rectus femoris muscle, vastus medialis muscle thickness, vastus intermedius muscle thickness, rectus femoris muscle thickness, and lateral femoris muscle thickness were significantly less in the frail group than those of the no-frail group (all P<0.001). Multifactorial logistic regression analysis showed that BMI, surgical duration, vastus medialis muscle thickness, vastus intermedius muscle thickness, rectus femoris muscle thickness, and lateral femoral muscle thickness were independent risk factors affecting frailty status in elderly patients undergoing abdominal surgery (all P<0.05). The predictive model demonstrated high accuracy with an AUC of 0.926. CONCLUSION: BMI and thickness of all quadriceps muscle components were significant factors affecting the frailty status of elderly patients undergoing abdominal surgery. In addition, the developed model, with excellent accuracy, offers a potential tool for preoperative risk assessment in this patient population.

Comparison of body size and reproductive hormones in high- and low-yielding Wulong geese.

Wulong geese are renowned for their egg-laying and reproductive abilities. This work investigated the potential of using body size traits in the selection and breeding of high-yielding Wulong geese. A total of forty 479day-old female geese (high-yielding geese, n = 20; low-yielding geese, n = 20) were selected to evaluate the relationship between body weight, body size trait indicators, serum reproductive hormones, and biochemical indicators. The results showed that serum estradiol (E2), glucose (GLU), and triglyceride (TG) concentrations, together with pubic spacing and abdominal circumference were significantly higher in high-yielding geese (P < 0.01), whereas the opposite was true for neck circumference, neck length, and tibial circumference. In addition, the serum testosterone (T) concentration and body weight were higher in high-yielding geese (P < 0.05). Neck circumference and neck length were negatively correlated with E2 and TG (P < 0.01); while pubic spacing and abdominal circumference were positively correlated with E2, GLU, and TG (P < 0.01), the highest correlation coefficient was 0.777 between TG and pubic spacing; T was also strongly associated with neck circumference (P < 0.01). In conclusion, high-yielding Wulong geese can be selected through neck circumference, neck length, pubic spacing, and abdominal circumference.

Microperc with Self-Assembled Fr 4.85 Visual Needle and Ureteral Access Sheath.

BACKGROUND: Micropercutaneous nephrolithotomy (microperc) is the least invasive among percutaneous nephrolithotripsy (PCNL) procedures. Although microperc has a high stone-free rate and certain advantages over other methods, modifications may be needed to improve the technique. We describe our experience performing microperc using a self-assembled visual needle and ureteral access sheath (UAS). METHODS: Between June 2016 and April 2019, the data of 30 patients with kidney stones undergoing microperc with our self-assembled 4.8 Fr visual needle combined with a UAS was retrospectively analyzed. Patients were placed in an obilique spine lithotomy position. RESULTS: Two cases were excluded: one due to conversion to mini PCNL and the other required flexible ureteroscopy during microperc. The remaining 28 cases included 18 men and 10 women, age 38.4 ± 7.5 years, stone size 1.7 ± 0.4 cm, and stone density on CT 969 ± 233 HU. Operative time was 47 ± 9.9 minutes, visual analogue scale score of tract pain on postoperative day 1 was 2.5 ± 1.0, hemoglobin decrease was 6.4 ± 1.0 g/L, and hospital stay was 3.1 ± 0.8 days. There was 1 case of fever and urinary infection, 2 cases of hematuria, and 1 case of flank pain. All symptoms resolved after conservative or antibiotic treatment. On postoperative day 1, 12 (42.9%) caseswere stone-free. The stone-free rates at postoperative month 1 and 3 were 92.9% (26/28) and 100% (28/28), respectively. CONCLUSIONS: Our self-assembled visual needle and UAS instrument is effective for microperc. Use of the UAS may improve the operative outcome.

Comparing endoscopic thyroidectomy using the breast approach and conventional open thyroidectomy: A retrospective analysis.

