Recurrence Of Malignant Disease Research Articles

Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin.

Inflammation is activated by diverse triggers that induce the expression of cytokines and adhesion molecules, which permit a succession of molecules and cells to deliver stimuli and functions that help the immune system clear the primary cause of tissue damage, whether this is an infection, a tumor, or a trauma. During inflammation, short-term changes in the expression and secretion of strong mediators of inflammation occur, while long-term changes occur to specific groups of cells. Long-term changes include cellular transdifferentiation for some types of cells that need to regenerate damaged tissue, as well as death for specific immune cells that can be detrimental to tissue integrity if they remain active beyond the boundaries of essential function. The transcriptional regulator NFκB enables some of the fundamental gene expression changes during inflammation, as well as during tissue development. During recurrence of malignant disease, cell stress-induced alterations enable the growth of cancer cell clones that are substantially resistant to therapeutic intervention and to the immune system. A number of those alterations occur due to significant defects in feedback signal cascades that control the activity of NFκB. Specifically, cell stress contributes to feedback defects as it overrides modules that otherwise control inflammation to protect host tissue. NFκB is involved in both the suppression and promotion of cancer, and the key distinctive feature that determines its net effect remains unclear. This paper aims to provide a clear answer to at least one aspect of this question, namely the mechanism that enables a divergent response of cancer cells to critical inflammatory stimuli and to cell stress in general.

A D-Dimer and Thrombin Generation-Based Risk Score Predicts Early-Disease Recurrence in a Prospective Cohort of 1,059 High-Risk Breast Cancer Patients

Introduction: Hemostatic biomarkers have been widely explored in different cancer types as possible predictors of specific cancer outcomes, including survival, malignant disease recurrence, and progression. Results from many small and single-center studies are promising, stimulating confirmatory data from large, prospective studies. In a large cohort of high-risk breast cancer patients enrolled in the prospective, observational, multicenter HYPERCAN study, we aim to establish whether prechemotherapy hemostatic levels can predict disease recurrence (DR). Methods: TheHYPERCAN study (ClinicalTrials.gov ID#NCT02622815) is a prospective, observational, multicenter study, specifically designed to evaluate the role of hemostatic biomarkers in relation to disease recurrence, disease progression, mortality response to therapy and thrombosis. Patients with surgically resected high-risk breast cancer enrolled between 2012 and 2019, from the HYPERCAN study were analyzed. Blood samples collected at enrollment, before starting anticancer treatment, were tested for thrombin generation (TG) by both the ST-Genesia system (STG-ThromboScreen reagent, with and without thrombomodulin) and the calibrated automated thrombogram (CAT) at 5 pM TF. D-dimer, fibrinogen, prothrombin fragment 1+2 (F1+2), and proteins C and free protein S (FPS) were also measured. Outcome analyzed was early-DR (E-DR) within 2 years. Results: A total of 1,059 patients (15M/1,044F), mean age 53 years (SD±11) were analyzed. Breast conserving-resection was performed in 53% and mastectomy in 47% of patients. HER-2 expression was positive in 26% of tumor specimens. The most frequent molecular subtype was Luminal B HER2 negative (32%), followed by Luminal A (22%), Luminal B HER2 positive (19%), Triple negative (13%) and HER2 positive (8%). The largest proportion of tumors were classified as invasive ductal carcinoma, diagnosed in 86% of subjects. All patients were eligible for systemic adjuvant chemotherapy, and for receiving trastuzumab in case of HER-2 positivity. Within 2 years from enrollment, 53 (5.5 %) patients experienced an E-DR, 8 died, while 92 were lost at follow-up. E-DR patients were characterized by worse stage (IIIC), more frequently triple-negative, and less often Luminal-B/HER2-positive molecular subtypes (p<0.05). In addition, E-DR subjects were characterized by increased pre-chemotherapy levels of D-dimer (p=0.004), and peak of TG performed by both Genesia (p=0.001), with and without thrombomodulin, and by CAT (p<0.001) assays. The remaining coagulation parameters were not significantly different between the two groups. The competitive multivariable proportional hazard regression model, corrected for age and surgery status, identified D-dimer and TG peak (by both methods) as independent risk factors for E-DR. This model was internally validated by 1,000-bootstrapping resampling correction. A continuous risk score was therefore generated including D-dimer and TG, which provided a ROC AUC of 0.652 (p<0.001). By this score the patients were significantly stratified in a high- vs low-risk for E-DR (HR 23 vs 0%: Log-rank <0.001). Conclusions: In this large prospective cohort of surgically resected breast cancer patients at high-risk of DR, we could generate and internally validate a risk assessment model based on pre-treatment values of TG and D-dimer, able to identify those subjects at higher risk of DR in the first 2 years after tumor resection. This score, if externally validated, may help the clinical surveillance and serve as treatment guidance in patients with primary breast cancer that are at high risk of recurrence, avoiding overtreatment in those at low risk.

