Low-grade endometrial stromal sarcoma with inferior vena cava tumor thrombus and intracardiac extension: radical resection may improve recurrence free survival

BACKGROUND: Endometrial stromal sarcoma (ESS) represents 0.2% of all uterine malignancies. Based on the mitotic activity, a distinction is made between low and high-grade ESS. Although the overall five-year survival rate for low-grade ESS exceeds 80%, about 50% of the patients show tumor recurrence, mostly after a long latency period. Tumor invasion of the great vessels is extremely rare. We describe a patient with advanced low-grade ESS with tumor invasion of the infrarenal aorta and the inferior vena cava. The patient presented with a large tumor thrombus extending from the inferior vena cava into the right atrium. METHODS: Review of literature and identification of 19 patients, including our own case report, with advanced low-grade ESS with invasion of the great vessels and formation of an inferior vena cava tumor thrombus. RESULTS: All 19 patients presented with an abdominal tumor mass and a tumor thrombus protruding into the inferior vena cava. The tumor thrombus extended into the right heart cavities in nine patients reaching the right atrium in four, the right ventricle in three and the pulmonary artery in two patients. There were 5 patients with an advanced primary tumor and 14 patients with an advanced recurrent tumor. Seven patients presented with synchronous metastatic disease and six patients with a pelvic tumor infiltrating the bladder, the rectosigmoid colon or the infrarenal aorta. Mean age at surgery was 45.9+/-12.3 years (median 47, range 25-65 years). Tumor thrombectomy was accomplished by cavatomy or by right atriotomy after installation of a cardiopulmonary bypass. There was no peri-operative mortality and a very low morbidity. Radical tumor resections were achieved in 10 patients. The follow-up for these 10 patients was 2+/-1.3 years (median 2, range 0.3-4.5 years). Nine patients remained recurrence free whereas one patient suffered an asymptomatic local recurrence. CONCLUSIONS: Low-grade ESS is a rare angioinvasive tumor with a high recurrence rate. Resection of an inferior vena cava tumor thrombus, even with extension into the right heart cavities, can be performed safely. Extensive radical surgery is therefore justified in the treatment of advanced tumor manifestations of a low-grade ESS potentially improving recurrence free survival.

[Tumor surveillance after resection of colorectal cancer]

Because recurrent adenocarcinoma of the colon and rectum (CRC) can still be treated with acceptable 5-year survival rates, tumor surveillance plays an important role. Early detection of recurrent disease from CRC allows for effective treatment with intention for cure. This is why, in 2007, an interdisciplinary group modified the popular "FAGAS" criteria, a proposition for surveillance after curative resection of colorectal cancer. Proposed are the 3-monthly follow-up of the tumor marker CEA (carcino embryonic antigen), which, in case of lower sigmoid or rectal cancer, would be completed by rectosigmoidoscopy and endosonography every 6 months. As a major change liver sonography is now proposed to be replaced by annual thoraco-abdominal CT scan. Colonoscopy within the first year after resection has its place in the surveillance due to a high rate of metachronous secondary tumors missed in the initial endoscopy. Once completed it needs not to be repeated for at least 3 years. Only in cases where early stage CRC was been completely resected no schematic surveillance must take place.

Survival in surgically treated, nodal positive prostate cancer patients is predicted by histopathological characteristics of the primary tumor and its lymph node metastases

BACKGROUND: Histopathological risk factors for survival stratification of surgically treated nodal positive prostate cancer patients are poorly defined as reflected by only one category for nodal metastases. METHODS: We evaluated biochemical recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in 102 nodal positive, hormone treatment-naïve prostate cancer patients (median age: 65 years, range: 45-75 years; median follow-up 7.7 years, range: 1.0-15.9 years) who underwent radical prostatectomy and standardized extended lymphadenectomy. RESULTS: A significant stratification was possible, with the Gleason score of the primary and virtually all nodal parameters favoring patients with better differentiated primaries and metastases, lower nodal tumor burden, and without extranodal extension of metastases. In multivariate analyses, diameter of the largest metastasis (< or =10 mm vs. >10 mm) was the strongest independent predictor for RFS (P < 0.001), DSS (P < 0.001), and OS (P < 0.001) with a more than quadrupled relative risk of cancer related deaths for patients with larger metastases (Hazard ratio: 4.2, Confidence interval: 2.0-8.9; 5-year RFS/DSS/OS: 18%/57%/54%). The highest 5-year survival rates were seen in patients with micrometastases only (RFS/DSS/OS: 47%/94%/94%). CONCLUSION: The TNM classification's current allocation of only one category for nodal metastases in prostate cancers is unsatisfactory since subgroups with significantly different prognoses can be identified. The diameter of the patient's largest metastasis (< or =10 mm vs. >10 mm) should be used for substaging because of its independent prognostic value. The substage "micrometastasis only" is also useful in nodal positive prostate cancer since it designates the subgroup with the most favorable outcome.

Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression

Chronic myeloid leukemia (CML) is a malignant myeloproliferative disease with a characteristic chronic phase (cp) of several years before progression to blast crisis (bc). The immune system may contribute to disease control in CML. We analyzed leukemia-specific immune responses in cpCML and bcCML in a retroviral-induced murine CML model. In the presence of cpCML and bcCML expressing the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen, leukemia-specific cytotoxic T lymphocytes (CTLs) became exhausted. They maintained only limited cytotoxic activity, and did not produce interferon-gamma or tumor necrosis factor-alpha or expand after restimulation. CML-specific CTLs were characterized by high expression of programmed death 1 (PD-1), whereas CML cells expressed PD-ligand 1 (PD-L1). Blocking the PD-1/PD-L1 interaction by generating bcCML in PD-1-deficient mice or by repetitive administration of alphaPD-L1 antibody prolonged survival. In addition, we found that PD-1 is up-regulated on CD8(+) T cells from CML patients. Taken together, our results suggest that blocking the PD-1/PD-L1 interaction may restore the function of CML-specific CTLs and may represent a novel therapeutic approach for CML.

A shift from oral to intravenous iron supplementation therapy is observed over time in a large swiss cohort of patients with inflammatory bowel disease

BACKGROUND In 2007, leading international experts in the field of inflammatory bowel disease (IBD) recommended intravenous (IV) iron supplements over oral (PO) ones because of superior effectiveness and better tolerance. We aimed to determine the percentage of patients with IBD undergoing iron therapy and to assess the dynamics of iron prescription habits (IV versus PO). METHODS We analyzed anonymized data on patients with Crohn's disease and ulcerative colitis extracted from the Helsana database. Helsana is a Swiss health insurance company providing coverage for 18% of the Swiss population (1.2 million individuals). RESULTS In total, 629 patients with Crohn's disease (61% female) and 398 patients with ulcerative colitis (57% female) were identified; mean observation time was 31.8 months for Crohn's disease and 31.0 months for ulcerative colitis patients. Of all patients with IBD, 27.1% were prescribed iron (21.1% in males; 31.1% in females). Patients treated with steroids, immunomodulators, and/or anti-tumor necrosis factor drugs were more frequently treated with iron supplements when compared with those not treated with any medications (35.0% versus 20.9%, odds ratio, 1.94; P < 0.001). The frequency of IV iron prescriptions increased significantly from 2006 to 2009 for both genders (males: from 2.6% to 10.1%, odds ratio = 3.84, P < 0.001; females: from 5.3% to 12.1%, odds ratio = 2.26, P = 0.002), whereas the percentage of PO iron prescriptions did not change. CONCLUSIONS Twenty-seven percent of patients with IBD were treated with iron supplements. Iron supplements administered IV were prescribed more frequently over time. These prescription habits are consistent with the implementation of guidelines on the management of iron deficiency in IBD.

Patients with oral tumors. Part 1: Prosthetic rehabilitation following tumor resection. Resection prosthetics: surgery, implants and prosthetic treatment

The present study reports on the surgical and prosthodontic rehabilitation of 46 patients, 31 male and 15 female, after resection of oral tumors. The treatment was carried out from 2004 to 2007 at the Department of Prosthodontics, University of Bern, with a follow-up time of 3 to 6 years. The average age at diagnosis was 54 years. 76% of all tumors were squamous cell carcinoma, followed by adenocarcinoma. Resection of the tumors including soft and/or hard tissues was performed in all patients. 80% of them additionally underwent radiotherapy and 40% chemotherapy. A full block resection of the mandible was perfomed in 23 patients, and in 10 patients, the tumor resection resulted in an oronasal communication. 29 patients underwent grafting procedures, mostly consisting of a free fibula flap transplant. To enhance the prosthetic treatment outcome and improve the prosthesis stability, a total of 114 implants were placed. However, 14 implants were not loaded because they failed during the healing period or the patient could not complete the final treatment with the prostheses. The survival rate of the implants reached 84.2% after 4 to 5 years. Many patients were only partially dentate before the tumors were detected, and further teeth had to be extracted in the course of the tumor therapy. Altogether, 31 jaws became or remained edentulous. Implants provide stability and may facilitate the adaptation to the denture, but their survival rate was compromised. Mostly, patients were fitted with removable prostheses with obturators in the maxilla and implant-supported complete dentures with bars in the mandible. Although sequelae of tumor resection are similar in many patients, the individual intermaxillary relations, facial morphology and functional capacity vary significantly. Thus, individual management is required for prosthetic rehabilitation.

Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naive prostate cancer and are elevated in castration-resistant disease

Patients with advanced prostate cancer (PC) are usually treated with androgen withdrawal. While this therapy is initially effective, nearly all PCs become refractory to it. As hormone receptors play a crucial role in this process, we constructed a tissue microarray consisting of PC samples from 107 hormone-naïve (HN) and 101 castration-resistant (CR) PC patients and analyzed the androgen receptor (AR) gene copy number and the protein expression profiles of AR, Serin210-phosphorylated AR (pAR(210)), estrogen receptor (ER)β, ERα and the proliferation marker Ki67. The amplification of the AR gene was virtually restricted to CR PC and was significantly associated with increased AR protein expression (P<0.0001) and higher tumor cell proliferation (P=0.001). Strong AR expression was observed in a subgroup of HN PC patients with an adverse prognosis. In contrast, the absence of AR expression in CR PC was significantly associated with a poor overall survival. While pAR(210) was predominantly found in CR PC patients (P<0.0001), pAR(210) positivity was observed in a subgroup of HN PC patients with a poor survival (P<0.05). Epithelial ERα expression was restricted to CR PC cells (9%). ERβ protein expression was found in 38% of both HN and CR PCs, but was elevated in matched CR PC specimens. Similar to pAR(210), the presence of ERβ in HN patients was significantly associated with an adverse prognosis (P<0.005). Our results strongly suggest a major role for pAR(210) and ERβ in HN PC. The expression of these markers might be directly involved in CR tumor growth.

Multidrug resistance protein 4 (MRP4) expression in prostate cancer is associated with androgen signaling and decreases with tumor progression

Multidrug resistance protein 4 (MRP4) is a transmembrane transport protein found in many cell types and is involved in substrate-specific transport of endogenous and exogenous substrates. Recently, it has shown to be expressed in prostate cancer cell lines and to be among the most commonly upregulated transcripts in prostate cancer, although a comprehensive expression analysis is lacking so far. We aimed to investigate its expression by immunohistochemistry in a larger cohort of neoplastic and nonneoplastic prostate tissues (n = 441) and to correlate its expression with clinicopathological parameters including PSA-free survival times and molecular correlates of androgen signaling (androgen receptor (AR), prostate-specific antigen (PSA), and forkhead box A (FoxA)). MRP4 is widely expressed in benign and neoplastic prostate epithelia, but its expression gradually decreases during tumor progression towards castrate-resistant disease. Concordantly, it correlated with conventional prognosticators of disease progression and-within the group of androgen-dependent tumors-with AR and FoxA expression. Moreover, lower levels of MRP4 expression were associated with shorter PSA relapse-free survival times in the androgen-dependent group. In benign tissues, we found zone-dependent differences of MRP4 expression, with the highest levels in the peripheral and central zones. Although MRP4 is known to be regulated in prostate cancer, this study is the first to demonstrate a gradual downregulation of MRP4 protein during malignant tumor progression and a prognostic value of this loss of expression.

Role of Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma: Is Tumor Budding the Missing Link?

Pancreatic ductal adenocarcinoma (PDAC) ranks as the fourth commonest cause of cancer death while its incidence is increasing worldwide. For all stages, survival at 5 years is<5%. The lethal nature of pancreatic cancer is attributed to its high metastatic potential to the lymphatic system and distant organs. Lack of effective therapeutic options contributes to the high mortality rates of PDAC. Recent evidence suggests that epithelial-mesenchymal transition (EMT) plays an important role to the disease progression and development of drug resistance in PDAC. Tumor budding is thought to reflect the process of EMT which allows neoplastic epithelial cells to acquire a mesenchymal phenotype thus increasing their capacity for migration and invasion and help them become resistant to apoptotic signals. In a recent study by our own group the presence and prognostic significance of tumor budding in PDAC were investigated and an association between high-grade budding and aggressive clinicopathological features of the tumors as well as worse outcome of the patients was found. The identification of EMT phenotypic targets may help identifying new molecules so that future therapeutic strategies directed specifically against them could potentially have an impact on drug resistance and invasiveness and hence improve the prognosis of PDAC patients. The aim of this short review is to present an insight on the morphological and molecular aspects of EMT and on the factors that are involved in the induction of EMT in PDAC.

