Intravascular administration of tumor tropic neural progenitor cells permits targeted delivery of interferon-beta and restricts tumor growth in a murine model of disseminated neuroblastoma

Background

Interferon-β (IFN-β) has potent antitumor activity; however, systemic toxicity has limited its clinical use. We investigated the potential of targeted delivery using tumor-tropic neural progenitor cells (NPCs) transduced to express human IFN-β (hIFN-β).

Methods

Disseminated neuroblastoma was established in SCID mice by tail vein injection of tumor cells. Fourteen days after tumor cell inoculation, systemic disease was confirmed with bioluminescence imaging (BLI). Mice were then treated by intravenous injection of human F3.C1 NPCs that had been transduced with a replication deficient adenovirus to overexpress hIFN-β (F3-IFN-β). Two injections were given: the first at 14 days and the second at 28 days following tumor cell injection. Control mice received NPCs transduced with empty vector adenovirus at the same time points. Progression of disease was monitored using BLI. At sacrifice, organ weights and histology further evaluated tumor burden.

Results

After initiation of therapy, BLI demonstrated a significant decrease in the rate of disease progression in mice receiving F3-IFN-β. At necropsy, control mice had bulky tumor replacing the liver and kidneys, as well as extensive retroperitoneal and mediastinal adenopathy. Impressively, these sites within mice receiving F3-IFN-β therapy appeared grossly normal with the exception of small nodules within the kidneys of some of the F3-IFN-β-treated mice. The accumulation of F3.C1 cells within sites of tumor growth was confirmed by fluorescence imaging. Importantly, systemic levels of hIFN-β in the treated mice remained below detectable levels.

Conclusions

These data indicate that in this model of disseminated neuroblastoma, the tumor-tropic property of F3.C1 NPCs was exploited to target delivery of IFN-β to disseminated tissue foci, resulting in significant tumor growth delay. The described novel approach for effective IFN-β therapy may circumvent limitations associated with the systemic toxicity of IFN-β.     

In vivo serial selection of human pancreatic cancer cells in orthotopic mouse models produces high metastatic variants irrespective of Kras status

Introduction

Kras mutations have been thought to play an important role in pancreatic cancer progression. In this study, we evaluated how serially passaging primary pancreatic tumors with and without Kras mutations, in nude mice, can generate more aggressive variants of human pancreatic cancer.

Materials & methods

Orthotopic mouse models of human pancreatic cancer were established by injecting 1 × 10⁶ cells of the Kras wildtype BxPC-3 cell line, expressing red fluorescent protein or the Kras mutant Panc-1 cell line expressing green fluorescent protein, into the pancreas. Pancreatic tumors were harvested from premorbid mice to establish cell lines. One million passaged cells were then orthotopically injected into another set of mice. Serial passaging continued until decreasing lifespan of the implanted mice stabilized, which occurred by six passages. Mice harboring serially-passaged cell lines were followed with weekly imaging.

Results

Serially passaging generated more aggressive variants of both human pancreatic cancer cell lines, one of which was Kras wild-type (BXPC-3) and the other Kras mutant, Panc-1, which displayed faster tumor growth and shortened survival time. Overall survival decreased from 18 wk in mice with the parental cell line (passage 0) tumor to ∼6 wk in mice by passage 6. Average time to metastasis was shortened from 14 wk to ∼3 wk or less. At termination, mice with the passaged tumor demonstrated a greater extent of distant metastasis.

Conclusions

Serial passaging of tumor creates more aggressive variants of human pancreatic cancer cell lines regardless of Kras mutation. The aggressive variants can be used to study the molecular basis of highly malignant pancreatic cancer and to screen for effective agents against this disease.     

Intrahepatic Segmental Portal Vein Thrombosis After Living-Related Donor Liver Transplantation

Background

Intrahepatic segmental portal vein thrombosis after living-related liver transplantation (LRLT) is uncommon. The cause remains unclear.

Methods

After providing written informed consent, 25 recipients receiving LRLT at our institution from January 2011 to September 2013 were enrolled in this study. We performed triphase computerized tomographic (CT) study of the liver graft of each recipient 1 month after LRLT. The patencies of hepatic artery, portal vein, and hepatic vein were evaluated in detail. The triphase CT scans of the liver of each donor before transplantation also were reviewed. Thrombosis of the intrahepatic segmental portal vein was defined as the occlusion site of the portal vein being intrahepatic. Extrahepatic portal vein thrombosis was excluded in this study.

