Patterns and Drivers of Costs for Neuroendocrine Tumor Care: A Comparative Population-Based Analysis.

BACKGROUND: Little is known about resource use in the care of neuroendocrine tumors (NETs). This study defined patterns of costs in NET management and compared them with those of a more common malignancy, colon cancer (CC). METHODS: Using a provincial cancer registry (2004-2012), NET patients were identified and matched at a ratio of 1-3 with CC patients. Four phases of care were examined: pre-diagnostic (PreDx: -2 years to -181 days), diagnostic (Dx: -180 days to +180 days), postdiagnostic (PostDx: +181 days to +3 years), and prolonged post-diagnostic (PPostDx: +181 days to +9 years). The mean costs per patient were compared, and cost predictors were analyzed with quintile regression. RESULTS: Of 3827 NETs, 3355 were matched with 9320 CCs. The PreDx mean NET costs were higher than the CC costs ($5877 vs $5368; p = 0.06), driven by nondrug costs. They were lower in the Dx and PostDx phases (both p < 0.01). For PPostDx, the drug costs were higher for NETs ($26,788 vs $7827; p < 0.01), representing 41% of the costs versus 16% of the costs for CC. Older age and comorbidities predicted higher NET costs in all phases. Lower socioeconomic status (SES) predicted higher costs in the initial phases and higher SES costs in the PPost-Dx phase. Gastroenteric NETs were associated with lower costs in the Dx phase [parameter estimate (PE), -$13,644] and pancreatic NETs with higher costs in PostDx phase (PE, $3348). CONCLUSION: Currently, NETs represent a potential important health care burden. The NET cost patterns differed from those for CC, with the highest costs during the PPostDx phase. The SES and primary NET site affected costs differently at different time points. These data can inform resource allocation tailored to the needs for NETs.

Three-point transfusion risk score in hepatectomy.

BACKGROUND: Perioperative red blood cell transfusions are required in up to 23 per cent of patients undergoing hepatectomy. Previous research has developed three transfusion risk scores to assess risk of perioperative red blood cell transfusion. Here, the performance of these transfusion risk scores was evaluated in a multicentre cohort of patients who underwent hepatectomy and compared with that of a simplified transfusion risk score. METHODS: A database of patients undergoing hepatectomy at four specialized centres between 2008 and 2012 was developed. External validity was assessed by discrimination and calibration. Discrimination was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Calibration was evaluated by the degree of agreement between predicted and actual red blood cell transfusion probabilities. A simplified transfusion risk score using variables common to the three models was created, and discrimination and calibration were evaluated. RESULTS: There were 1287 patients included in this study, with 341 (26·5 per cent) receiving a red blood cell transfusion. Discriminative ability was similar between the three transfusion risk scores, with AUCs of 0·66-0·68 and good calibration. A new three-point risk score was developed based on factors present in all models: haemoglobin 12·5 g/dl or less, primary liver malignancy and major resection (at least 4 segments). Discriminative ability and calibration of the three-point model were similar to those of the three existing models, with an AUC of 0·66. CONCLUSION: The three-point transfusion risk score simplifies assessment of perioperative transfusion risk in hepatectomy without sacrificing predictive ability.

Negative predictive value of preoperative computed tomography in determining pathologic local invasion, nodal disease, and abdominal metastases in gastric cancer.

BACKGROUND: Before undergoing curative-intent resection of gastric adenocarcinoma (ga), most patients undergo abdominal computed tomography (ct) imaging to determine contraindications to resection (local invasion, distant metastases). However, the ability to detect contraindications is variable, and the literature is limited to single-institution studies. We sought to assess, on a population level, the clinical relevance of preoperative ct in evaluating the resectability of ga tumours in patients undergoing surgery. METHODS: In a provincial cancer registry, 2414 patients with ga diagnosed during 2005-2008 at 116 institutions were identified, and a primary chart review of radiology, operative, and pathology reports was performed for all patients. Preoperative abdominal ct reports were compared with intraoperative findings and final pathology reports (reference standard) to determine the negative predictive value (npv) of ct in assessing local invasion, nodal involvement, and intra-abdominal metastases. RESULTS: Among patients undergoing gastrectomy, the npv of ct imaging in detecting local invasion was 86.9% (n = 536). For nodal metastasis, the npv of ct was 43.3% (n = 450). Among patients undergoing surgical exploration, the npv of ct for intra-abdominal metastases was 52.3% (n = 407). CONCLUSIONS: Preoperative abdominal ct imaging reported as negative is most accurate in determining local invasion and least accurate in nodal assessment. The poor npv of ct should be taken into account when selecting patients for staging laparoscopy.