AIMS: Endoscopic thyroidectomy (ET) using the breast approach and conventional open thyroidectomy (OT) are effective approaches to treating thyroid tumors. This study evaluates the effectiveness of ET and OT regarding safety, cosmetic effects, and feasibility. SUBJECTS AND METHODS: Four hundred and fifty-six patients who underwent thyroidectomy in our department from January 2019 to August 2020 were included in this study. Based on the intraoperative rapid pathology, all patients with papillary thyroid carcinoma underwent unilateral thyroid lobectomy and central neck lymph node dissection. Whereas all benign patients underwent unilateral thyroid lobectomy. Differences in various factors such as clinical characteristics, operation time, postoperative drainage volume, parathyroid hormone (PTH) levels, calcium (Ca) levels, total number of central lymph nodes resected, the number of metastatic central lymph nodes resected, hospital duration, hospitalization costs, and cosmetic effects were compared in each group. RESULTS: Baseline characteristics among the four groups were similar, except for patient age and tumor size. Patients in the malignant ET group were younger than those in the malignant OT group with smaller tumors (P < 0.05). There were no significant differences between the OT and ET groups in postoperative Ca levels, PTH levels, the total number of lymph nodes resected, and the number of metastatic central lymph nodes resected. CONCLUSIONS: Compared with conventional OT, ET is a feasible, practical, and safe procedure with excellent cosmetic benefits.

Excretion of urine extracellular vesicles bearing markers of activated immune cells and calcium/phosphorus physiology differ between calcium kidney stone formers and non-stone formers.

BACKGROUNDS: Previous studies have demonstrated that excretion of urinary extracellular vesicles (EVs) from different nephron segments differs between kidney stone formers and non-stone formers (NSFs), and could reflect pathogenic mechanisms of urinary stone disease. In this study we quantified selected populations of specific urinary EVs carrying protein markers of immune cells and calcium/phosphorus physiology in calcium oxalate stone formers (CSFs) compared to non-stone formers (NSFs). METHODS: Biobanked urine samples from CSFs (n = 24) undergoing stone removal surgery and age- and sex- matched NSFs (n = 21) were studied. Urinary EVs carrying proteins related to renal calcium/phosphorus physiology (phosphorus transporters (PiT1 and PiT2), Klotho, and fibroblast growth factor 23 (FGF23); markers associated with EV generation (anoctamin-4 (ANO4) and Huntington interacting protein 1 (HIP1)), and markers shed from activated immune cells were quantified by standardized and published method of digital flow cytometry. RESULTS: Urine excretion of calcium, oxalate, phosphorus, and calcium oxalate supersaturation (SS) were significantly higher in CSFs compared to NSFs (P < 0.05). Urinary excretion of EVs with markers of total leukocytes (CD45), neutrophils (CD15), macrophages (CD68), Klotho, FGF23, PiT1, PiT2, and ANO4 were each markedly lower in CSFs than NSFs (P < 0.05) whereas excretion of those with markers of monocytes (CD14), T-Lymphocytes (CD3), B-Lymphocytes (CD19), plasma cells (CD138 plus CD319 positive) were not different between the groups. Urinary excretion of EVs expressing PiT1 and PiT2 negatively (P < 0.05) correlated with urinary phosphorus excretion, whereas excretion of EVs expressing FGF23 negatively (P < 0.05) correlated with both urinary calcium and phosphorus excretion. Urinary EVs with markers of HIP1 and ANO4 correlated negatively (P < 0.05) with clinical stone events and basement membrane calcifications on papillary tip biopsies. CONCLUSIONS: Urinary excretion of EVs derived from specific types of activated immune cells and EVs with proteins related to calcium/phosphorus regulation differed between CSFs and NSFs. Further validation of these and other populations of urinary EVs in larger cohort could identify biomarkers that elucidate novel pathogenic mechanisms of calcium stone formation in specific subsets of patients.

Detection and risk assessments of multi-pesticides in 1771 cultivated herbal medicines by LC/MS-MS and GC/MS-MS.