Results

Among the 25 patients, 2 (8%) developed thrombosis of intrahepatic segmental portal vein. One 47-year-old man received LRLT for hepatitis B viral infection–related liver cirrhosis (Child-Pugh class C) with 3 hepatocellular carcinomas (total tumor volume <8 cm). Another 53-year-old man received LRLT for alcoholic liver cirrhosis (Child-Pugh class C). Both had developed progressive jaundice and cholangitis 1 month after surgery. Intrahepatic biliary stricture was found on the follow-up magnetic resonance images. However, liver triphase CT study demonstrated occlusion of intrahepatic portal vein of segment 8 in each patient. Radiologic interventions and balloon dilatation therapy via percutaneous transhepatic biliary drainage route improved the symptoms and signs of cholangitis and obstructive jaundice for both.

Conclusions

Thrombosis of intrahepatic segmental portal vein is not common but is usually associated with complications of intrahepatic bile duct. Early detection is important, and follow-up CT study of liver is suggested.     

Depressive burden is associated with a poorer surgical outcome among lumbar spinal stenosis patients: a 5-year follow-up study

Background context

In lumbar spinal stenosis (LSS), conservative treatment is usually the first choice of treatment. If conservative treatment fails, surgery is indicated. Psychological factors such as depression and anxiety are known to affect the outcome of surgery. Previous studies on depression and surgery outcome using long follow-up times are scarce.

Purpose

The purpose of this study was to investigate the effect of depressive symptoms on the surgical outcome during a 5-year follow-up among patients with LSS.

Study design

A prospective observational study.

Patient sample

Patient sample included 102 LSS patients who needed surgical treatment.

Outcome measures

The outcome of surgery was evaluated with the Oswestry Disability Index (ODI), visual analog scale pain assessment, and self-reported walking capacity.

Methods

The patients completed a set of questionnaires preoperatively and 3 and 6 months, as well as 1, 2, and 5 years after the surgery. Depressive symptoms were assessed with the Beck Depression Inventory. The depressive burden was estimated by summing all individual Beck Depression Inventory scores. Statistical analyses included cross-sectional group comparisons and linear regression analyses. No conflicts of interest.

Results

On 5-year follow-up, a high depressive burden associated with a poorer outcome of surgery when assessed with the ODI. In linear regression analysis, a high depressive burden associated with higher ODI score.

Conclusions

Even slightly elevated long-term depressive symptoms in LSS patients are associated with an increased risk of a poorer functional ability after decompressive surgery.     

Intrahepatic portal venous systems in children with noncirrhotic prehepatic portal hypertension: Anatomy and clinical relevance

Background

Children with extrahepatic portal hypertension typically present with cavernomatous transformation of the portal vein and a poorly defined intrahepatic portal vein system on conventional imaging. With the Meso-Rex Bypass becoming the gold-standard intervention for a cure, a precise assessment of the intrahepatic portal vein system provides helpful data for deciding whether a Meso-Rex Bypass is feasible or not.

Methods

All children with extrahepatic portal hypertension were prospectively assessed by wedged hepatic venous portography. Venous anatomy was categorized into five subtypes (A to E), depending on the presence of thrombosis in the Rex recessus, or not, and its extension within the intrahepatic portal venous system.

Results

Eighty-nine children entered the study. Previous umbilical vein catheterization is usually associated with Rex thrombosis, while the Rex recessus and the intrahepatic portal venous system are patent in idiopathic cases, thus allowing for the performance of a Meso-Rex Bypass with a good outcome.

Conclusions

Wedged hepatic venous portography is a very effective tool for detailed preoperative assessment and identification of children being considered for Meso-Rex Bypass surgery. An anatomic–radiological classification is useful in selecting patients for Meso-Rex Bypass with anticipation of a high rate of success.     

Renal Tumor Contact Surface Area: A Novel Parameter for Predicting Complexity and Outcomes of Partial Nephrectomy

Background

The contact surface area (CSA) of a tumor with adjacent renal parenchyma may determine the complexity and thus the perioperative outcomes of partial nephrectomy (PN).