Efficacy and Safety of Natalizumab in Crohn’s Disease Patients Treated at 6 Boston Academic Hospitals

BACKGROUND: Despite trials demonstrating its efficacy, many physicians harbor concerns regarding the use of natalizumab in the treatment of patients with refractory Crohn's disease (CD). The purpose of this study was to perform a descriptive analysis of a series of CD patients not currently enrolled in a clinical trial. METHODS: A retrospective case review of patients treated with natalizumab at 6 sites in Massachusetts: Boston Medical Center, Beth Israel Deaconess Medical Center, Brigham & Women's Hospital, Lahey Clinic, Massachusetts General Hospital, and UMass Medical Center. RESULTS: Data on 69 CD patients on natalizumab were collected. At the start of treatment, patients' disease duration was 12 years. A high proportion of patients were women (68%), presented with perianal disease (65%) and upper gastrointestinal tract involvement (14%). Prior nonbiologic therapies were steroids (96%), thiopurines (94%), antibiotics (74%), methotrexate (58%), and at least two anti-tumor necrosis factor agent failures (81%). Sixty-nine percent (44 of 64 patients) with available medical evaluation had a partial or complete clinical response. Loss of response was 13% after an average of 1 year of treatment. Adverse events were infusion reactions, headaches, fever, and infections. No case of progressive multifocal leukoencephalopathy was observed. CONCLUSIONS: In our clinical experience outside the context of a clinical trial, natalizumab is largely reserved for CD patients with extensive ileocolonic disease who have failed conventional immunosuppressants and of at least 2 anti-tumor necrosis factor agents. This drug is, however, well tolerated and offers significant clinical improvement for more than a year in one-third of these difficult-to-treat CD patients.

Cancer intelligence acquired (CIA): tumor glycosylation and sialylation codes dismantling antitumor defense

Aberrant glycosylation is a key feature of malignant transformation and reflects epigenetic and genetic anomalies among the multitude of molecules involved in glycan biosynthesis. Although glycan biosynthesis is not template bound, altered tumor glycosylation is not random, but associated with common glycosylation patterns. Evidence suggests that acquisition of distinct glycosylation patterns evolves from a ‘microevolutionary’ process conferring advantages in terms of tumor growth, tumor dissemination, and immune escape. Such glycosylation modifications also involve xeno- and hypersialylation. Xeno-autoantigens such as Neu5Gc-gangliosides provide potential targets for immunotherapy. Hypersialylation may display ‘enhanced self’ to escape immunosurveillance and involves several not mutually exclusive inhibitory pathways that all rely on protein–glycan interactions. A better understanding of tumor ‘glycan codes’ as deciphered by lectins, such as siglecs, selectins, C-type lectins and galectins, may lead to novel treatment strategies, not only in cancer, but also in autoimmune disease or transplantation.

Tumor budding in upper gastrointestinal carcinomas.

The basis of personalized medicine in oncology is the prediction of an individual's risk of relapse and death from disease. The presence of tumor budding (TB) at the tumor-host interface of gastrointestinal cancers has been recognized as a hallmark of unfavorable disease biology. TB is defined as the presence of dedifferentiated cells or small clusters of up to five cells at the tumor invasive front and can be observed in aggressive carcinomas of the esophagus, stomach, pancreas, ampulla, colon, and rectum. Presence of TB reproducibly correlates with advanced tumor stage, frequent lymphovascular invasion, nodal, and distant metastasis. The UICC has officially recognized TB as additional independent prognostic factor in cancers of the colon and rectum. Recent studies have also characterized TB as a promising prognostic indicator for clinical management of esophageal squamous cell carcinoma, adenocarcinoma of the gastro-esophageal junction, and gastric adenocarcinoma. However, several important issues have to be addressed for application in daily diagnostic practice: (1) validation of prognostic scoring systems for TB in large, multi-center studies, (2) consensus on the optimal assessment method, and (3) inter-observer reproducibility. This review provides a comprehensive analysis of TB in cancers of the upper gastrointestinal tract including critical appraisal of perspectives for further study.

The tumor border configuration of colorectal cancer as a histomorphological prognostic indicator.