Fully automatable two-dimensional hydrophilic interaction liquid chromatography-reversed phase liquid chromatography with online tandem mass spectrometry for shotgun proteomics.

We have developed a fully automatable two-dimensional liquid chromatography platform for shotgun proteomics analyses based on the online coupling of hydrophilic interaction liquid chromatography (HILIC) - using a nonionic type of TSKgel Amide 80 at either pH 6.8 (neutral) or 2.7 (acidic) - with conventional low-pH reversed-phase chromatography. Online coupling of the neutral-pH HILIC and reversed phase chromatography systems outperformed the acidic HILIC-reversed phase chromatography combination, resulting in 18.4% (1914 versus 1617 nonredundant proteins) and 41.6% (12,989 versus 9172 unique peptides) increases in the number of identified peptides and proteins from duplicate analyses of Rat pheochromocytoma lysates. Armed with this optimized HILIC-reversed phase liquid chromatography platform, we identified 2554 nonredundant proteins from duplicate analyses of a Saccharomyces cerevisiae lysate, with the detected protein abundances spanning from approximately 41 to 10(6) copies per cell, which contained up to approximately 2092 different validated protein species with a dynamic range of concentrations of up to approximately 10(4) . This present study establishes a fully automated platform as a promising methodology to enable online coupling of different hydrophilic HILIC and reversed phase chromatography systems, thereby expanding the repertoire of multidimensional liquid chromatography for shotgun proteomics.

Access to care and outcomes for neuroendocrine tumours: does socioeconomic status matter?

Introduction: Neuroendocrine tumours (nets) are a poorly understood malignancy lacking standardized care. Differences in socioeconomic status (ses) might worsen the effect of non-standardized care. We examined the effect of ses on net peri-diagnostic care patterns and outcomes. Methods: In this population-based cohort study, net cases identified from a provincial cancer registry (1994-2009) were divided into low (1st and 2nd income quintiles) and high (3rd, 4th, and 5th quintiles) ses groups. We compared peri-diagnostic health care utilization (-2 years to +6 months), metastatic recurrence, and overall survival (os) between the groups. Results: Of 4966 net patients, 38.3% had a low ses. Neither the primary net sites (p = 0.15), nor the metastatic presentation (p = 0.31) differed. Patients with low ses had a higher mean number of physician visits (20.1 ± 19.9 vs. 18.1 ± 16.5, p = 0.001) and imaging studies (56 ± 50 vs. 52 ± 44, p = 0.009) leading to the net diagnosis. Rates of primary tumour resection (p = 0.14), hepatectomy (p = 0.45), systemic therapy (p = 0.38), and liver embolization (p = 0.13) did not differ with ses. In the low-ses group, metastatic recurrence was more likely (41.1% vs. 37.6%, p = 0.01) during a median follow-up of 61.7 months, and the 10-year os was inferior (47.1% vs. 52.2%, p < 0.01). Low ses was associated with worse os (hazard ratio: 1.16; 95% confidence interval: 1.06 to 1.26) after adjustment for age, sex, comorbidity burden, primary net site, and rural living. Conclusions: Low ses was associated with more physician visits and imaging before a net diagnosis, but not with more advanced stage at presentation nor with an effect on the pattern of therapy. Long-term outcomes were inferior in the low-ses group. These data can help to inform the design of health care delivery for nets.

Hepatitis B antigen in the liver cells in cirrhosis and hepatocellular carcinoma.

The demonstration of hepatitis B antigen in the liver cells in formalin fixed paraffin embedded tissues by Shikata's orcein staining method affords an opportunity to conduct retrospective studies on necrospy materials. Such a study in Singapore showed orcein-positive liver cells in 22 out of 52 (42.3%) and 37 out of 50 (74.0%) cases of cirrhosis of the liver and hepatocellular carcinoma respectively, while only 5 out of 113 (4.4%) 'normal' livers gave positive results. There is a significant difference in the frequency of hepatocellular carcinoma in orcein-positive and orcein-negative cirrhotic livers (28 out of 50, 10 out of 40 respectively). These results suggest a possible aetiological relationship between hepatitis B antigen and hepatocellular carcinoma.

Glomerular lesions in patients with asymptomatic persistent andorthostatic proteinuria discovered on routine medical examination.