Objective

We devised a novel imaging parameter, renal tumor CSA, and correlate it with perioperative outcomes in patients undergoing PN.

Design, setting, and participants

Of 200 patients undergoing PN for a tumor (January 2010 to August 2011), 162 had renal protocol computed tomography scanning data available. CSA was calculated using image-rendering software (Synapse 3D, Fujifilm), and interobserver variability was determined between three independent observers.

Outcome measurements and statistical analysis

CSA was correlated to baseline demographics and perioperative outcomes as a continuous and categorical variable using multivariable logistic regression analysis. The ability of CSA to predict adverse perioperative events was compared with demographic factors and nephrometry scoring systems.

Results and limitations

The mean tumor size was 3.1 cm; CSA was 18.3 cm². CSA ≥20 cm² correlated with adverse tumor characteristics (greater tumor size, volume, and complexity) and perioperative outcomes (more parenchymal volume loss, blood loss, and complications) compared with CSA <20 cm². On multivariable logistic regression, CSA independently predicted operative time, complications, hospital stay, and renal functional outcomes. This predictive ability of CSA was superior to the other parameters evaluated.

Conclusions

CSA is a novel imaging parameter that quantifies the CSA of renal tumor with adjacent parenchyma. Our preliminary data indicate that CSA correlates with PN outcomes. If validated externally in a larger cohort, CSA could be incorporated into future versions of nephrometry scoring systems.

Patient summary

In this study we outline the method of calculating the contact surface area (CSA) of renal tumors with the surrounding normal kidney using image-rendering software. We found that CSA correlates with a number of important surgical outcomes including operative time, loss of renal function, and complications.     

Preoperative imaging does not predict intrahepatic involvement in choledochal cysts

Introduction

Choledochal cyst (CDC) is a congenital malformation of the bile ducts, which can include the intrahepatic or extrahepatic bile ducts. We hypothesize that preoperative intrahepatic ductal dilation is not predictive of postoperative intrahepatic involvement.

Methods

We retrospectively reviewed all cases of CDC in children diagnosed at a single institution between 1991 and 2013.

Results

Sixty-two patients were diagnosed with CDC during the study period with a median follow-up time of 2.25 (range 0–19.5) years. Forty-two patients (68%) were diagnosed with type I disease preoperatively, and 15 patients (24%) were diagnosed with type IV-A disease. The most common presenting symptoms included pain (34%), jaundice (28%), and pancreatitis (25%). There were no deaths or malignancies and only one postoperative stricture. Forty-two patients (68%) had intrahepatic ductal dilation preoperatively. Only four patients (9%) had intrahepatic ductal dilation following resection (P < 0.0001). In one patient, this dilation resolved following stricture revision. Of the four patients with postoperative dilation, two were diagnosed with type I disease, and the other two were diagnosed with type IV-A disease preoperatively.

Conclusion

Preoperative intrahepatic ductal dilation is not predictive of postoperative intrahepatic ductal involvement in children with CDC. The preoperative distinction between type I and IV disease is not helpful in treating these patients.     

Role of tumor-infiltrating CD11b antigen-presenting cells in the progression of gastric cancer

Background

Tumor-infiltrating antigen-presenting cells (APCs), involving tumor-associated macrophages and tumor-infiltrating dendritic cells, play an important role in tumor immunity and immune escape. The aim of this study was to determine whether tumor infiltrating CD11b⁺ APCs may affect tumor progression and clinical outcome.

Methods

The immunohistochemical analysis was used to evaluate the expression of CD11b, FOXP3, and CD8 in 214 gastric cancer tissues. Concentrations of immunosuppressive cytokines in medium conditioned by gastric cancer cells were measured by enzyme-linked immunosorbent assay. Effects of addition of tumor-conditioned media on CD11c⁺ cells were examined by flow cytometry.