Graft-versus-host disease: new insights into disease pathogenesis

Graft-versus-host disease (GVHD) is a potentially life-threatening complication associated with allogeneic hematopoietic stem cell transplantation (allo-SCT). Although prophylaxis and GVHD treatment using immunosuppressants are essential for a successful allo-SCT, profound immunosuppression could lead to an infection and/or the recurrence of malignant diseases. Recently, the concept of tissue tolerance has emerged. This concept has been identified as a means to suppress GVHD by relying on tissue-intrinsic mechanisms that are independent from those underlying immune tolerance. Thus, GVHD prophylaxis and treatments targeting the mechanisms that promote tissue tolerance could help suppress GVHD and maintain leukocyte-mediated immune responses against tumors and infectious pathogens. Epithelial regeneration from LGR5-positive intestinal stem cells and epithelial maintenance mediated by metabolites from the intestinal microbiota are representative mechanisms that promote tissue tolerance in the gut. However, these protective mechanisms are weakened by GVHD and conditioning regimens. This review focuses on the pathophysiology of acute GVHD and tissue-intrinsic mechanisms that promote tissue tolerance.

P54 INCIDENCE AND OUTCOME OF HIATAL HERNIA AFTER OESOPHAGECTOMY: COMPARISON OF TRADITIONAL OPEN AND MINIMALLY INVASIVE APPROACH

Abstract Aim The primary aim of this retrospective study is to evaluate the incidence of symptomatic and asymptomatic hiatal hernia (HH) in patients who have undergone intended curative open or minimally invasive oesophagectomy (MIO) for cancer of the oesophagus in a high-volume surgical centre. The secondary aim is to describe the treatment and outcome after HH treatment. Background & Methods MIO for the treatment of oesophageal cancer has emerged as an alternative to traditional open oesophagectomy without compromising disease free or overall survival1. HH of abdominal viscera other than the gastric conduit is an infrequent but potentially life-threatening complication following oesophagectomy. HH may present with grievous complications, such as severe respiratory failure, intestinal ischemia with perforation, bowel obstruction, and strangulation leading to emergency surgery2,3. Surgical repair of these HHs is associated with a high morbidity rate and in the emergent setting even a high mortality4. In meta-analysis, the pooled incidence of symptomatic HH after MIO was 4.5 %, compared to a pooled incidence of 1.0 % after open oesophagectomy5. However, studies on the subject, often do not describe whether patients are asymptomatic or simply have not been examined for the existence of HH. The actual HH incidence may therefore be underestimated and may be more sufficiently reported when including patient material with comprehensive follow-up. This retrospective cohort study includes all patients (n≈455) who have undergone curative intended resection for malignant disease in the oesophagus at The Department of Surgery, Odense University Hospital, from 1th January 2012 – 31th December 2018. Patient demography, perioperative data including surgical approach and follow-up, including occurrence and treatment of hiatal hernia, mortality and recurrence of malignant disease will be extracted from complete electronic patient records. Follow-up ranges from 6-84 months. Primary outcome is occurrence of hiatal hernia after oesophagectomy determined by CT-scan or during surgery. Results As of abstract deadline for ESDE 2019, we have only just received permission for the study from The Danish Patient Safety Authority and can unfortunately not present our results yet. However, we expect that results are ready for presentation at ESDE 2019 and hope for your understanding.

Thrombotic biomarkers for risk prediction of malignant disease recurrence in patients with early stage breast cancer.

In cancer patients, hypercoagulability is a common finding. It has been associated with an increased risk of venous thromboembolism, but also to tumor proliferation and progression. In this prospective study of a large cohort of breast cancer patients, we aimed to evaluate whether pre-chemotherapy abnormalities in hemostatic biomarkers levels: (i) are associated with breast cancer-specific clinico-pathological features; and (ii) can predict for disease recurrence. D-dimer, fibrinogen, prothrombin fragment 1+2, and FVIIa/antithrombin levels were measured in 701 early-stage resected breast cancer patients candidate to adjuvant chemotherapy and prospectively enrolled in the HYPERCAN study. Significant prognostic parameters for disease recurrence were identified by Cox regression multivariate analysis and used for generating a risk assessment model. Pre-chemotherapy D-dimer, fibrinogen, and pro-thrombin fragment 1+2 levels were significantly associated with tumor size and lymph node metastasis. After 3.4 years of follow up, 71 patients experienced a recurrence. Cox multivariate analysis identified prothrombin fragment 1+2, tumor size, and Luminal B HER2-negative or triple negative molecular subtypes as independent risk factors for disease recurrence. Based on these variables, we generated a risk assessment model that significantly differentiated patients at low- and high-risk of recurrence (cumulative incidence: 6.2 vs. 20.7%; Hazard Ratio=3.5; P<0.001). Our prospective clinical and laboratory data from the HYPERCAN study were crucial for generating a scoring model for assessing risk of disease recurrence in resected breast cancer patients, candidate to systemic chemotherapy. This finding stimulates future investigations addressing the role of plasma prothrombin fragment 1+2 in the management of breast cancer patients to provide the rationale for new therapeutic strategies. (The HYPERCAN study is registered at clinicaltrials.gov identifier 02622815.)

