Utility of cell-based vaccines as cancer therapy: Systematic review and meta-analysis.

Cell-based therapeutic cancer vaccines use autologous patient-derived tumor cells, allogeneic cancer cell lines or autologous antigen presenting cells to mimic the natural immune process and stimulate an adaptive immune response against tumor antigens. The primary objective of this study is to perform a systematic literature review with an embedded meta-analysis of all published Phase 2 and 3 clinical trials of cell-based cancer vaccines in human subjects. The secondary objective of this study is to review trials demonstrating biological activity of cell-based cancer vaccines that could uncover additional hypotheses, which could be used in the design of future studies. We performed the systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The final review included 36 studies - 16 single-arm studies, and 20 controlled trials. Our systematic review of the existing literature revealed largely negative trials and our meta-analysis did not show evidence of clinical benefit from cell-based cancer-vaccines. However, as we looked beyond the stringent inclusion criteria of our systematic review, we identified significant examples of biological activity of cell-based cancer vaccines that are worth highlighting. In conclusion, the existing literature on cell-based cancer vaccines is highly variable in terms of cancer type, vaccine therapies and the clinical setting with no overall statistically significant clinical benefit, but there are individual successes that represent the promise of this approach. As cell-based vaccine technology continues to evolve, future studies can perhaps fulfill the potential that this exciting field of anti-cancer therapy holds.

Perspectives of patients with advanced or metastatic non-small cell lung cancer on symptoms, impacts on daily activities, and thresholds for meaningful change: a qualitative research study.

Introduction: Advanced or metastatic non-small cell lung cancer (NSCLC) is associated with significant symptom burden. It is important to understand the impact of these disease-and treatment-related symptoms on patients' daily lives and explore from a patient perspective what constitutes a meaningful change in NSCLC symptoms. Methods: Patient experience of advanced or metastatic NSCLC was explored in this prospective, non-interventional qualitative research study recruiting patients from the United States (US). Interviews were conducted to explore the most important symptoms, daily life impacts, and patients' perspectives of what constitutes meaningful change when considering their current symptoms versus 6-12 months prior, based on the Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Change (PGI-C) items. Results: Between February and April 2022, 19 US-based patients with Stage IV NSCLC were recruited; 95% were female, 63% were White, 79% had been diagnosed >1 year prior, and 63% were receiving targeted therapy. Over half the patients indicated their most important symptoms were fatigue, shortness of breath, and cough. Patient differentiation between whether symptoms were disease- or treatment-related lacked concordance, and often patients were unable to distinguish the two. The most frequently mentioned impacts of these symptoms on patients' daily lives were difficulty walking, sleep disturbance, anxiety/depression, impact on relationships, and difficulty doing daily tasks. Most patients considered a one-point change on the PGI-S or PGI-C to be meaningful based on rating their symptom severity at the time of the interview compared with 6-12 months before the interview. Conclusion: Based on their own symptom experience, patients with advanced or metastatic NSCLC indicated a one-point threshold for meaningful change, whether improvement or worsening. This suggests a one-point change on the PGI-S or PGI-C may be a potential anchor for patient-reported outcome (PRO) endpoints used in clinical trials. It is important to use PRO instruments that capture the symptoms and impacts identified as most important to patients. These findings highlight the importance of using qualitative methods to assess disease-related symptoms, treatment-related side effects, and the impacts on daily life for patients with advanced or metastatic NSCLC, underscoring how qualitative assessments can complement quantitative PRO instruments for evaluating clinical trials.

Metastatic non-small-cell lung cancer without driver mutations: projections by therapy line in Western Europe, 2021-2026.

Aim: To estimate the incidence, prevalence and treated prevalence by line of therapy (LOT) for non-small-cell lung cancer (NSCLC) patients without driver mutations from 2021 to 2026. Materials & methods: Country-specific registry data for Western Europe were used to project incidence and prevalence of NSCLC; LOT information was obtained from CancerMPact® Treatment Architecture physician surveys. Results: Incidence, prevalence and treated prevalence across LOTs for NSCLC are projected to increase across five WE countries, including for stage IV patients without driver mutations (184,966 cases [2021] to 197,925 [2026]). Pembrolizumab monotherapy is utilized by ∼50% of NSCLC patients with programmed death-ligand 1 expression ≥50%. Conclusion: Improved treatment options for NSCLC patients without known driver mutations are important for combating the projected increase in prevalence.