Results

Almost all tumor-infiltrating CD11b⁺ cell expressed CD11c and was considered to be APCs. High CD11b⁺ cell infiltration was significantly correlated with huge tumor, positive venous invasion, lymph node metastasis, and tumor, node, metastasis stage. Patients with high CD11b⁺ cell infiltration had a poorer surgical outcome than those with low CD11b infiltration. Multivariate analysis revealed that CD11b⁺ cell infiltration was one of the independent prognostic factors. Tumor-conditioned medium obtained from several gastric cancer cell lines contained immunosuppressive cytokines, transforming growth factor-beta, interleukin-10, and vascular endothelial growth factor. The addition of tumor-conditioned medium decreased the expression of major histocompatibility complex-II and increased the expression of CD11b and programmed death ligand 2 on CD11c⁺ APCs. Infiltration of CD11b⁺ cells significantly correlate with the degree of FOXP3⁺ cell infiltration but not with CD8⁺ cell infiltration.

Conclusions

Tumor-infiltrating CD11b⁺ APCs affected local tumor cell-immune cell interactions and correlated to the poor prognosis of the patients with gastric cancer.     

Predicting Recurrence and Progression of Noninvasive Papillary Bladder Cancer at Initial Presentation Based on Quantitative Gene Expression Profiles

Background

Currently, tumor grade is the best predictor of outcome at first presentation of noninvasive papillary (Ta) bladder cancer. However, reliable predictors of Ta tumor recurrence and progression for individual patients, which could optimize treatment and follow-up schedules based on specific tumor biology, are yet to be identified.

Objective

To identify genes predictive for recurrence and progression in Ta bladder cancer at first presentation using a quantitative, pathway-specific approach.

Design, setting, and participants

Retrospective study of patients with Ta G2/3 bladder tumors at initial presentation with three distinct clinical outcomes: absence of recurrence (n = 16), recurrence without progression (n = 16), and progression to carcinoma in situ or invasive disease (n = 16).

Measurements

Expressions of 24 genes that feature in relevant pathways that are deregulated in bladder cancer were quantified by real-time polymerase chain reaction on tumor biopsies from the patients at initial presentation.

Results and limitations

CCND3 (p = 0.003) and HRAS (p = 0.01) were predictive for recurrence by univariate analysis. In a multivariable model based on CCND3 expression, sensitivity and specificity for recurrence were 97% and 63%, respectively. HRAS (p < 0.001), E2F1 (p = 0.017), BIRC5/Survivin (p = 0.038), and VEGFR2 (p = 0.047) were predictive for progression by univariate analysis. Multivariable analysis based on HRAS, VEGFR2, and VEGF identified progression with 81% sensitivity and 94% specificity. Since this is a small retrospective study using medium-throughput profiling, larger confirmatory studies are needed.

Conclusions

Gene expression profiling across relevant cancer pathways appears to be a promising approach for Ta bladder tumor outcome prediction at initial diagnosis. These results could help differentiate between patients who need aggressive versus expectant management.     

Development and characterization of clinically relevant tumor models from patients with renal cell carcinoma

Background

Animal models are instrumental in understanding disease pathophysiology and mechanisms of therapy action and resistance in vivo.

Objective

To establish and characterize a panel of mouse models of renal cell carcinoma (RCC) derived from patients undergoing radical nephrectomy.

Design, setting, and participants

In vivo and in vitro animal experiments.

Measurements

Tumor tissues obtained during surgery were implanted into the subcutaneous space of female BALB/c nude mice and serially passaged into new mice. Tumors were characterized by histology, short tandem repeat (STR) fingerprinting, von Hippel-Lindau (VHL) gene sequencing, and single nucleotide polymorphism (SNP) analysis. Tumor-bearing mice were treated with sunitinib or everolimus. Primary cell cultures were derived from patient tumors and transfected with a lentivirus carrying the luciferase gene. Four subcutaneous xenograft mouse models were developed, representing papillary type 1, papillary type 2, clear cell, and clear cell with sarcomatoid features RCC.

Results and limitations

RCC mouse models were established from four patients with distinct histologies of RCC. Tumor growth was dependent on histologic type, the size of the implanted tumor chip, and the passage number. Mouse tumors accurately represented their respective original patient tumors, as STR fingerprints were matching, histology was comparable, and SNP profiles and VHL mutation status were conserved with multiple passages. Bioluminescence imaging results were commensurate with subcutaneous xenograft growth patterns. Mice treated with sunitinib and everolimus exhibited an initial response, followed by a later stage of resistance to these agents, which mimics the clinical observations in patients with RCC.