Focus on the safety of herbal medicines has mainly been directed towards the presence of intrinsic toxicity, as found in the cases of renal and hepatic dysfunction caused by aristolochic acids. However, contamination from extrinsic hazards may impart an even greater reduction in their safety and efficacy. This study reveals that pesticides were present in the majority (88%) of a comprehensive cross-section (n = 1771) of herbal medicine samples. Alarmingly, more than half (59%) contained pesticides over the European Pharmacopoeia (EP) limit, and 43% of them contained 35 varieties of banned, extremely toxic pesticides, eight of which were detected at levels over 500 times higher than the default Maximum Residue Limit (MRL). DDTs, carbofuran, and mevinphos were confirmed as being among the most risk-inducing pesticides by three different risk assessment methods, reported to produce carcinogenic, genotoxic, reproductive, and developmental effects, in addition to carrying nephrotoxicity and hepatotoxicity. In light of these findings, and withstanding that extrinsic hazards can be controlled unlike intrinsic toxicity, the authors here strongly recommend the application of herbal medicine quality-control measures and solutions to safeguard against a neglected but certainly potentially serious health risk posed to the majority of the global population that consumes herbal medicines.

Heavy Metal Contaminations in Herbal Medicines: Determination, Comprehensive Risk Assessments, and Solutions.

Heavy metal contamination in herbal medicines is a global threat to human beings especially at levels above known threshold concentrations. The concentrations of five heavy metals cadmium (Cd), lead (Pb), arsenic (As), mercury (Hg) and copper (Cu) were investigated using Inductively Coupled Plasma Optical Mass Spectrometry (ICP-MS) with 1773 samples around the world. According to Chinese Pharmacopoeia, 30.51% (541) samples were detected with at least one over-limit metal. The over-limit ratio for Pb was 5.75% (102), Cd at 4.96% (88), As at 4.17% (74), Hg at 3.78% (67), and of Cu, 1.75% (31). For exposure assessment, Pb, Cd, As, and Hg have resulted in higher than acceptable risks in 25 kinds of herbs. The maximal Estimated Daily Intake of Pb in seven herbs, of Cd in five, of Hg in four, and As in three exceeded their corresponding Provisional Tolerable Daily Intakes. In total 25 kinds of herbs present an unacceptable risk as assessed with the Hazard Quotient or Hazard Index. Additionally, the carcinogenic risks were all under acceptable limits. Notably, As posed the highest risk in all indicators including Estimated Daily Intake, Hazard Index, and carcinogenic risks. Therefore further study on enrichment effect of different states of As and special attention to monitoring shall be placed on As related contamination.

HBV infection and extra-hepatic cancers in adolescents and 20s: A retrospective study in China.

BACKGROUND: The mean age at cancer diagnosis is younger in hepatitis B virus (HBV) infected than non-infected patients. It remains unknown whether this association reflects an increase in the incidence rates of extra-hepatic cancers in adolescents and younger. METHODS: We examined 10 common extra-hepatic cancers (lung, breast, gastric, prostate, esophageal, rectal, cervical, nasopharyngeal, lymphatic, and urinary bladder) among patients diagnosed at three Chinese hospitals during 2007-2016. We compared the percentage distribution (frequencies at each age point are shown as a percentage of the total frequency) of HBsAg+ with HBsAg- patients, and calculated the standardized incidence ratio for each age group. RESULTS: A total of 60,323 patients were identified. The mean age at cancer diagnosis was 1.5-5.5 years younger in hepatitis B surface antigen (HBsAg) positive patients compared to HBsAg- patients (p ≤ 0.001). Lymphoma patients had the highest prevalence rate of HBV infection (20.7%). Among the pooled HBsAg+ cancer patients, 14.8% (1138/7666) were aged ≤39 years; by contrast, 9.7% (5122/52657) of HBsAg- cancer patients were in the same age range, giving an odds ratio of 1.6 [95%CI1.509-1.733)]. The observations were similar when each cancer was considered individually. The odds ratio was greater in pooled male patients aged ≤39 years [1.9(95%CI1.705-2.085)] compared with females [1.6(95%CI1.382-1.83)]. The ratio of the observed to the expected number of HBsAg+ patients aged 15-19, 20-24, and 25-29 years were 3.3, 4.8 and 2.0, respectively, higher than 1.2-1.7 observed for older age-groups. CONCLUSION: HBV infection is a risk factor for diverse extra-hepatic cancers in adolescents and 20s.

Correction to: Sepsis increases perioperative metastases in a murine model.