Lung cancer is the leading cause of cancer-related death in Europe. This study estimated how the number of patients living with, and being treated for, lung cancer is projected to change between 2021 and 2026 in Western Europe by collecting past data on lung cancer in France, Germany, Italy, Spain and the UK, and analyzing the trends to create estimates for the future. The number of new cases of lung cancer is projected to increase each year from 2021 to 2026, and in line with this, the number of patients receiving treatment for their disease will increase. Improving treatment options for lung cancer will be an important step to combat the expected increase in cancer cases.

Real-world treatment patterns and clinical outcomes after introduction of immune checkpoint inhibitors: Results from a retrospective chart review of patients with advanced/metastatic non-small cell lung cancer in the EU5.

BACKGROUND: Real-world evidence is increasingly used to guide treatment and regulatory decisions for non-small cell lung cancer (NSCLC). Real-world treatment patterns and clinical outcomes among patients with advanced/metastatic NSCLC in France, Germany, Italy, Spain, and the UK (EU5) were assessed. METHODS: This retrospective physician-completed patient chart review assessed treatment patterns (regimen, duration of treatment [DOT], time to discontinuation), and clinical outcomes (duration of response [DOR], progression-free survival [PFS], and overall survival [OS]) of patients with stage IIIB/C or IV NSCLC who received pembrolizumab-based first-line induction chemotherapy. RESULTS: Overall, 322 patients were included; at first-line maintenance (1LM), 92% had stage IV NSCLC, 68% had nonsquamous histology, and 89% had no central nervous system (CNS)/brain metastasis. The two most common 1LM regimens were pembrolizumab monotherapy (76% overall) and pembrolizumab + pemetrexed (21% overall). Docetaxel monotherapy was the most common second-line regimen in all countries except Germany (54% overall). For 1LM therapy, the overall median DOT and DOR were 5 and 10 months, respectively; PFS was 7 months and OS was 8 months. Germany had a longer duration of each outcome except for DOR which was longer in Spain. Clinical outcomes were generally poorer for patients with squamous histology and CNS/brain metastases. CONCLUSIONS: This study demonstrated differences in treatment patterns and clinical outcomes in NSCLC across the EU5 and patient subgroups. Improved survival was generally associated with response to first-line therapy, nonsquamous histology, and CNS/brain metastases absence. These real-world data provide valuable insights which may aid treatment decision-making and clinical trial design.

The Utility of ctDNA in Lung Cancer Clinical Research and Practice: A Systematic Review and Meta-Analysis of Clinical Studies.

This systematic review with embedded meta-analysis aimed to evaluate the clinical utility of circulating tumor DNA (ctDNA) in lung cancer. After screening and review of the Embase database search, 111 studies from 2015 to 2020 demonstrated ctDNA's value in prognostication/monitoring disease progression, mainly in patients with advanced/metastatic disease and non-small cell lung cancer. ctDNA positivity/detection at any time point was associated with shorter progression-free survival and overall survival, whereas ctDNA clearance/decrease during treatment was associated with a lower risk of progression and death. Validating these findings and addressing challenges regarding ctDNA testing integration into clinical practice will require further research.

The most likely but largely ignored triggering factor for breast (or all) cancer invasion.

Breast cancer development and progression are believed to be a sequential process, from normal to hyperplastic, to in situ, and to invasive and metastatic stages. Given that over 90% of cancer deaths are caused by invasive and metastatic lesions, countless factors and multiple theories have been proposed as the triggering factor for the cascade of actions of cancer invasion. However, those factors and theories are largely based on the studies of cell lines or animal models. In addition, corresponding interventions based on these factors and theories have failed to reduce the incidence rate of invasive and metastatic lesions, suggesting that previous efforts may have failed to arm at the right target. Considering these facts and observations, we are proposing "A focal aberrant degeneration in the myoepithelial cell layer (MECL) as the most likely triggering factor for breast cancer invasion". Our hypothesis is based on our recent studies of breast and multiple other cancers. Our commentary provides the rationale, morphologic, immunohistochemical, and molecular data to support our hypotheses. As all epithelium-derived cancers share a very similar architecture, our hypothesis is likely to be applicable to invasion of all cancer types. We believe that human tissue-derived data may provide a more realistic roadmap to guide the clinic practice.