Conclusions

We developed four mouse xenograft models of RCC with clear-cell and papillary histologies, with stable histologic and molecular characteristics. These models can be used to understand the basic biology of RCC as well as response and resistance to therapy.     

Use of in vivo bioluminescence imaging to predict hepatic tumor burden in mice

BACKGROUND: We used bioluminescence imaging (BLI) to validate serial assessment of neoplastic growth within the murine liver. We hypothesized that, in mice bearing luciferase-expressing liver metastases, bioluminescence would reflect neoplastic burden estimated by liver weight. MATERIALS AND METHODS: Murine colon carcinoma cells were infected with a retroviral vector encoding luciferase. Bioluminescence was measured in vitro, and in vivo following intrasplenic tumor cell inoculation into Balb/C mice. At varying time intervals, mice were imaged and immediately killed to determine correlation of in vivo and ex vivo BL with liver weight. To examine sensitivity in vivo, we performed direct intrahepatic inoculation. RESULTS: In vitro, photon emission correlated with increasing cell numbers. In the metastatic model, a statistically significant increase was depicted in both liver weight and bioluminescence 20 days after tumor inoculation compared with earlier time points (P < 0.0001). With progressively increasing tumor burden, however, a poor correlation between in vivo BL and liver weight was observed. When livers with very large tumors were excluded, R(2) = 0.90. In contrast, correlation between ex vivo BL and liver weight remained high throughout the study period (R(2) = 0.94). CONCLUSIONS: When imaging tumors at end-stages of disease, in vivo BL underestimates actual tumor burden. If context-specific limitations are recognized, however, BLI is a sensitive approach to temporal monitoring of tumor progression in preclinical models.     

Attenuated Salmonella typhimurium prevents the establishment of unresectable hepatic metastases and improves survival in a murine model

Purpose

The authors investigated the utility of attenuated Salmonella typhimurium for preventing the establishment of hepatic metastases in a murine model.

Methods

A single, oral 10⁸ cfu dose of attenuated S typhimurium was given 8 days before the establishment of a model of unresectable hepatic metastases. Animals were assessed for hepatic tumor number and volume, hepatic lymphocyte population analysis, and survival.

Results

Pretreatment with Salmonella provided a 10-fold reduction in hepatic tumor burden compared with saline-treated controls. The antitumor effect is associated with markedly elevated natural killer (NK), CD8+ and CD4+ hepatic lymphocytes. Pretreatment with Salmonella provided a 90-day survival rate of 30%, whereas control animals were dead by 30 days. All long-term survivors were devoid of hepatic tumor.

Conclusions

Attenuated S typhimurium effectively prevents the establishment of hepatic metastases in a murine model, providing a clear survival benefit. Thus, it may represent a novel form of in vivo immunotherapy for the prevention of hepatic metastases for patients with locally advanced colorectal cancer.     

Response to HER-2 Pulsed DC1 Vaccines is Predicted by Both HER-2 and Estrogen Receptor Expression in DCIS

Background

Patients with estrogen-independent (ER^neg) human epidermal growth factor receptor-2 (HER-2)-positive ductal carcinoma in situ (DCIS) treated with lumpectomy alone or lumpectomy and radiation are at increased risk of developing subsequent breast cancer events.

Methods

Thirty-eight patients with HER-2 expressing DCIS received a HER-2 pulsed autologous dendritic cell (DC1) vaccine administered over 4–6 weeks before surgical resection. HER-2 and estrogen receptor (ER) expression were determined by immunohistochemistry. In 35 patients, CD4^pos T-cell sensitization to HER-2 peptides was identified by ELISPOT. In 19 patients, CD8^pos T-cell responses were identified by ELISA. Clinical and immune responses postvaccination were compared between intermediate-expressing HER-2 (2+) and high-expressing HER-2 (3+) patients, as well as ER^neg and estrogen-dependent (ER^pos) patients.

Results

There was no significant difference in immune response after HER-2 vaccination in patients with HER-2 (2+) and (3+) tumors or ER^neg and ER^pos tumors. Complete tumor regression rates were similar in patients with HER-2 (2+) and (3+) DCIS. Overall, clinical response rates were similar in patients with ER^neg and ER^pos DCIS, but complete tumor regression was significantly more common in patients with ER^neg DCIS.