It has been highlighted that the original manuscript [1] contains a typesetting error in Fig. 1 and the Fig. 1c panel gas been inadvertently duplicated in panel Fig. 1d. This does not affect the results and conclusions of the article. The correct version of Fig. 1 is included with this Correction. The original article has been updated.

Sepsis increases perioperative metastases in a murine model.

BACKGROUND: Cancer surgery can promote tumour metastases and worsen prognosis, however, the effect of perioperative complications on metastatic disease remains unclear. In this study we sought to evaluate the effect of common perioperative complications including perioperative blood loss, hypothermia, and sepsis on tumour metastases in a murine model. METHODS: Prior to surgery, pulmonary metastases were established by intravenous challenge of CT26LacZ colon cancer cells in BALB/c mice. Surgical stress was generated through partial hepatectomy (PH) or left nephrectomy (LN). Sepsis was induced by puncturing the cecum to express stool into the abdomen. Hemorrhagic shock was induced by removal of 30% of total blood volume (i.e. stage 3 hemorrhage) via the saphenous vein. Hypothermia was induced by removing the heating apparatus during surgery and lowering core body temperatures to 30 °C. Lung tumour burden was quantified 3 days following surgery. RESULTS: Surgically stressed mice subjected to stage 3 hemorrhage or hypothermia did not show an additional increase in lung tumour burden. In contrast, surgically stressed mice subjected to intraoperative sepsis demonstrated an additional 2-fold increase in the number of tumour metastases. Furthermore, natural killer (NK) cell function, as assessed by YAC-1 tumour cell lysis, was significantly attenuated in surgically stressed mice subjected to intraoperative sepsis. Both NK cell-mediated cytotoxic function and lung tumour burden were improved with perioperative administration of polyI:C, which is a toll-like receptor (TLR)-3 ligand. CONCLUSIONS: Perioperative sepsis alone, but not hemorrhage or hypothermia, enhances the prometastatic effect of surgery in murine models of cancer. Understanding the cellular mechanisms underlying perioperative immune suppression will facilitate the development of immunomodulation strategies that can attenuate metastatic disease.

Penoscrotal Strangulation Caused by a Steel Ring: A Case Report.

INTRODUCTION: Strangulation of the penis and scrotum by a constricting object has been rarely reported. AIM: To describe a man with penoscrotal strangulation caused by a steel ring and its successful removal. METHODS: A 28-year-old man presented to the emergency department with a 7-hour history of a steel ring lodged at the base of his penis and scrotum. Removal was accomplished with the assistance of fire brigade personnel who used their hydraulic cable cutter to shear the ring. During the removal, there were no complications. RESULTS: The hydraulic cable cutter avoided thermal injury and shortened removal time compared with procedures described in the literature. The patient's recovery was uneventful, with erectile function restored after 1 week. CONCLUSION: Genital incarceration is an urgent clinical situation requiring prompt treatment. However, suitable tools for removing the foreign object are not readily available in emergency and urology departments. Cooperation with other disciplines, even non-medical disciplines, can result in creative and timely measures for removal of the object. Zhang J, Wang X, Zhang J, et al. Penoscrotal Strangulation Caused by a Steel Ring: A Case Report. Sex Med 2017;5:e131-e133.

NK-Cell Recruitment Is Necessary for Eradication of Peritoneal Carcinomatosis with an IL12-Expressing Maraba Virus Cellular Vaccine.

Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death from abdominal cancers. Immunotherapies have been effective for selected solid malignancies, but their potential in PC has been little explored. Here, we report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex vivo with an oncolytic Maraba MG1 virus expressing IL12, promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of IFNγ-induced protein-10 (IP-10) from dendritic cells. The recruitment of cytotoxic, IFNγ-secreting NK cells was associated with reduced tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors > 8 mm), a complete radiologic response was demonstrated within 8 to14 weeks, associated with 100% long-term survival. The impact of MG1-IL12-ICV upon NK-cell recruitment and function observed in the murine system was recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. These findings suggest that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year. Cancer Immunol Res; 5(3); 211-21. ©2017 AACR.

Retrospective Analysis of Ultrasound-guided Flexible Ureteroscopy in the Management of Calyceal Diverticular Calculi.