Prospective Non-Randomized Study of Intraoperative Assessment of Surgical Resection Margin of Colo-Rectal Liver Metastases.

Introduction: More than 50% of patients with colorectal cancer (CRC) develop liver metastases during the natural course of disease. Surgical resection is currently the most potentially curative method in the treatment of colorectal liver metastases (CRLM). The goal of surgery is to achieve a negative resection margin (RM) of at least 1 mm, which provides the best prognosis for patients. The RM can be assessed by the pathologist of the resected liver specimen (RLS) and by the surgeon intraoperatively. The aim of this research paper is to determine the degree of agreement on intraoperative assessment of the RM by the surgeon and histopathological RM assessment by the pathologist. Material and methods: This prospective non-randomized double-blind study was approved by the Ethics Committee of the Oncology Institute of Vojvodina and registered on ClinicalTrials.gov #NCT04634526. The study was conducted at the Oncology Institute of Vojvodina, Sremska Kamenica, Serbia. An experienced hepatobiliary surgeon assessed RM for every specimen intra-operatively, immediately after CRLM resection. Resected CRLM lesions were analyzed by two experienced pathologists. These data were compared with pathological RM assessment as a "gold standard". RM of 1 mm or more was rated as negative RM (RM-). Disease-free survival (DFS) and recurrence rate was calculated by RM status defined by surgeon and by pathologist. Results: From 01 January 2015 to 31 August 2019, 98 patients were enrolled in the study. There were 219 RLS with 245 CRLM. The surgeon registered positive RM (RM+) of <1mm in 41 (18.7%) RLS. Taking the result of the histopathological assessment (HPA) as the "gold standard", it was determined that RM was true positive in 32 (14.6%) cases. False positive RM was found in 9 (4.1%) cases. False negative RM was found in 20 (9.1%) cases. True negative RM was found in 158 (72.2%) cases. Sensitivity of surgical assessment (SA) of RM+ was 61.5% (32/52). Specificity of SA of RM+ was 94.6% (158/167). The positive predictive value (PPV) was 78.0% (32/41), while the negative predictive value (NPV) was 88.8% (158/178). The overall accuracy of the RM+ SA was 86.8% (190/219). There was no statistically significant difference in the assessment of RM+ per RLS by surgeon and pathologists (p=0.061), but it was significant when analyses per patients was performed (p=0.017). Recurrence rate for RM+ patients was 48.1% (13/27, p=0.05) for SA and 35.0% (14/40, p=0.17) for HPA. Three year DFS for RM- and RM+ was 66.5% and 27.9% (p=0.04), respectively, by SA, and 64.8% and 42.1% (p=0.106), respectively, by HPA. Conclusion: Intraoperative assessment of RM- by surgeon of RLS is clinically meaningful. There is not a statistically significant difference in the assessment of RM+ by surgeon and pathologists per RLS, but it was statically significant on a per patient basis. RM determined by surgeon has better prognostic impact on recurrence rate and 1- and 3-year DFS than standard histopathological assessment.

Antibiotics for cancer treatment: A double-edged sword.

Various antibiotics have been used in the treatment of cancers, via their anti-proliferative, pro-apoptotic and anti-epithelial-mesenchymal-transition (EMT) capabilities. However, increasingly studies have indicated that antibiotics may also induce cancer generation by disrupting intestinal microbiota, which further promotes chronic inflammation, alters normal tissue metabolism, leads to genotoxicity and weakens the immune response to bacterial malnutrition, thereby adversely impacting cancer treatment. Despite the advent of high-throughput sequencing technology in recent years, the potential adverse effects of antibiotics on cancer treatments via causing microbial imbalance has been largely ignored. In this review, we discuss the double-edged sword of antibiotics in the field of cancer treatments, explore their potential mechanisms and provide solutions to reduce the potential negative effects of antibiotics.