Conclusions

Despite equivalent immune responses after vaccination in patients with HER-2 (2+), HER-2 (3+), ER^neg and ER^pos DCIS, HER-2 pulsed DC1 induces more complete responses in patients with ER^neg DCIS. These data provide a rationale for developing vaccinations to reduce recurrence in patients with ER^neg DCIS for whom there are currently limited adjuvant options.     

Characteristics of fatal and hospital admissions for burns in Fiji: a population-based study (TRIP Project-2)

Background

Over 95% of burn deaths are estimated to occur in low-and-middle-income countries. However, the epidemiology of burn-related injuries in Pacific Island Countries is unclear. This study investigated the incidence and demographic characteristics associated with fatal and hospitalised burns in Fiji.

Methods

This cross-sectional study utilised the Fiji Injury Surveillance in Hospital database to estimate the population-based incidence and contextual characteristics associated with burns resulting in death or hospital admission (≥12 h) during a 12-month period commencing 1st October 2005.

Results

116 people were admitted to hospital or died as a result of burns during the study period accounting for an overall annual incidence of 17.8/100,000 population, and mortality rate of 3.4/100,000. Most (92.2%) burns occurred at home, and 85.3% were recorded as unintentional. Burns were disproportionately higher among Fijian children compared with Fijian–Indian children with the converse occurring in adulthood. In adults, Indian women were at particularly high risk of death from self-inflicted burns as a consequence of ‘conflict situations’.

Conclusion

Burns are a significant public health burden in Fiji requiring prevention and management strategies informed by important differences in the context of these injuries among the major ethic groups of the country.     

CSE1L modulates Ras-induced cancer cell invasion: correlation of K-Ras mutation and CSE1L expression in colorectal cancer progression

Background

Ras plays an important role in colorectal cancer progression. CSE1L (chromosome segregation 1-like) gene maps to 20q13, a chromosomal region that correlates with colorectal cancer development. We investigated the association of CSE1L with Ras in colorectal cancer progression.

Methods

The effect of CSE1L on metastasis-stimulating activity of Ras was studied in an animal model with tumor cells expressing CSE1L-specific shRNA and v-H-Ras. CSE1L expression was evaluated by the immunohistochemical analysis of 127 surgically resected colorectal tumors. K-Ras mutations were analyzed by direct sequencing.

Results

CSE1L knockdown reduced Ras-induced metastasis of B16F10 melanoma cells in C57BL/6 mice. v-H-Ras expression altered the cellular trafficking of CSE1L and increased CSE1L secretion. Most colorectal tumors were positive for CSE1L staining (98.4%, 125 of 127). Colorectal tumors with K-Ras mutation or high cytoplasmic CSE1L expression were correlated with T status (depth of tumor penetration; P = .004), stage (P = .004), and lymph node metastasis (P = .019).

Conclusions

CSE1L may be a target for treating Ras-associated tumors. Analysis of K-Ras mutation and CSE1L expression may provide valuable clinical and pathological information to aid in the determination of treatment options for colorectal cancer.     

A short-duration restrictive diet reduces visceral adiposity in the morbidly obese surgical patient

Background

This study aims to determine if visceral obesity can be reduced after a brief preoperative diet in obese patients.

Methods

Forty morbidly obese patients were placed on a 1,000 kCal per day diet for 14 days before bariatric surgery. Patients had weight measurements and an abdominal ultrasound performed on days 1 and 14. The ultrasound measured visceral obesity using the distance between the abdominal muscle and the aorta, the fat thickness of the perinephric space, and the distance between the abdominal muscle and splenic vein. Mesenteric fat burden was calculated and compared.

Results

Thirty-eight patients (95%) lost weight on the diet, with a mean loss of 5.2 lbs. Twenty-five patients (63%) had a reduction in mesenteric fat. The average visceral obesity lost was 7.76 cm³ or 3% of the visceral adiposity of the average obese patient (250 cm³).

Conclusions

A short preoperative calorie restricting diet is well tolerated and results in a reduction in visceral obesity.     