Danish Childhood Cancer Registry

Aim of databaseThe overall aim is to monitor the quality of childhood cancer care in Denmark; to register late effects of treatment; to analyze complications of permanent central venous catheters (CVCs); to study blood stream infections in children with cancer; and to study acute toxicity of high-dose methotrexate infusions in children with leukemia.Study populationAll children below 15 years of age at diagnosis living in Denmark diagnosed after January 1, 1985 according to the International Classification of Diseases 10, including diagnoses DC00–DD48.Main variablesCancer type, extent of disease, treatment, participation in international studies, recurrence of malignant disease, survival, yearly follow-up status, causes of death, and development of secondary malignancies. Type of CVC, causes for removal of the CVC, type of blood stream infection, pathogens isolated, antimicrobial sensitivity, and outcome of antimicrobial chemotherapy.Descriptive dataSince 1985, 4,944 children below 15 years of age have been registered in the database. There has been no significant change in the incidence of childhood cancer in Denmark since 1985. The 5-year survival has increased significantly since 1985 and is now 86%. The median number of days from diagnosis to initiation of therapy is 7 days and in 80% of the children less than 14 days. Clinical data of 95% of the patients are reported to open international studies.ConclusionThe survival of Danish children with cancer since 2003 compares favorably with other international population-based studies. The annual reports support the collaboration within pediatric oncology in Denmark.

Risk factors for future repeat abdominal surgery.

PurposeToday, 40 to 66 % of elective procedures in abdominal surgery are reoperations. Reoperations show increased operative time and risk for intraoperative and postoperative complications, mainly due to the need to perform adhesiolysis. It is important to understand which patients will require repeat surgery for optimal utilization and implementation of anti-adhesive strategies. Our aim is to assess the incidence and identify risk factors for repeat abdominal surgery.MethodsThis is the long-term follow-up of a prospective cohort study (Laparotomy or Laparoscopy and Adhesions (LAPAD) study; clinicaltrials.gov NCT01236625). Patients undergoing elective abdominal surgery were included. Primary outcome was future repeat abdominal surgery and was defined as any operation where the peritoneal cavity is reopened. Multivariable logistic regression analysis was used to identify risk factors.ResultsSix hundred four (88 %) out of 715 patients were included; median duration of follow-up was 46 months. One hundred sixty (27 %) patients required repeat abdominal surgery and underwent a total of 234 operations. The indication for repeat surgery was malignant disease recurrence in 49 (21 %), incisional hernia in 41 (18 %), and indications unrelated to the index surgery in 58 (25 %) operations. Older age (OR 0.98; p 0.002) and esophageal malignancy (OR 0.21; p 0.034) significantly reduced the risk of undergoing repeat abdominal surgery. Female sex (OR 1.53; p 0.046) and hepatic malignancy as indication for surgery (OR 2.08; p 0.049) significantly increased the risk of requiring repeat abdominal surgery.ConclusionsOne in four patients will require repeat surgery within 4 years after elective abdominal surgery. Lower age, female sex, and hepatic malignancy are significant risk factors for requiring repeat abdominal surgery.

Hypercoagulation Screening As a Marker of Thrombosis and Poor Disease Prognosis in Cancer Patients: The Hypercan Prospective Study