The incidence of asymptomatic proteinuria in young healthy men entering the army service in Singapore was 0.94%; 0.56% had intermittent orthostatic proteinuria and 0.38% with persistent proteinuria. Renal biopsies from 45 cases with persistent proteinuria and 10 cases with orthostatic proteinuria were studied by light microscopy, electron microscopic and immunofluorescent antibody techniques. Three cases with orthostatic proteinuria showed a minimal lesion ('Nil'), and 7 a minimal lesion with increased centrilobular mesangial matrix and mild focal and segmental mesangial hypercellularity. Focal and segmental capillary loop changes were seen in two cases. No immunoglobulin deposits were found in orthostatic proteinuria. A raised anti-streptolysin O titer was found in 3 cases. 13.3% of cases with persistent proteinuria showed a minimal lesion ('Nil'); 66.6% a minimal lesion with increased centrilobular mesangial matrix and mild focal and segmental mesangial hypercellularity: Focal global sclerosis, focal segmental sclerosing glomerulonephritis and diffuse proliferative GN (mesangial hypercellularity) were each found in 6.7% of patients in this group. Focal and segmental changes in capillary loops were found in 30% of cases. Changes in visceral epithelium such as the appearance of cytoplasmic swelling, vesicles and dense aggregates, and areas of focal foot process fusion were common findings. Mesangial deposits of IgA were found in 34.3%, with an IgA-IgG-beta1C globulin combination in 28.6% of cases. IgM-beta1C globulin was present in 5.7% of cases with persistent proteinuria. Early complement components, C1q and C4, and IgA secretory piece were absent. A raised antistreptolysin O titer was found in 25% of cases. The changes inthe glomeruli may represent the end or healing stages of an early bout of glomerulonephritis. Changed hemodynamic responses on assuming an upright position may play a role in the loss of protein across the glomerular basement membrane in patients with orthostatic proteinuria.

Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease.

BACKGROUND: The Ki67-LI is a valid surrogate for biologic behavior of neuroendocrine tumors (NETs), with higher levels associated with aggressive behavior. The World Health Organization (WHO) classifies NETs according to Ki67-LI (G1: <3%; G2 : 3-20%; G3: >20%). Little is known about the evolution of NETs histologic characteristics over the disease course. We sought to evaluate variations in Ki67-LI throughout NETs disease course. METHODS: We retrospectively reviewed the Sunnybrook Odette Cancer Center NET database for patients with multiple pathology specimens. Primary outcome was the WHO NET class based on Ki67-LI for each specimen. We assessed change in WHO class between specimens. RESULTS: Forty-three patients were retrieved, of which 39 had specimens from the primary tumor and a metastatic focus, and 4 had specimens from multiple metastatic foci. Sixteen (37.0%) were identified with Ki67-LI falling in different WHO classes on distinct biopsies. For 12 (75.0%) of those 16 patients, Ki67-LI showed enough variability for WHO class to be upstaged: 5 (31%) from G1 to G2, 2 (13%) from G2 to G3, and 5 (31%) from G1 to G3. CONCLUSION: When multiple pathology specimens were available, Ki67-LI varied throughout NETs disease course, with a majority of cases upgraded to a higher WHO class. If confirmed, this finding may have implications in how neuroendocrine tumors are monitored and treated. Further research is warranted to confirm these findings, understand better the underlying mechanisms of Ki67 variability, and define its relationship to prognosis.

Use of a collagen-sealing device in hepatic resection: a comparative analysis to standard resection technique.

BACKGROUND: Blood transfusion has been reported as an independent risk factor for poor outcome after liver resection in spite of its well known benefits. Refinements in parenchymal dissection have been pursued to reduce blood loss and transfusion. A collagen-sealing device (CSD) has recently been touted as an alternative technique that aids in blood conservation. We report the results of our initial series of patients undergoing a CSD-assisted resection and present a historical comparison. PATIENTS AND METHODS: Consecutive patients who were undergoing liver resection at a single tertiary cancer centre were enrolled in this study. The Ligasure Atlas device (Valleylab Inc., Division of Tyco Healthcare) was used for parenchymal division in the CSD group. Known blood conservation techniques (i.e. low central venous pressure, ultrasonic dissection, Pringle clamp) were standardized in both groups. Clinical and outcome variables including operative time, estimated blood loss and transfusion requirements were collected. All statistical analyses were performed with SAS version 8.2e. RESULTS: In all, 28 consecutive patients underwent CSD-assisted hepatic resection between October 2003 and September 2004. The control group included 188 patients treated between January 1991 and September 2003. In the CSD group, we observed a reduction in mean estimated blood loss (930 vs 1450 ml, p=0.002) and mean transfusion requirements (0.46 vs 1.19 units, p=0.002). There was no increase in operative time with the new instrument (326 vs 363 min, p=0.167). DISCUSSION: Use of a CSD has the potential to further reduce blood loss and transfusion requirements without increasing operative time.