Histomorphological features of colorectal cancers (CRC) represent valuable prognostic indicators for clinical decision making. The invasive margin is a central feature for prognostication shaped by the complex processes governing tumor-host interaction. Assessment of the tumor border can be performed on standard paraffin sections and shows promise for integration into the diagnostic routine of gastrointestinal pathology. In aggressive CRC, an extensive dissection of host tissue is seen with loss of a clear tumor-host interface. This pattern, termed "infiltrative tumor border configuration" has been consistently associated with poor survival outcome and early disease recurrence of CRC-patients. In addition, infiltrative tumor growth is frequently associated with presence of adverse clinicopathological features and molecular alterations related to aggressive tumor behavior including BRAFV600 mutation. In contrast, a well-demarcated "pushing" tumor border is seen frequently in CRC-cases with low risk for nodal and distant metastasis. A pushing border is a feature frequently associated with mismatch-repair deficiency and can be used to identify patients for molecular testing. Consequently, assessment of the tumor border configuration as an additional prognostic factor is recommended by the AJCC/UICC to aid the TNM-classification. To promote the assessment of the tumor border configuration in standard practice, consensus criteria on the defining features and method of assessment need to be developed further and tested for inter-observer reproducibility. The development of a standardized quantitative scoring system may lay the basis for verification of the prognostic associations of the tumor growth pattern in multivariate analyses and clinical trials. This article provides a comprehensive review of the diagnostic features, clinicopathological associations, and molecular alterations associated with the tumor border configuration in early stage and advanced CRC.

Impact of synchronous metastasis distribution on cancer specific survival in renal cell carcinoma after radical nephrectomy with tumor thrombectomy

PURPOSE Metastatic renal cell carcinoma can be clinically diverse in terms of the pattern of metastatic disease and response to treatment. We studied the impact of metastasis and location on cancer specific survival. MATERIALS AND METHODS The records of 2,017 patients with renal cell cancer and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 centers in the United States and Europe were analyzed. Number and location of synchronous metastases were compared with respect to patient cancer specific survival. Multivariable Cox regression models were used to quantify the impact of covariates. RESULTS Lymph node metastasis (155) or distant metastasis (725) was present in 880 (44%) patients. Of the patients with distant disease 385 (53%) had an isolated metastasis. The 5-year cancer specific survival was 51.3% (95% CI 48.6-53.9) for the entire group. On univariable analysis patients with isolated lymph node metastasis had a significantly worse cancer specific survival than those with a solitary distant metastasis. The location of distant metastasis did not have any significant effect on cancer specific survival. On multivariable analysis the presence of lymph node metastasis, isolated distant metastasis and multiple distant metastases were independently associated with cancer specific survival. Moreover higher tumor thrombus level, papillary histology and the use of postoperative systemic therapy were independently associated with worse cancer specific survival. CONCLUSIONS In our multi-institutional series of patients with renal cell cancer who underwent radical nephrectomy and tumor thrombectomy, almost half of the patients had synchronous lymph node or distant organ metastasis. Survival was superior in patients with solitary distant metastasis compared to isolated lymph node disease.

Treatment with tumor necrosis factor inhibitors in axial spondyloarthritis: comparison between private rheumatology practices and academic centers in a large observational cohort

OBJECTIVE To evaluate the initiation of and response to tumor necrosis factor (TNF) inhibitors for axial spondyloarthritis (axSpA) in private rheumatology practices versus academic centers. METHODS We compared newly initiated TNF inhibition for axSpA in 363 patients enrolled in private practices with 100 patients recruited in 6 university hospitals within the Swiss Clinical Quality Management (SCQM) cohort. RESULTS All patients had been treated with ≥ 1 nonsteroidal antiinflammatory drug and > 70% of patients had a baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 before anti-TNF agent initiation. The proportion of patients with nonradiographic axSpA (nr-axSpA) treated with TNF inhibitors was higher in hospitals versus private practices (30.4% vs 18.7%, p = 0.02). The burden of disease as assessed by patient-reported outcomes at baseline was slightly higher in the hospital setting. Mean levels (± SD) of the Ankylosing Spondylitis Disease Activity Score were, however, virtually identical in private practices and academic centers (3.4 ± 1.0 vs 3.4 ± 0.9, p = 0.68). An Assessment of SpondyloArthritis international Society (ASAS40) response at 1 year was reached for ankylosing spondylitis in 51.7% in private practices and 52.9% in university hospitals (p = 1.0) and for nr-axSpA in 27.5% versus 25.0%, respectively (p = 1.0). CONCLUSION With the exception of a lower proportion of patients with nr-axSpA newly treated with anti-TNF agents in private practices in comparison to academic centers, adherence to ASAS treatment recommendations for TNF inhibition was equally high, and similar response rates to TNF blockers were achieved in both clinical settings.