BACKGROUND: Percutaneous nephrolithotomy (PCNL) is the most widely recommended treatment for calyceal diverticular calculi, providing excellent stone-free results. However, its invasiveness is not negligible considering its major complication rates. Flexible ureteroscopy (FURS) is currently used to treat calyceal diverticula. However, the greatest drawback of FURS is locating the diverticulum since its neck is narrow and concealed. In such a case, the FURS procedure must be converted to PCNL. The aim of this study was to evaluate ultrasound-guided flexible ureteroscopy (UFURS) identifying diverticulum and the management of calyceal diverticular calculi. METHODS: A retrospective analysis was conducted on 24 patients who had calyceal diverticular calculi. In all 12 patients in the UFURS group, direct FURS failed to find evidence of calyceal diverticula but were confirmed with imaging. The other 12 patients in the PCNL group received PCNL plus fulguration of the diverticular walls. RESULTS: Puncture of calyceal diverticulum was successful in all 12 UFURS patients. Two patients in this group had postoperative residual calculi and two patients developed fever. In the PCNL group, percutaneous renal access and lithotomy were successful in all 12 patients. One patient in this group had residual calculi, one had perirenal hematoma, and two patients developed fever. No significant difference was found in the operating time (UFURS vs. PCNL, 91.8 ± 24.2 vs. 86.3 ± 18.7 min), stone-free rate (UFURS vs. PCNL, 9/12 vs. 10/12), and rate of successful lithotripsy (UFURS vs. PCNL, 10/12 vs. 11/12) between the two groups (all P> 0.05). Postoperative pain scores in the FURS group were significantly lower than that in the PCNL group (2.7 ± 1.2 vs. 6.2 ± 1.5, P< 0.05). Hospital stay in the UFURS group was significantly shorter than that in the PCNL group (3.4 ± 0.8 vs. 5.4 ± 1.0 days, P< 0.05). All patients were symptom-free following surgery (UFURS vs. PCNL, 10/10 vs. 12/12). CONCLUSION: Ultrasound-guided puncture facilitates identification of calyceal diverticula during FURS and improves the success rate of FURS surgery.

Correction: Surgical Stress Abrogates Pre-Existing Protective T Cell Mediated Anti-Tumor Immunity Leading to Postoperative Cancer Recurrence.

[This corrects the article DOI: 10.1371/journal.pone.0155947.].

Surgical Stress Abrogates Pre-Existing Protective T Cell Mediated Anti-Tumor Immunity Leading to Postoperative Cancer Recurrence.

Anti-tumor CD8+ T cells are a key determinant for overall survival in patients following surgical resection for solid malignancies. Using a mouse model of cancer vaccination (adenovirus expressing melanoma tumor-associated antigen (TAA)-dopachrome tautomerase (AdDCT) and resection resulting in major surgical stress (abdominal nephrectomy), we demonstrate that surgical stress results in a reduction in the number of CD8+ T cell that produce cytokines (IFNγ, TNFα, Granzyme B) in response to TAA. This effect is secondary to both reduced proliferation and impaired T cell function following antigen binding. In a prophylactic model, surgical stress completely abrogates tumor protection conferred by vaccination in the immediate postoperative period. In a clinically relevant surgical resection model, vaccinated mice undergoing a positive margin resection with surgical stress had decreased survival compared to mice with positive margin resection alone. Preoperative immunotherapy with IFNα significantly extends survival in surgically stressed mice. Importantly, myeloid derived suppressor cell (MDSC) population numbers and functional impairment of TAA-specific CD8+ T cell were altered in surgically stressed mice. Our observations suggest that cancer progression may result from surgery-induced suppression of tumor-specific CD8+ T cells. Preoperative immunotherapies aimed at targeting the prometastatic effects of cancer surgery will reduce recurrence and improve survival in cancer surgery patients.

Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity.

Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-ß (TGF-ß) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.

Maraba MG1 virus enhances natural killer cell function via conventional dendritic cells to reduce postoperative metastatic disease.