Qualitative assessment of patient experiences related to extended pelvic resection for rectal cancer.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) represent a complex management challenge. While there is potential for cure in a subset of patients, the cost in terms of morbidity can be high. Few descriptions of the physical, psychological, social, and emotional experiences of these patients exist. METHODS: Face-to-face interviews were completed with ten LARC and LRRC patients treated with multimodal therapy that included surgery. Patient opinions and experiences were explored in depth until information redundancy and common themes were delineated using qualitative research methods. Clinical information was obtained from the database. RESULTS: Nine of the ten patients were male, seven had LARC, and the median age was 71. Six themes were identified from the patient interviews. Themes reflected patients' highly focused desire to seek wellness and cure, but also revealed misunderstanding of their disease biology, probability of cure, therapeutic options, and treatment morbidity. CONCLUSIONS: Patient experiences confirm that this is challenging treatment to complete, and that patient understanding of pre-operative information is incomplete. Our findings underscore the need for a multidisciplinary approach when managing this patient population, with emphasis on both supportive care needs and the technically skilled delivery of surgery, chemotherapy, and radiotherapy.

The association between tamoxifen and the development of hepatocellular carcinoma: case report and literature review.

Tamoxifen has become one of the most widely used drugs in the treatment of breast cancer, and concerns about its long-term safety and efficacy are being raised. Investigations in rats have suggested an association between the administration of tamoxifen and the development of hepatocellular carcinoma. However, no studies to date have demonstrated an increased incidence of hepatocellular carcinoma in women treated with tamoxifen. In the case reported, a 56-year-old woman presented with hepatocellular tumours after 6 years of tamoxifen therapy for breast cancer. The patient had no other risk factors for the development of hepatocellular carcinoma. She underwent successful resection of the lesions, and subsequent pathological studies confirmed hepatocellular carcinoma with a trabecular growth pattern similar to the histologic pattern seen in tamoxifen-induced hepatocellular carcinoma occurring in rat models.

Incidence rates of specific histological types of lung cancer in Singapore Chinese dialect groups, and their aetiological significance.

Significant differences in the incidence levels of lung cancer have been observed among major Chinese dialect groups or communities (Kokkien, Teochew and Cantonese) in Singapore. Among males, the incidence rate is highest in the Hokkiens (age-standardized incidence rate per 100,000 persons per year in Hokkien 67.8, Teochew 55.3, Cantonese 54.0) and among females, it is highest in the Cantonese (Hokkien 12.4, Teochew 12.8, Cantonese 27.2). The present investigation was undertaken to determine the incidence rates of each of the main histological types of lung cancer in the Chinese population and to determine whether there are any correlations between histological patterns and the dialect group differentials that may be of aetiological significance. During the period 1968-1972, a total of 1,747 cases of lung cancer (1,285 males and 462 females) were reported to the Singapore Cancer Registry. It proved possible to type the neoplasms histologically in 476 males (37.0%) and 154 females (33.3%). Age-standardized rates by histological type were computed on the assumption that those histologically typed were a representative sample of all lung cancers. This study shows that Hokkien males have a significantly higher incidence rate of epidermoid carcinoma than the other dialect groups (Hokkien 36.1, Teochew 21.1, Cantonese 17.3). The Cantonese females have significantly higher incidence rates of both epidermoid carcinoma (Hokkien 3.7, Teochew 2.3, Cantonese 5.9) and adenocarcinoma (Hokkien 4.6, Teochew 3.6, Cantonese 11.9). Various sources of bias in studied of this type were examined; it is concluded that the differences in the histologic-specific incidence rates of lung cancer among the various Chinese dialect groups in Singapore are real and not artefactual. The significance of these findings in relation to possible aetiological factors is discussed.

Outcomes after localized axillary node recurrence in breast cancer.