Technical Feasibility of Tissue Microarray (TMA) Analysis of Tumor-Associated Immune Response in Prostate Cancer.

Introduction: The androgen receptor (AR) regulates immune-related epithelial-to-mesenchymal transition (EMT), and prostate cancer (PCa) metastasis. Primary tumor-infiltrating lymphocytes (TILs) [CD3+, CD4+, and CD8+ TILs] are potential prognostic indicators in PCa, and variations may contribute to racial disparities in tumor biology and PCa outcomes. Aim: To assess the technical feasibility of tumor microarray (TMA)-based methods to perform multi-marker TIL profiling in primary resected PCa. Methods: Paraffin-embedded tissue cores of histopathologically-confirmed primary PCa (n = 40; 1 TMA tissue specimen loss) were arrayed in triplicate on TMAs. Expression profiles of AR, CD3+, CD4+, and CD8+ TILs in normal prostate, and the center and periphery of both the tumor-dominant nodule and highest Gleason grade were detected by IHC and associated with clinical and pathological data using standard statistical methodology. An independent pathologist, blinded to the clinical data, scored all samples (percent and intensity of positive cells). Results: TMAs were constructed from 21 (53.8%) Black and 18 (46.2%) White males with completely-resected, primarily pT2 stage PCa [pT2a (n = 3; 7.7%); pT2b (n = 2; 5.1%); pT2c (n = 27; 69.2%); pT3a (n = 5; 12.8%); mean pre-op PSA = 8.17 ng/ml]. The CD3, CD4, CD8, and CD8/CD3 cellular protein expression differed from normal in the periphery of the dominant nodule, the center of the highest Gleason grade, and the periphery of the highest Gleason grade (P < 0.05). Correlations between TIL expression in the center and periphery of the dominant nodule, with corresponding center and periphery of the highest Gleason grade, respectively, were robust, and the magnitude of these correlations differed markedly by race (P < 0.05). Conclusions: Multi-marker (AR, CD3, CD4, CD8) profiling with IHC analysis of TMAs consisting of primary, non-metastatic resected prostate cancer is technically feasible in this pilot study. Future studies will evaluate primary tumor immunoscore using semi-quantitative, IHC-based methodology to assess differences in the spectrum, quantity, and/or localization of TILs, and to gain insights into racial disparities in PCa tumor biology and clinical outcomes.

The Negative Impact of Body Mass Index on the Tumor Microenvironment in Colon Cancer: Results of a Prospective Trial.

BACKGROUND: The association between tumor mismatch repair status and obesity in colon cancer is not well understood. The authors of this study hypothesized that mismatch repair deficiency in colon cancer may be associated with a lower Body Mass Index (BMI) and improved patient outcome due to an enhanced tumor immune microenvironment. METHODS: For this study, 70 patients were randomly selected from a prospective trial evaluating nodal ultrastaging for colon cancer. The mismatch repair status of tumors and immunomarker expression were correlated with clinicopathologic characteristics and evaluated for disease-free survival. RESULTS: Patients with mismatch repair-deficient tumors (n = 11) had a lower mean BMI than those with mismatch repair-proficient tumors (n = 59) (22.16 vs. 26.30 kg/m2, respectively; p = 0.029).The findings showed that CD3+ T cells were inversely associated with mismatch repair proficiency (p = 0.048). Mismatch repair-proficient tumors in nonobese patients (BMI < 30 kg/m2) versus obese patients had a higher density of CD8+ (p = 0.008) and FOXP3+ (p = 0.005) T cells. Multivariable analysis linked CD4+ (hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.35-0.76), CD8+ (HR 0.67; 95% CI 0.50-0.89), and number of tumor-positive lymph nodes (HR 1.19; 95% CI 1.03-1.36) to disease-free survival for patients with mismatch repair-proficient tumors. CONCLUSIONS: Tumor mismatch repair status and obesity are correlated in patients with colon cancer. Increased intratumoral T cells in nonobese patients suggests an unexplored link between tumor mismatch repair and immunoprofile.

A novel serum based biomarker panel has complementary ability to preclude presence of early lung cancer for low dose CT (LDCT).