Introduction Malignant tumor progression and poor prognosis have been repeatedly associated with the occurrence of hypercoagulation and overt thrombotic events. The HYPERCAN is an ongoing prospective Italian multicentre study, structured in two sub-projects that involve respectively non-cancer and cancer subjects. The HYPERCAN sub-project on cancer patients aims to evaluate whether thrombotic markers may predict for malignant disease recurrence and/or for venous thromboembolic events (VTE) in these patients.Methods Consecutive adult patients with limited resected or metastatic non-small cell-lung (NSCLC), gastric, colorectal, or breast cancers are enrolled, after informed written consent, and followed up for 5 years or death. Enrollment will be continued for up to 3 years (total 4,000 patients planned). Blood sample collection is planned according to tumor stage. Particularly, for metastatic disease, patient citrated whole blood is collected: 1. at enrollment, 2. after the 3rd cycle of anticancer therapy, 3. after the 6thcycle of anticancer therapy, 4. at the end of treatment, or earlier if disease progression. For patients with limited disease, whole blood samples are collected at enrollment (i.e. after surgery, before starting any medical anticancer treatment), and thereafter once a year for 4 years, or at disease recurrence. At each time point, information on treatment, clinical response, and disease outcome, are collected. Plasma samples and clinical information are centralized at the Division of Immunohematology and Transfusion Medicine - Bergamo Hospital (coordinating center). Patient plasma is tested for a preliminary panel of hemostatic markers (D-dimer, Fibrinogen) and thrombin generation (TG).Results Between April 2012 and February 2014, 1,113 cancer patients were enrolled into the study. Follow-up data were available for 1,045 patients (359 metastatic/686 limited-resected) with NSCLC (n=252), gastric (n=74), colorectal (n=163) and breast (n=556) cancers, with an observation median time of 340 days. Forty-eight patients (4.6%) developed VTE with a median time of 123 days from enrollment. VTE was more frequent in metastatic compared to limited resected cancer patients (9.2% vs 2.2%); colorectal and lung cancer patients showed the highest VTE rate, 8.5% and 7.9%, respectively, independently of tumor stage. Currently plasma from 474 patients (196 metastatic/278 limited resected) were tested. Increased D-dimer and fibrinogen levels at enrollment showed to be significant risk factors for VTE by Kaplan-Meier analysis (HR: 5.4, 95% CI 2.2-13.2 p=0.000 for D-dimer; HR: 4.3, 95% CI 1.8-10.4 p=0.004 for fibrinogen) as well as the endogenous thrombin potential (HR: 4.5, 95% CI 1.8-11.4 p=0.000) and the TG peak (HR: 4.0, 95% CI 1.5-10.2 p=0.009). In the group with limited resected disease, the cumulative incidence of recurrence was 3.2% with a median time of 186 days. Increased D-dimer and fibrinogen levels at enrollment were predictive for disease recurrence by Kaplan-Meier analysis (HR: 9.9, 95% CI 2.4-40.1 p=0.001 for D-dimer; HR: 5.9, 95% CI 1.5-23.6 p=0.012 for fibrinogen).Conclusions These early results reveal that tumor stage and site, as well as elevated levels of D-dimer, fibrinogen and TG at enrollment, are associated with an increased risk of VTE in cancer patients. In subjects with limited resected cancer, elevated D-dimer and fibrinogen levels also predict for disease recurrence. These results support the hypothesis that testing for relatively easy plasma markers of thrombosis may be worth for monitoring the cancer response to therapy beyond the thrombotic risk.Project funded by AIRC “5xMILLE” n. 12237 grant from the “Italian Association for Cancer Research (AIRC)”. DisclosuresNo relevant conflicts of interest to declare.

Akt Signalling Inhibition Promotes The Ex Vivo generation Of Minor Histocompatibility Antigen-Specific CD8+ Memory Stem T Cells

Allogeneic hematopoietic stem cell transplantation (allo-SCT) followed by donor lymphocyte infusion (DLI) is a potential curative treatment for patients suffering from a hematological malignancy. Efficacy is attributed to the graft-versus-tumor (GVT) response, during which engrafted donor T cells become activated by recipient minor histocompatibility antigens (MiHA) presented on dendritic cells (DC). Subsequently, these activated T cells expand, acquire effector functions and kill MiHA-positive tumor cells. However, persistence and recurrence of malignant disease is often observed, indicating that insufficient GVT immunity is induced. This imperfect alloreactive response is probably due to insufficient numbers of MiHA-specific effector T cells and/or defective antigen-presentation and costimulation. Therefore, adoptive transfer of potent ex vivo-generated MiHA-specific T cells, restricted to the hematopoietic system, would boost the GVT-effect without increasing the risk for GVHD. Although successful in vitro induction of MiHA-specific CD8+ T cells from naive precursors has been reported, the resulting antigen-experienced T cell population consist of fully differentiated effector-memory T cells (TEM). Over the past years it has been described that this T cell subset is not the most potent memory subset in anti-tumor responses in vivo following T cell transfer. In this regard, the less-differentiated memory subset called stem cell memory T cells (TSCM) with superior in vivo expansion, self-renewal capacity and plasticity to differentiate in potent effectors would generate a stronger GVT response. In this study, we aimed to investigate the in vivo availability and ex vivo generation of TSCM-like MiHA-specific T cells as additive treatment option for allo-SCT patients. First, we investigated whether in allo-SCT patients MiHA-specific T cells could be detected with a TSCM phenotype defined by the expression of CD45RO, CCR7, CD27 and CD95. Though TSCM cells could be clearly detected within CMV-specific CD8+ T cells in allo-SCT patients, similar to healthy controls, no MiHA-specific TSCM cells could be detected. This emphasises the need for more potent adoptive MiHA-specific T cell therapy following allo-SCT. Therefore, we next explored the possibility of generating TSCM-like CD8+ T cells by interfering with the Akt signalling pathway. Emerging findings indicate that the differentiation program of CD8+ T cells is dictated by the strength and duration of AKT activity. Therefore, we explored whether the pharmacological inhibition of this signaling pathway could results in the generation of TSCM-like CD8+ T cells. We stimulated CCR7+CD45RA+ naive CD8+ T cells with CD3/CD28 beads plus IL-2, IL-7 and/or IL-15 in the presence an Akt inhibitor. Interestingly, CD8+ T cells in these Akt-cultures were inhibited in their differentiation stage, expressing higher levels of CD45RA and CCR7 compared to controls. In addition, expression of CD95, IL2Rβ, and IL7Rα was also elevated confirming the TSCM-like phenotype. Although proliferation of the Akt-inhibited CD8+ T cells was decreased as shown by less PBSE dilution, expansion could be significantly preserved. Next, we investigated whether the established culture conditions could be used to generate MiHA-specific TSCM-like cells. Therefore, CD8+ T cells from MiHA-negative donors were primed using autologous MiHA peptide-loaded moDCs in the presence of the Akt-inhibitor. Interestingly, MiHA-specific T cell priming could be induced, consisting of mainly TCM and TSCM-like cells compared to almost entirely TEM cells in the control setting. Akt-inhibited MiHA-specific T cells showed higher expression of CCR7, CD45RA, CD62L, CD28, CD95, and IL7Rα. Importantly, for the Akt-inhibited MiHA-specific T cells, proliferation was reserved, resulting in robust proliferation capacity during restimulation after removal of the Akt-inhibitor. The resulting TEFF cells were highly functional, showing capacity to degranulate and produce IFNγ upon peptide restimulation. In conclusion, by inhibiting the Akt-pathway, in vitro CD8+ T cell differentiation can be reduced. Therefore, Akt signalling inhibition can be exploited for generating TSCM-like MiHA-specific T cells in adoptive immunotherapy after allo-SCT. Disclosures:No relevant conflicts of interest to declare.