Limitations of somatostatin scintigraphy in primary small bowel neuroendocrine tumors

Background

Somatostatin receptor scintigraphy (SRS; octreoscan) is used in neuroendocrine tumors to locate the primary tumor site and delineate the extent of disease. SRS has decreased sensitivity for small bowel neuroendocrine tumors (SBNETs). The reasons for SRS nonlocalization are not clear. We sought to determine factors that correlate with successful primary tumor localization by SRS in patients with resected SBNETs, and also identify factors that confound interpretation of SRS reports.

Methods

Records of patients with resected SBNETs were reviewed for SRS results, tumor size, multifocality, N, and M status. Somatostatin receptor 2 (SSTR2) expression was analyzed in resected tumors by quantitative polymerase chain reaction. SRS reports were reviewed and categorized as localizing the primary tumor or not. A nuclear medicine physician independently reviewed available images.

Results

Of 37 patients with preoperative SRS, the primary tumor was localized in 37%. Of all the factors tested, only small tumor size correlated significantly with SRS nonlocalization. Overexpression of SSTR2 was not significantly different between tumors that were or were not localized by SRS, regardless of tumor size. There were three instances where the SRS report did not agree with the nuclear medicine physician's interpretation as to whether SRS localized the primary tumor. In each case, uptake in mesenteric nodes was a confounding factor.

Conclusions

SBNETs <2 cm are most likely to be missed by SRS. SSTR2 expression did not correlate with SRS nonlocalization of the primary tumor. Uptake in mesenteric nodes may help indicate an SBNET primary but can also interfere with its visualization within the small bowel.     

The extent of thermal injury affects fractions of mononuclear cells

Background

The mononuclear cell (MNC) fraction contains a variety of cell types, including stem cells such as endothelial progenitor cells (EPCs). EPC can rapidly revascularise ischaemic areas, but their role in burns is unclear.

Aim

This study investigates how thermal injury to the skin might influence mononuclear cells, CD34⁺ cells and circulating EPC.

Methods

The study group comprised 17 people with burns and 17 age-matched controls. Blood samples were collected at five different time points during the first 5 days of hospitalisation. Clinical parameters and scores were documented as well as cell counts for MNC, CD34⁺ cells and EPC. Counts were quantified by fluorescence-activated cell sorting. Serum was tested for vascular endothelial growth factor VEGF¹⁶⁵ by ELISA.

Results

All cell populations displayed significant, differing changes in counts and percentages after burn. These effects varied markedly over time and expressed different patterns if clinical scores were subjected to significance testing. EPC counts were significantly lowered in cases with fatal outcome.

Conclusion

Burn affects the numbers of circulating MNC, CD34⁺ and EPC. These time-dependent changes imply involvement of these cell groups in the trauma. EPC counts seem to be a predictive factor for outcome of cases of severe burn.     

FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours

Background

Promoter hypermethylation and microsatellite instability are frequent in tumours of the upper urinary tract (UTT) and infrequent in bladder tumours. FGFR3 mutations are common findings in bladder tumours and are associated with a good prognosis.

Objective

To investigate the occurrence of FGFR3 mutations in UTT and determine the prognostic effect of these genetic changes.

Design, setting, and participants

Tissue from the initial tumour was obtained from 280 patients (117 bladder tumours and 163 UTT). Patients were selected from pathologic archives to represent the disease spectrum of UCC throughout the urinary tract. Following UCC excision, patients underwent surveillance for a median of 56 mo (range 1–216 mo) or until death.

Measurements

FGFR3 mutation analysis was successfully performed on 252 of the 280 primary tumours using the SNaPshot method. Two-tailed statistical analyses were done using the χ², Fisher exact tests, and log rank tests. Cox proportional hazard ratios were estimated to obtain risks of recurrence, progression, and death, and to find independent prognostic factors in a multivariate model.

Results and limitations

FGFR3 mutations occurred with the same frequency in bladder and upper tract tumours. Mutations were associated with low-stage tumours and a milder disease course in bladder, ureter, and renal pelvis tumours. Strikingly, our data suggest that these mutations indicate a better survival in patients with invasive tumours from the bladder and upper urinary tract.

Conclusions

FGFR3 mutation status might be used to select patients with invasive UCC who have a lower risk of death.