BACKGROUND: Localized axillary recurrence (LAR) is an uncommon event. It is estimated to occur in 0.5% to 3% of patients when adequate axillary surgery has been performed. Although relatively sparse data exist on the outcome of patients with LAR, in the era of sentinel node biopsy (SNB) these data may have increased relevance. This study assesses the survival outcomes in these patients. METHODS: A retrospective chart review was completed. Patient age, tumor size, pathology, receptor status, and treatment of the primary breast carcinoma were reviewed. Axillary recurrence, treatment, and overall survival data were collected. RESULTS: Fifteen patients were identified with LAR that developed at a median of 77 months after their initial dissection. At the time of treatment for their LAR, all patients had completion axillary clearance and six also had a concurrent completion mastectomy. Further adjuvant treatment was individualized. Five patients (33%) have died, including all patients (3) who developed a LAR within 2 years of their initial breast cancer presentation. Ten-year overall survival is 56%. CONCLUSION: Our experience suggests early (<24 months) LAR is indicative of a poor prognosis. With multimodal treatment, ten-year overall survival is 56%.

Ex vivo sentinel lymph node biopsy in colorectal cancer: a feasibility study.

BACKGROUND AND OBJECTIVES: Sentinel lymph node (SLN) biopsy may improve staging of colorectal cancer. We tested the feasibility of ex vivo SLN dissection. MATERIALS AND METHODS: Patients undergoing resection of a primary colorectal cancer were included in this study. SLN identification involved ex vivo injection of 1 cc isosulfan blue dye subserosally in the colon or submucosally in the rectum on a separate field. SLNs were cut at 2 mm intervals. Three hematoxylin and eosin-stained (HE) sections were prepared in addition to a middle level for cytokeratin immunostaining. RESULTS: Twenty-six patients with varying tumor location and stage were enrolled and the SLN was identified in 88% (23/26) cases. Three failures occurred in patients with rectal cancer. The average number of SLN harvested was 2.5. The status of the nodal basin was accurately predicted in 91% (21/23) of patients. Two false negative sentinel lymph nodes were harvested in 2 of 3 patients with stage III/IV colorectal cancer. The SLN upstaged 2 patients as a result of HE stained step sections (n = 1) and immunostaining (n = 1). CONCLUSIONS: This data suggests that ex vivo SLN biopsy is feasible in colorectal cancer. Although ex vivo SLN biopsy does not alter the lymphatic dissection, it may upstage a subset of patients. The ex vivo technique may be less applicable in rectal cancer and false negative results may occur.

Post-traumatic small-bowel stricture: a case report.

The use of lap seat belts has recently been recognized as a mechanism of blunt injury to the small bowel. Patients usually present immediately after injury and require urgent laparotomy. An unusual case of delayed small-bowel stricture after conservative management of an injury resulting from blunt trauma is reported. A 37-year-old woman involved in a high-speed motor vehicle accident was managed in hospital by observation. She had abdominal distension and pain, which gradually decreased and allowed slow introduction of a liquid diet. She was discharged from hospital but returned 6 weeks after injury with pain, abdominal distension, vomiting and obstipation. Stricture of an 8-cm segment of distal jejunum was found. Resection of the involved segment with primary anastomosis was curative.

Risk factors for lung cancer in Singapore Chinese, a population with high female incidence rates.

The high incidence of lung cancer in Chinese females in Singapore, especially among those belonging to the Cantonese dialect group, and the relatively high rates in Chinese males have been studied by means of interviews of cases and controls. A significant dose-response effect of cigarette smoking was found for all male and female groups, but neither smoking nor any other exposure explains the high incidence of lung cancer observed in Cantonese females who exhibit high rates of adenocarcinoma appraently unrelated to smoking. In general, persons with a low consumption of green vegetables were at higher risk for lung cancer. This finding might be due to an increased susceptibility in the presence of a relative deficiency of vitamin A.

Biallelic inactivation of the APC gene is associated with hepatocellular carcinoma in familial adenomatous polyposis coli.

BACKGROUND: Certain primary hepatic tumors have been associated with familial adenomatous polyposis (FAP), a condition caused by germline mutations of the adenomatous polyposis coli (APC) gene. However, a genetic association between FAP and hepatocellular carcinoma (HCC) has not been shown. This study tested the hypothesis that biallelic inactivation of the APC gene contributed to the development of HCC in a patient with FAP and a known germline mutation of the APC gene at codon 208, but no other risk factors for HCC. METHODS: Total RNA and genomic DNA were isolated from the tumor, and in vitro synthesized protein assay and DNA sequencing analysis were used to screen for a somatic mutation in the APC gene. RESULTS: A somatic one-base pair deletion at codon 568 was identified in the wild-type allele of the APC gene. CONCLUSIONS: To the authors' knowledge, this study provides the first evidence that biallelic inactivation of the APC gene may contribute to the development of HCC in patients with FAP.