Functional effects of SDF-1α on a CD44+ CXCR4+ squamous cell carcinoma cell line as a model for interactions in the cancer stem cell niche

Stromal cell-derived factor-1α (SDF-1α), also known as CXCL12, has variable effects on a plurality of cells. It is known to have selective effects on cell migration, morphology, survival and cell homing. As such the SDF-1-CXCR4 axis is postulated to be a crucial key pathway in the interaction between (cancer) stem cells and their surrounding supportive cells, the so-called (cancer) stem cell niche. We evaluated the expression of CD44 as a cancer stem cell (CSC) marker and the expression of CXCR4 in the head and neck squamous cell carcinoma (HNSCC) cell line UM-SCC 11A. In addition, we monitored proliferation, formation of podia and migration of UM-SCC 11A cells under the influence of SDF-1α. Whereas SDF-1α induced the formation of podia of CD44(+) CXCR4(+) UM-SCC 11A cells in a dose-dependent manner and the maximum number of cells exhibiting the formation of podia was observed under the influence of 10 ng/ml SDF-1α (P=5.3x10(-6)), the highest number of migrating cells was noted using a concentration of 100 ng/ml (P=0.027). Proliferation and survival were not affected by SDF-1α. We showed that UM-SCC 11A cells could be a target for SDF-1α by CXCR4 expression and these cells also showed characteristics of HNSCC CSCs via CD44 expression. We demonstrated that SDF-1α is a chemoattractant for UM-SCC 11A cells, and a maximum directed migration was achieved under the influence of 100 ng/ml SDF-1α. Changes in cell morphology by presenting filopodia or a prominent uropod were noted following treatment of 10 ng/ml SDF-1α. The SDF-CXCR4 axis may play a crucial role in the interaction between CSCs and their supportive cells in the CSC niche. Understanding these interactions may help to gain further insight into the pathophysiology of the progression and recurrence of malignant diseases and thus help to develop novel strategies for therapy.

Minimal Residual Disease following Allogeneic Hematopoietic Stem Cell Transplantation

Minimal residual disease (MRD), both before and after transplantation, is a clinically important yet relatively poorly defined aspect of allogeneic hematopoietic stem cell transplantation (alloHSCT). The clinical relevance of MRD in the context of alloHSCT has been demonstrated by its association with the development of clinical relapse. However, with the possible exception of chronic myeloid leukemia (CML), the specific techniques, timing, frequency, and clinical utility, relative to improvement in patient outcomes, for monitoring MRD in the setting of alloHSCT has yet to be clearly defined. A concise overview of monitoring techniques for detecting MRD, as well as treatment strategies and biological and clinical research initiatives for MRD suggested by the National Cancer Institute First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation, is covered in this article.

Liver transplantation and pancreatic resection: A single-center experience and a review of the literature

Liver transplantation may occasionally be indicated in patients with unique clinical scenarios. Little is known regarding the outcomes of patients who have had a pancreatic resection prior to, in combination with, or after liver transplantation. A retrospective review of all patients undergoing liver transplantation from March 1998 to March 2008 identified 17 patients who also underwent pancreatic resection. An additional literature review was performed. Five underwent pancreatic resection prior to liver transplantation (1.7, 3.6, 3.8, 6.8, and 8.1 years), another 9 underwent pancreatic resection together with liver transplantation, and 3 underwent pancreatic resection after liver transplantation (2.2, 2.6, and 3.8 years). Indications for pancreatic resection included cholangiocarcinoma (n = 6), neuroendocrine tumor (n = 5), pancreatic cancer (n = 2), gastrointestinal stromal tumor (n = 1), periampullary adenocarcinoma (n = 1), duodenal adenomas (n = 1), and benign pancreatic mass (n = 1). Indications for liver transplantation were metastatic neuroendocrine tumor disease (n = 5), primary sclerosing cholangitis (n = 5), hepatitis C virus (n = 2), metastatic gastrointestinal stromal tumor (n = 1), Klatskin tumor (n = 1), alcohol cirrhosis (n = 1), alpha-1 antitrypsin deficiency (n = 1), and chemotherapy-induced cirrhosis (n = 1). One patient died intraoperatively, 7 patients died of tumor recurrence, 2 patients died from transplant complications, and 7 patients are still alive. Pancreatic resection-related complications included 4 pancreatic fistulas. A literature review confirmed liver transplantation/pancreatic resection-related complications. In conclusion, liver transplantation and pancreatic resection remain uncommon, and a good outcome can be achieved. Recurrence of malignant disease is the main factor limiting survival, and specific morbidity may be related to pancreatic resection and liver transplantation.