Low Dosage Computerized Tomography (LDCT) has been shown to improve early detection of lung cancer and mortality rates in high-risk individuals, which was, however, limited by specifically coverage for heavy smokers and high rates of false positivity. Here, we aim to investigate a novel biomarker for early detection of lung cancer, and further extend to concentrate high-risk subjects for increasing specificity and coverage of LDCT. We performed retrospective blinded evaluation of lung cancer and healthy controls in training and validation cohorts. Macrophage inhibitory cytokine 1 (MIC-1) alone and panel were assessed. Our data showed the sensitivity of MIC-1 was 72.2% and 67.1% for lung cancer diagnosis and early diagnosis respectively, at 96.6% specificity, which were significantly higher than Cyfra21-1, NSE CA125, CEA and SCC. At 90% specificity, the panel of MIC-1, Cyfra21-1, CA125 and CEA provided 89.5% sensitivity for early diagnosis of lung cancer, which could be used to concentrate the high-risk subjects for further LDCT screening. We conclude that MIC-1 have great capacity in early lung cancer diagnosis. The algorithmic panel of MIC-1, Cyfra21-1, CA125 and CEA could be used to refine the preselection criteria of high-risk subjects, and thus might facilitate the widespread implementation of LDCT screening.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in treatment of gastric cancer with peritoneal carcinomatosis.

Although gastric cancer with peritoneal carcinomatosis is associated with poor prognosis and is generally treated with palliative systemic therapy, recent studies have shown that cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may prove to be an efficacious treatment option. In addition to reviewing the natural history of gastric cancer with peritoneal carcinomatosis, this mini-review examines literature on the efficacy of CRS and HIPEC as compared to chemotherapy and surgical options. Both randomized and non-randomized studies were summarized with the emphasis focused on overall survival. In summary, CRS and HIPEC are indeed a promising treatment option for gastric cancer with peritoneal carcinomatosis and large randomized clinical trials are warranted.

Sex-Specific Differences in Colon Cancer when Quality Measures Are Adhered to: Results from International, Prospective, Multicenter Clinical Trials.

BACKGROUND: There is no consensus on the relationship between patient sex and the location, stage, and oncologic outcome of colon cancer (CC). We hypothesized that there is a sex-specific difference in the biology and management of CC. STUDY DESIGN: Our cohort was drawn from a database of patients enrolled in international trials of nodal ultrastaging for nonmetastatic CC. These trials required strict adherence to surgical and pathologic quality measures. Postoperative follow-up included colonoscopy at 1 and 4 years and annual CT scans. Sex-specific differences in tumor biology, location, stage, and recurrence were evaluated by chi-square, Fischer's exact, and independent t-tests. RESULTS: The cohort included 435 males (median age 69 years) and 423 females (median age 70 years). Females had more right-sided (p = 0.03) and earlier T stage (p = 0.05) tumors, but there was no sex-based difference in pathologic grade, total lymph nodes retrieved, nodal positivity (p = 0.47) or lymphovascular invasion (p = 0.45). The overall 4-year disease-free survival (DFS) was comparable in females and males (77.9% and 77.5%, respectively). By multivariate analysis, only nodal positivity and cancer recurrence affected overall survival (OS) (p = 0.008). Neither sex nor primary tumor affected DFS or OS. CONCLUSIONS: This is the first prospective study to demonstrate sex-specific differences in location and T stage of CC when surgical and pathologic management adhered to strict quality standards. The predominance of right-sided CC in females suggests that flexible sigmoidoscopy may be inadequate for screening and surveillance. Interestingly, earlier stage and right-sided location did not confer a DFS or OS advantage for women. Additional studies are needed to determine why females have a higher propensity for right-sided lesions and a potential difference in CC biology.

Prospective randomized controlled trial comparing standard analgesia with combined intra-operative cystic plate and port-site local anesthesia for post-operative pain management in elective laparoscopic cholecystectomy.