This study characterizes the ability of novel oncolytic rhabdoviruses (Maraba MG1) to boost natural killer (NK) cell activity. Our results demonstrate that MG1 activates NK cells via direct infection and maturation of conventional dendritic cells. Using NK depletion and conventional dendritic cells ablation studies in vivo, we established that both are required for MG1 efficacy. We further explored the efficacy of attenuated MG1 (nonreplicating MG1-UV(2min) and single-cycle replicating MG1-Gless) and demonstrated that these viruses activate conventional dendritic cells, although to a lesser extent than live MG1. This translates to equivalent abilities to remove tumor metastases only at the highest viral doses of attenuated MG1. In tandem, we characterized the antitumor ability of NK cells following preoperative administration of live and attenuated MG1. Our results demonstrates that a similar level of NK activation and reduction in postoperative tumor metastases was achieved with equivalent high viral doses concluding that viral replication is important, but not necessary for NK activation. Biochemical characterization of a panel of UV-inactivated MG1 (2-120 minutes) revealed that intact viral particle and target cell recognition are essential for NK cell-mediated antitumor responses. These findings provide mechanistic insight and preclinical rationale for safe perioperative virotherapy to effectively reduce metastatic disease following cancer surgery.

A mouse tumor model of surgical stress to explore the mechanisms of postoperative immunosuppression and evaluate novel perioperative immunotherapies.

Surgical resection is an essential treatment for most cancer patients, but surgery induces dysfunction in the immune system and this has been linked to the development of metastatic disease in animal models and in cancer patients. Preclinical work from our group and others has demonstrated a profound suppression of innate immune function, specifically NK cells in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Relatively few animal studies and clinical trials have focused on characterizing and reversing the detrimental effects of cancer surgery. Using a rigorous animal model of spontaneously metastasizing tumors and surgical stress, the enhancement of cancer surgery on the development of lung metastases was demonstrated. In this model, 4T1 breast cancer cells are implanted in the mouse mammary fat pad. At day 14 post tumor implantation, a complete resection of the primary mammary tumor is performed in all animals. A subset of animals receives additional surgical stress in the form of an abdominal nephrectomy. At day 28, lung tumor nodules are quantified. When immunotherapy was given immediately preoperatively, a profound activation of immune cells which prevented the development of metastases following surgery was detected. While the 4T1 breast tumor surgery model allows for the simulation of the effects of abdominal surgical stress on tumor metastases, its applicability to other tumor types needs to be tested. The current challenge is to identify safe and promising immunotherapies in preclinical mouse models and to translate them into viable perioperative therapies to be given to cancer surgery patients to prevent the recurrence of metastatic disease.

Perioperative influenza vaccination reduces postoperative metastatic disease by reversing surgery-induced dysfunction in natural killer cells.

PURPOSE: Surgical removal of solid primary tumors is an essential component of cancer treatment. Surgery-induced dysfunction in natural killer (NK) cells has been linked to the development of metastases in animal models and patients with cancer. We investigated the activation of NK cells using influenza vaccine in the perioperative period to eradicate micrometastatic disease. EXPERIMENTAL DESIGN: Both the B16lacZ and 4T1 tumor models in immunocompetent mice were used to assess the in vivo efficacy of perioperative influenza vaccine administration. In healthy human donors and cancer surgery patients, we assessed NK cell function pre- and post-influenza vaccination using both in vivo and ex vivo assays. RESULTS: Using the TLR3 agonist poly(I:C), we showed as proof-of-principle that perioperative administration of a nonspecific innate immune stimulant can inhibit surgery-induced dysfunction in NK cells and attenuate metastases. Next, we assessed a panel of prophylactic vaccines for NK cell activation and determined that inactivated influenza vaccine was the best candidate for perioperative administration. Perioperative influenza vaccine significantly reduced tumor metastases and improved NK cytotoxicity in preclinical tumor models. Significantly, IFNα is the main cytokine mediator for the therapeutic effect of influenza vaccination. In human studies, influenza vaccine significantly enhanced NK cell activity in healthy human donors and cancer surgery patients. CONCLUSION: These results provide the preclinical rationale to pursue future clinical trials of perioperative NK cell activation, using vaccination in cancer surgery patients. Research into perioperative immune therapy is warranted to prevent immune dysfunction following surgery and eradicate metastatic disease.