Surgical treatment of hepatic tumors in children: lessons learned from liver transplantation

Purpose Hepatectomy remains a complex operation even in experienced hands. The objective of the present study was to describe our experience in liver resections, in the light of liver transplantation, emphasizing the indications for surgery, surgical techniques, complications, and results. Methods The medical records of 53 children who underwent liver resection for primary or metastatic hepatic tumors were reviewed. Ultrasonography, computed tomographic (CT) scan, and needle biopsy were the initial methods used to diagnose malignant tumors. After neoadjuvant chemotherapy, tumor resectability was evaluated by another CT scan. Surgery was performed by surgeons competent in liver transplantation. As in liver living donor operation, vascular anomalies were investigated. The main arterial anomalies found were the right hepatic artery emerging from the superior mesenteric artery and left hepatic artery from left gastric artery. Hilar structures were dissected very close to liver parenchyma. The hepatic artery and portal vein were dissected and ligated near their entrance to the liver parenchyma to avoid damaging the hilar vessels of the other lobe. During dissection of the suprahepatic veins, the venous infusion was decreased to reduce central venous pressure and potential bleeding from hepatic veins and the vena cava. Results Fifty-three children with hepatic tumors underwent surgical treatment, 47 patients underwent liver resections, and in 6 cases, liver transplantation was performed because the tumor was considered unresectable. There were 31 cases of hepatoblastoma, with a 9.6% mortality rate. Ten children presented with other malignant tumors—3 undifferentiated sarcomas, 2 hepatocellular carcinomas, 2 fibrolamellar hepatocellular carcinomas, a rhabdomyosarcoma, an immature ovarian teratoma, and a single neuroblastoma. These cases had a 50% mortality rate. Six children had benign tumors—4 mesenchymal hamartoma, 1 focal nodular hyperplasia, and a mucinous cystadenoma. All of these children had a favorable outcome. Hepatic resections included 22 right lobectomies, 9 right trisegmentectomies, 8 left lobectomies, 5 left trisegmentectomies, 2 left segmentectomies, and 1 case of monosegment (segment IV) resection. The overall mortality rate was 14.9%, and all deaths were related to recurrence of malignant disease. The mortality rate of hepatoblastoma patients was less than other malignant tumors ( P = .04). Conclusion The resection of hepatic tumors in children requires expertise in pediatric surgical practice, and many lessons learned from liver transplantation can be applied to hepatectomies. The present series showed no mortality directly related to the surgery and a low complication rate.

Antibody Response to Polysaccharide Conjugate Vaccines after Nonmyeloablative Allogeneic Stem Cell Transplantation

After allogeneic stem cell transplantation with reduced-intensity conditioning regimens (allo-RIST) patients are susceptible to bacterial and viral infections for a period that may last several years. The efficacy of the recommended vaccination schedules, in terms of induction of a protective antibody response, is unknown. In this study, the reconstitution of humoral immunity after allo-RIST is determined by measuring the vaccination-induced antibody response against Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and tetanus toxoid (TT) 1 year posttransplantation. Patients who underwent allo-RIST were vaccinated according to a schedule starting at 12 months following transplantation with conjugated vaccines against S. pneumoniae, Hib, and TT. Of twenty-six patients both pre- and postvaccination sera were available. Patients were required to be off immunosuppression at the time of vaccination, and, therefore, 9 of the 26 patients did not start vaccination at 12 months post-stem cell transplantation but rather at a median range of 15 (12-36 months) posttransplantation. Except for pneumococcal serotype 6B, more than 73% of the patients developed antibody levels >or=0.35 microg/mL for all pneumococcal serotypes included in the vaccine. For Hib and TT, protective antibody levels were found in 77% and 96% of the patients, respectively. Vaccination of patients at a median of 15 months post-allo-RIST leads to significant rise in concentrations of pneumococcal, Hib, and TT antibodies in the majority of patients.