BACKGROUND: Various mechanisms, including somatic and visceral nociceptive stimulation, have been suggested as a cause for pain after laparoscopic cholecystectomy (LC). We therefore conducted a prospective randomized controlled trial (PRCT) to evaluate whether somatovisceral pain blockade reduces pain after LC. HYPOTHESIS: Analgesic efficacy of multimodal analgesia is superior to standard analgesia for patients undergoing elective LC for symptomatic cholelithiasis. Specifically, topical cystic plate and port-site injection with 0.25 % bupivacaine significantly reduces pain after LC. DESIGN: This study was designed as single-blinded PRCT. SETTING: This study was conducted in an academic medical center. PATIENTS AND METHODS: Between February and May 2010 we randomly assigned 63 patients with symptomatic cholelithiasis in a 1:1 ratio to non-opioid/opioid analgesic combinations (Control Group, n = 32) and non-opioid/opioid analgesic combinations plus topical 0.25 % bupivacaine onto the cystic plate and local 0.25 % bupivacaine port-site injection, post-LC (Study Group, n = 31). Primary endpoint was patient-reported pain 1, 4, 6, 12, 24 h and 1 week post-LC using the Visual Analog Scale (VAS 0-10). RESULTS: Study groups were comparable clinicopathologically. There were no adverse events. A statistically significant reduction in mean pain score was apparent in Study Group patients in comparison with Control Group (mean VAS 4.83 ± 2.33 vs. 6.80 ± 1.87; p < 0.001) at all early (1-6 h) post-operative time points following LC. CONCLUSION: This PRCT shows significantly improved pain control with somatovisceral pain blockade over non-opioid/opioid analgesic combinations following LC for symptomatic cholelithiasis. For centers not utilizing adjunctive local anesthetic for LC, this topical use of bupivacaine may improve patient comfort during recovery. This trial was registered on www.ClinicalTrials.gov NCT# 01972620.

Liver Label Retaining Cancer Cells Are Relatively Resistant to the Reported Anti-Cancer Stem Cell Drug Metformin.

BACKGROUND & AIMS: Recently, we reported that liver Label Retaining Cancer Cells (LRCC) can initiate tumors with only 10 cells and are relatively resistant to the targeted drug Sorafenib, a standard of practice in advanced hepatocellular carcinoma (HCC). LRCC are the only cancer stem cells (CSC) isolated alive according to a stem cell fundamental function, asymmetric cell division. Metformin has been reported to preferentially target many other types of CSC of different organs, including liver. It's important to know if LRCC, a novel class of CSC, are relatively resistant to metformin, unlike other types of CSC. As metformin inhibits the Sorafenib-Target-Protein (STP) PI3K, and LRCC are newly described CSC, we undertook this study to test the effects of Metformin on Sorafenib-treated HCC and HCC-derived-LRCC. METHODS: We tested various STP levels and phosphorylation status, associated genes' expression, proliferation, viability, toxicity, and apoptosis profiles, before and after treatment with Sorafenib with/without Metformin. RESULTS: Metformin enhances the effects of Sorafenib on HCC, and significantly decreased viability/proliferation of HCC cells. This insulin-independent effect was associated with inhibition of multiple STPs (PKC, ERK, JNK and AKT). However, Metformin increased the relative proportion of LRCCs. Comparing LRCC vs. non-LRCC, this effect was associated with improved toxicity and apoptosis profiles, down-regulation of cell death genes and up-regulation of cell proliferation and survival genes in LRCC. Concomitantly, Metformin up-regulated pluripotency, Wnt, Notch and SHH pathways genes in LRCC vs. non-LRCC. CONCLUSIONS: Metformin and Sorafenib have enhanced anti-cancer effects. However, in contradistinction to reports on other types of CSC, Metformin is less effective against HCC-derived-CSC LRCC. Our results suggest that combining Metformin with Sorafenib may be able to repress the bulk of tumor cells, but as with other anti-cancer drugs, may leave LRCC behind leading to cancer recurrence. Therefore, liver LRCC, unlike other types of CSC, are relatively resistant to the reported anti-cancer stem cell drug metformin. This is the first report that there is a type of CSC that is not relatively resistant to the CSC-targeting drug. Our findings suggest that a drug targeting LRCC may be critically needed to target CSC and prevent cancer recurrence. These may significantly contribute to the understanding of Metformin's anti-cancer effects and the development of novel drugs targeting the relatively resistant LRCC.