T Cell Therapy in Allogeneic Stem Cell Transplantation

T cells derived from healthy stem cell donors can mediate curative immune responses after allogeneic stem cell transplantation (SCT) by eliminating (residual) hematopoietic tumor cells life-threatening viral infections. The first evidence for the crucial role of T cells came from the observations that depletion of T cells from a stem cell graft to prevent the development of acute graft versus host disease (GVHD) was associated with an increased incidence of relapse of the malignancy and life threatening viral infections including CMV disease and EBV mediated post-transplant lymphoproliferative disease (PTLD). Apparently, after allogeneic SCT T cells are not only responsible for the detrimental GVHD, but also can mediate a graft versus tumor (GVT) effect and are essential for long term of control of persistent endogenous viral infections. Unmanipulated T cell populations derived from the stem cell donor administered to the patient may result in concurrent development of GVHD, GVT and anti-virus responses. Immune suppression to control GVHD may lead to reduction or elimination of GVT and pathogen specific T cell responses. Obviously, if T cell responses leading to GVHD could be separated from GVL or pathogen-specific reactivity, morbidity and survival after allogeneic SCT can be significantly improved. One approach to manipulate the effect of donor T cells after transplantation has been the depletion of donor T cells from the graft with postponed administration of donor T cells 1. The rationale for this approach came from several mouse and human studies illustrating that the recipient microenvironment plays a significant role in the development of GVHD2. Tissue damage during the conditioning regimen leading to the initiation of a ‘cytokine storm’, the strong lymphodepletion after transplant leading to homeostatic proliferation of donor T cells shortly after transplant, and the presence of patient derived activated dendritic cells (DC) which are required for the induction of allo-immune responses all contribute to these strong allo-response immediately after transplantation. Postponed T cell administration at the time of replacement of the majority of recipient DC by donor DCs, after repair of the tissue damage, and after partial reconstitution of T cells in peripheral blood of patients is associated with lower risk of developing severe acute GVHD. Administration of T cells from 6 months after transplantation can be performed with relatively low risk of inducing severe GVHD, although chronic GVHD remains a significant complication. However, recurrence of the malignancy and the development of severe opportunistic infections frequently take place within the first half year after transplantation. Thus, although postponed administration of T cells can result in less severe GVHD, overall survival did not significantly improve. Delivering stem cell transplants that are free from GVHD while conferring enhanced protection against malignant disease recurrence and viral reactivation is considered by many transplanters to be a key goal (the “Holy Grail”) for improving transplant success. We will discuss several approaches for the selective administration of non-GVHD reactive donor T cells: selective allodepletion, adoptive transfer of virus-specific T cells, allo-reactive anti-tumor T cells recognizing minor histocompatibility antigens (mHag) or MHC molecules, or T cells recognizing tumor-associated self antigens.

Right Heart Free-Floating Thrombus In A Patient With History Of Breast Cancer

Free-floating right heart thrombi are a rare phenomenon, generally diagnosed when echocardiography is performed in patients with suspected or proven pulmonary embolism and have a dismal prognosis. A case of a 67-year-old female with a history of breast cancer and a free floating thrombus in the right atrium is presented. She was admitted with symptoms and signs of acute right heart failure. Further investigation revealed a large free serpentine right atrial thrombus, which sometimes prolapsed through the tricuspid valve into the right ventricle. The patient underwent surgical embolectomy with exploration of the right chambers and pulmonary arteries under full cardiopulmonary by pass. There were no perioperative complications. Screening tests for hypercoagulability were normal except for positive antiphospholipid antibodies. Eighteen months later the patient is free of symptoms and with no recurrence of malignant disease. Right heart thrombi are a severe form of venous thromboembolic disease and justify diagnosis and treatment in emergency. In our case, surgery was the treatment of choice although thrombolysis could be advocated first. Breast cancer is probably a predisposing factor for hypercoagulability.

First Line Antifungal Treatment with Caspofungin of Oncohemopatic Patients. A Single Centre Experience.

Infections are the main complication for patients (pts) with hematologic diseases and severe neutropenia and among them fungal infections are the most difficult to treat and a major cause of mortality. The availability of a new class of antifungal drugs (echinocandins) could improve the chance of cure. Caspofungin (Caspo) is the first drug which is able to destroy the fungal cell wall. Since January 2004 we have treated 28 consecutive adult oncohemopatic and neutropenic pts with Caspo as first line therapy. In case of persistent fever (4 days) despite broad spectrum antibiotic therapy (association of Tazobactam/Piperacillin, Amikacin with or without Vancomycin) with negative blood cultures, a high-resolution CT-scan of the lungs, an abdomen US-scan, swabs from pharynx, nose and rectum, galactomannan test (this test is available at our Centre since February 2006) were performed. In the presence of any other sign or symptom we performed any other test according to the physicyan's choice. In case of possible, probable or proven fungal infection (according to the EORTC criteria) Caspo was administered at the dosage of 70 mg i.v. on the first day followed by 50 mg i.v. in 1 hour daily. The pts were 15 males and 13 females; the mean age was 46 yrs (range 18–66 yrs). The diagnoses were: acute myeloid leukemia 13, acute lymphoblastic leukemia 5, multiple myeloma 2, lymphoma 8; the disease's phases were: onset 9, complete remission 11, relapse 2, resistant 6. Six pts received an allogeneic and 4 an autologous BMT; the other pts received an induction or consolidation or rescue chemotherapy course. All the pts had severe neutropenia and the fungal infections were proven in 3 cases (2 aspergillus spp and 1 aspergillus fumigatus), probable in 3 cases and possible in 22 cases. The first site of infection was the lung in 27 pts and paranasal sinuses in 1 patient. CT scan was positive (halo sign, air-crescent sign or cavitation) in all the pts with a lung localization. The mean time of treatment was 18 days (range 6–21 days). The treatment was not discontinued for anyone because of adverse events and no modifications of the dosage were necessary. All the pts submitted to an allogeneic BMT received concomitant therapy with Cyclosporine A and we had not to change the dosage and we did not found any renal or liver alterations. No adverse events during the infusion of Caspo were seen and it was not necessary to administer any drug before the infusion as premedication. No breakthrough fungal infections were found. The infection was cured in 24/28 pts; 4 pts died for fungal infection progression (3 with a progression to the brain and in 1 case the infection remained in the lungs). For all the cured pts there was a concomitant recovery of neutrophils so also in our experience this appears to be a crucial fact for the resolution of the infection. Among the 24 cured patients 8 died later: 5 for hematologic disease and 3 for sepsis during malignant disease recurrence. In 2 cases there was the recurrence of the fungal infection despite the secondary prophylaxis with Caspo. In conclusion we can say we have a new treatment option for fungal infections in neutropenic pts with a new mechanism of action; this option seems safe, it does not preclude any other treatment (such as Cyclosporine), it is well tolerated and the resolution rate of the infections is very high, probably because of the new mechanism of action of the drug. Moreover the cost is lower than other antifungal treatments.

Radiofrequency-ablation of unresectable primary and secondary liver tumors: results in 88 patients

Radiofrequency-ablation (RFA) is increasingly used for destruction of unresectable primary and secondary liver tumors. We report our experience in the use of RFA for the management of unresectable hepatic malignancies. Between February 2000 and December 2004 we have undertaken 120 RFA procedures to ablate 426 unresectable primary or metastatic liver tumors in 88 patients. RFA was performed via laparotomy (n=68), laparoscopy (n=9) or a percutaneous approach (n=43). Primary liver cancer was treated in seven patients (8%) and metastatic liver tumors were treated in 81 patients (92%). All patients were followed to assess complications, treatment response and recurrence of malignant disease. Procedure-related complication rate was low (3.4%). During a mean follow-up of 21.2 months, 15 patients had local tumor progression (17%), 21 patients (23.9%) had new malignant disease and 27 patients (30.7%) died from intervention-unrelated complications of their malignant disease. Additional liver lesions were identified in 27 (35%) of 77 cases by intraoperative ultrasound. Thirty-six patients received simultaneous resection and RFA. RFA is a safe, well-tolerated and effective treatment for patients with unresectable primary and secondary liver malignancies.

Restorative rectal resection: an audit of 220 cases.

Two hundred and twenty consecutive, unselected cases of restorative rectal resection are reported. The operative mortality was 8.3 per cent; 3.5 per cent in patients less than 70 years old and 13 per cent over that age. Leakage at the colorectal suture line was an intractable problem, uninfluenced by anastomotic technique, but the introduction of antimicrobial prophylaxis as a routine was followed by a statistically significant reduction in the leak rate. Postoperative rectal function was satisfactory but temporary stenosis at the suture line was not uncommon. In only one case was it permanent, requiring regular dilatation. Recurrence of malignant disease occurred in 50 per cent of cases followed for at least 2 years; 35 per cent general disease, 15 per cent localized to the pelvis. These figures do not differ significantly from those following total rectal excision, which is now necessary in only 1 in 10 cases where the growth lies within 10 cm of the anus.

Long-term survival and late graft loss in pediatric liver transplant recipients--a 15-year single-center experience.

Increasing numbers of children undergo successful liver transplantation. Limited data exist on long-term survival and late graft loss. Survival and graft loss were studied in 376 primary liver graft recipients who survived more than 3 months after transplantation (80.5% of all primary graft recipients). Patient records were reviewed retrospectively for causes of graft loss. Risk factors were identified by analyzing graft, recipient, and posttransplant variables using multivariate Cox regression. One-, 5-, and 10-year actuarial graft survival rates in the study population were 94.6%, 87.3%, and 86.3%, respectively. Corresponding patient survival rates were 95.7%, 91.4%, and 90.4%. Forty-seven (12.5%) grafts were lost subsequently, 15 by patient death with preserved graft function. Survival rate after late retransplantation was 63.3%. Causes of late graft loss were infection (21.2%), posttransplant lymphoproliferative disease (PTLD, 21.2%), chronic rejection (17%), biliary complications (14.8%), and recurrence of malignant disease (8.5%). Independent risk factors for late graft loss and patient death included liver malignancy as primary disease, steroid resistant rejection, and PTLD. Graft loss rate was significantly increased for reduced-size grafts. Patients undergoing transplantation after 1991 and recipients of full-size grafts were more likely to survive. In conclusion, the long-term outcome for pediatric primary liver graft recipients surviving the early postoperative period is excellent except for patients with liver malignancy. There is no increased risk of late graft loss with the use of split or living related donor grafts. Technical complications are only a minor factor in late graft loss, but complications related to immunosuppression and infection remain a major hazard and must be addressed.