Extracorporeal shockwave therapy (ESWT) ameliorates healing of tibial fracture non-union unresponsive to conventional therapy.

Tibial non-unions are common cause of demanding revision surgeries and are associated with a significant impact on patients' quality of life and health care costs. Extracorporeal shockwave therapy (ESWT) has been shown to improve osseous healing in vitro and in vivo. The main objective of present study was to evaluate the efficacy of ESWT in healing of tibial non-unions unresponsive to previous surgical and non-surgical measures. A retrospective multivariant analysis of a prospective open, single-centre, clinical trial of tibia non-union was conducted. 56 patients with 58 eligible fractures who met the FDA criteria were included. All patients received 3000-4000 impulses of electrohydraulic shockwaves at an energy flux density of 0.4mJ/mm(2) (-6dB). On average patients underwent 1.9 times (±1.3SD) surgical interventions prior to ESWT displaying the rather negatively selected cohort and its limited therapy responsiveness. In 88.5% of patients receiving ESWT complete bone healing was observed after six months irrespective of underlying pathology. The multivariant analysis showed that time of application is important for therapy success. Patients achieving healing received ESWT earlier: mean number of days between last surgical intervention and ESWT (healed - 355.1 days±167.4SD vs. not healed - 836.7 days±383.0SD; p<0.0001). ESWT proved to be a safe, effective and non-invasive treatment modality in tibial non-unions recalcitrant to standard therapies. The procedure is well tolerated, time-saving, lacking side effects, with potential to significantly decrease health care costs. Thus, in our view, ESWT should be considered the treatment of first choice in established tibial non-unions.

Epicardial shock-wave therapy improves ventricular function in a porcine model of ischaemic heart disease.

Previously we have shown that epicardial shock-wave therapy improves left ventricular ejection fraction (LVEF) in a rat model of myocardial infarction. In the present experiments we aimed to address the safety and efficacy of epicardial shock-wave therapy in a preclinical large animal model and to further evaluate mechanisms of action of this novel therapy. Four weeks after left anterior descending (LAD) artery ligation in pigs, the animals underwent re-thoracotomy with (shock-wave group, n = 6) or without (control group, n = 5) epicardial shock waves (300 impulses at 0.38 mJ/mm2 ) applied to the infarcted anterior wall. Efficacy endpoints were improvement of LVEF and induction of angiogenesis 6 weeks after shock-wave therapy. Safety endpoints were haemodynamic stability during treatment and myocardial damage. Four weeks after LAD ligation, LVEF decreased in both the shock-wave (43 ± 3%, p < 0.001) and control (41 ± 4%, p = 0.012) groups. LVEF markedly improved in shock-wave animals 6 weeks after treatment (62 ± 9%, p = 0.006); no improvement was observed in controls (41 ± 4%, p = 0.36), yielding a significant difference. Quantitative histology revealed significant angiogenesis 6 weeks after treatment (controls 2 ± 0.4 arterioles/high-power field vs treatment group 9 ± 3; p = 0.004). No acute or chronic adverse effects were observed. As a potential mechanism of action in vitro experiments showed stimulation of VEGF receptors after shock-wave treatment in human coronary artery endothelial cells. Epicardial shock-wave treatment in a large animal model of ischaemic heart failure exerted a positive effect on LVEF improvement and did not show any adverse effects. Angiogenesis was induced by stimulation of VEGF receptors. Copyright © 2014 John Wiley & Sons, Ltd.

Role of multi-modality therapy in peritoneal carcinomatosis and visceral metastasis: a case report and review of the literature.

INTRODUCTION: Treatment for advanced stage colorectal cancer with synchronous peritoneal carcinomatosis (PC) and hepatic metastasis (HM) has progressed significantly over the past 10 years. CASE REPORT: We present the case of a 39-year-old female patient with stage IV colorectal cancer with bilateral HM, pulmonary oligometastatic disease, and diffuse PC who underwent hyperthermic intraperitoneal chemotherapy (HIPEC) and complete cytoreductive surgery (CRS) for her intra-abdominal disease. The patient had an uneventful immediate post-operative recovery, and subsequently tolerated multiple cycles of adjuvant chemotherapy and percutaneous radiofrequency ablation of pulmonary lesions. At her 22-month follow-up assessment, the patient remains alive with disease. CONCLUSION: Current recommendations for surgical management of synchronous colorectal cancer PC and HM indicate that patients with less than three HMs, a low peritoneal cancer index (PCI), and good functional status will benefit most from CRS and HIPEC. Our patient had an elevated PCI of 12 as measured by computed tomography imaging, and five HMs (all less than 3 cm in size); however, given that her life expectancy on systemic chemotherapy was estimated to be approximately 12 months, we have observed carefully selected patients to benefit from an aggressive multi-modality approach. This case report demonstrates an all too common scenario for surgeons managing patients with advanced CRC, and highlights the importance of patient selection for surgical management as part of multidisciplinary cancer care in this patient population.

Prognostic Effect of Ultra-Staging Node-Negative Colon Cancer Without Adjuvant Chemotherapy: A Prospective National Cancer Institute-Sponsored Clinical Trial.

BACKGROUND: We recently reported, in a prospective randomized trial, that ultra-staging of patients with colon cancer is associated with significantly improved disease-free survival (DFS) compared with conventional staging. That trial did not control for lymph node (LN) number or adjuvant chemotherapy use. STUDY DESIGN: The current international prospective multicenter cooperative group trial (ClinicalTrials.gov identifier NCT00949312; "Ultra-staging in Early Colon Cancer") evaluates the 12-LN quality measure and nodal ultra-staging impact on DFS in patients not receiving adjuvant chemotherapy. Eligibility criteria included biopsy-proven colon adenocarcinoma; absence of metastatic disease; >12 LNs staged pathologically; pan-cytokeratin immunohistochemistry (IHC) of hematoxylin and eosin (H&E)-negative LNs; and no adjuvant chemotherapy. RESULTS: Of 445 patients screened, 203 patients were eligible. The majority of patients had intermediate grade (57.7%) and T3 tumors (64.9%). At a mean follow-up of 36.8 ± 22.1 months (range 0 to 97 months), 94.3% remain disease free. Recurrence was least likely in patients with ≥12 LNs, H&E-negative LNs, and IHC-negative LNs (pN0i-): 2.6% vs 16.7% in the pN0i+ group (p < 0.0001). CONCLUSIONS: This is the first prospective report to demonstrate that patients with optimally staged node-negative colon cancer (≥12 LNs, pN0i-) are unlikely to benefit from adjuvant chemotherapy; 97% remain disease free after primary tumor resection. Both surgical and pathologic quality measures are imperative in planning clinical trials in nonmetastatic colon cancer.

Immunoprofiling for prognostic assessment of colon cancer: a novel complement to ultrastaging.

BACKGROUND: Although AJCC/TNM staging remains the gold standard for prognostic assessment of colon cancer, stage-specific outcomes vary. We therefore prospectively evaluated the prognostic role of immunoprofiling. METHODS: Our cohort included 35 patients from an ongoing prospective trial of ultrastaging for colon cancer. Specimens were analyzed for T cell markers (CD3, CD4, CD8, and FoxP3). The number of tumor-infiltrating lymphocytes was analyzed at the tumor's margin and center and correlated with AJCC/TNM stage, clinicopathologic variables, and disease-free survival. RESULTS: There was a significant inverse association between number of CD3(+) cells in the tumor center and tumor stage (P = 0.05). The tumor center/margin ratio of CD3(+) cells also showed an inverse but non-significant relationship with nodal involvement (P = 0.07). Body mass index was inversely associated with numbers of CD3(+)(P = 0.04) and CD8(+)(P = 0.02) cells. Longer disease-free survival was correlated with higher CD8+ counts (P = 0.07), lower CD4(+)/CD8(+) ratios (P = 0.008), and higher CD8(+)/FoxP3(+) ratios (P = 0.02). CONCLUSIONS: This is the first prospective validation of immunoprofiling in patients whose colon cancer is staged with strict surgical and pathology quality measures. The apparent correlation between immunophenotypic response and clinical outcome warrants evaluation in a larger prospective trial.