Management of incidental gallbladder cancer in a national cohort.

BACKGROUND: Incidental gallbladder cancer is a rare event, and its prognosis is largely affected by the tumour stage and treatment. The aim of this study was to analyse the management, treatment and survival of patients with incidental gallbladder cancer in a national cohort over a decade. METHODS: Patients were identified through the Swedish Registry of Gallstone Surgery (GallRiks). Data were cross-linked to the national registry for liver surgery (SweLiv) and the Cancer Registry. Medical records were collected if registry data were missing. Survival was measured as disease-specific survival. The study was divided into two intervals (2007-2011 and 2012-2016) to evaluate changes over time. RESULTS: In total, 249 patients were identified with incidental gallbladder cancer, of whom 92 (36·9 per cent) underwent re-resection with curative intent. For patients with pT2 and pT3 disease, median disease-specific survival improved after re-resection (12·4 versus 44·1 months for pT2, and 9·7 versus 23·0 months for pT3). Residual disease was present in 53 per cent of patients with pT2 tumours who underwent re-resection; these patients had a median disease-specific survival of 32·2 months, whereas the median was not reached in patients without residual disease. Median survival increased by 11 months for all patients between the early and late periods (P = 0·030). CONCLUSION: Re-resection of pT2 and pT3 incidental gallbladder cancer was associated with improved survival, but survival was impaired when residual disease was present. A higher re-resection rate and more R0 resections in the later time period may have been associated with improved survival.

Anterior cruciate ligament injury after more than 20 years: I. Physical activity level and knee function.

Little is known about physical activity level and knee function including jump capacity and fear of movement/reinjury more than 20 years after injury of the anterior cruciate ligament (ACL). Seventy persons with unilateral ACL injury participated (23 ± 2 years post-injury): 33 treated with physiotherapy in combination with surgical reconstruction (ACLR ), and 37 treated with physiotherapy alone (ACLPT ). These were compared with 33 age- and gender-matched controls. Assessment included knee-specific and general physical activity level [Tegner activity scale, International Physical Activity Questionnaire (IPAQ)], knee function [Lysholm score, Knee injury and Osteoarthritis Outcome Score (KOOS)], jump capacity (one-leg hop, vertical jump, side hops), and fear of movement/reinjury [Tampa Scale for Kinesiophobia (TSK)]. Outcomes were related to degree of osteoarthritis (OA). ACL-injured had lower Lysholm, KOOS, and Tegner scores than controls (P < 0.001), while IPAQ score was similar. ACL-injured demonstrated inferior jump capacity in injured compared with noninjured leg (6-25%, P < 0.001-P = 0.010 in the different jumps), while noninjured leg had equal jump capacity as controls. ACL groups scored 33 ± 7 and 32 ± 7 of 68 on TSK. Lower scores on Lysholm and KOOS symptom were seen for persons with moderate-to-high OA than for no-or-low OA, while there were no differences for physical activity and jump capacity. Regardless of treatment, there are still negative knee-related effects of ACL injury more than 20 years later.

The clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort.

BACKGROUND: BRAF and NRAS mutations are frequently found in melanoma tumours, and recently developed BRAF-targeted therapies demonstrate significant clinical benefit. OBJECTIVES: We sought to investigate the clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort. METHODS: In total, 237 tumours, mostly metastatic lesions, from 203 patients were screened for mutations in exon 15 of BRAF and exon 2 of NRAS using Sanger sequencing. BRAF and NRAS mutation status was analysed in relation to clinical and histopathological characteristics, and outcome. RESULTS: Mutation in BRAF and NRAS was present in 43% (88% V600E, 10% V600K) and 30% (48% Q61K, 40% Q61R) of metastatic melanomas, respectively. We found consistent BRAF and NRAS mutation status in all but one of 27 patients with multiple metastases. BRAF mutation was associated with younger age at primary diagnosis (P = 0.02). Among patients with distant metastatic melanoma, patients with BRAF-mutant tumours without BRAF inhibitor treatment had inferior survival compared with patients with BRAF inhibitor treatment [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.10-5.01, P = 0.03]. We also observed a trend towards better prognosis for patients with wild-type and NRAS-mutant tumours compared with BRAF V600E-mutant tumours (HR 0.64, 95% CI 0.39-1.04, P = 0.07; and HR 0.76, 95% CI 0.48-1.21, P = 0.25, respectively). CONCLUSIONS: We were able to confirm the effect of BRAF inhibitor treatment in a single clinical institution. The results suggest further that BRAF mutation is a weak prognostic factor but a strong predictive factor and that BRAF-mutant melanoma might constitute one or more distinct subtypes of the disease with certain aetiology and clinical outcome.

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study.

BACKGROUND: This phase II study evaluated the safety and activity of ipilimumab, a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4, in patients with advanced melanoma. PATIENTS AND METHODS: Patients with previously treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. The primary end point was best overall response rate (BORR) using modified World Health Organization (WHO) criteria. We also carried out an exploratory analysis of proposed immune-related response criteria (irRC). RESULTS: BORR was 5.8% with a disease control rate (DCR) of 27% (N = 155). One- and 2-year survival rates (95% confidence interval) were 47.2% (39.5% to 55.1%) and 32.8% (25.4% to 40.5%), respectively, with a median overall survival of 10.2 months (7.6-16.3). Of 43 patients with disease progression by modified WHO criteria, 12 had disease control by irRC (8% of all treated patients), resulting in a total DCR of 35%. Adverse events (AEs) were largely immune related, occurring mainly in the skin and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs were manageable and generally reversible with corticosteroids. CONCLUSION: Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.

Cost-effectiveness of gallbladder histopathology after cholecystectomy for benign disease.

BACKGROUND: The prevalence of incidental gallbladder cancer is low when performing cholecystectomy for benign disease. The performance of routine or selective histological examination of the gallbladder is still a subject for discussion. The aim of this study was to assess the cost-effectiveness of these different approaches. METHODS: Four management strategies were evaluated using decision-analytical modelling: no histology, current selective histology as practised in Sweden, macroscopic selective histology, and routine histology. Healthcare costs and life-years were estimated for a lifetime perspective and combined into incremental cost-effectiveness ratios (ICERs) to assess the additional cost of achieving an additional life-year for each management strategy. RESULTS: In the analysis of the four strategies, current selective histology was ruled out due to a higher ICER compared with macroscopic selective histology, which showed better health outcomes (extended dominance). Comparison of routine histology with macroscopic selective histology resulted in a gain of 12 life-years and an incremental healthcare cost of approximately €1 000 000 in a cohort of 10 000 patients, yielding an estimated ICER of €76 508. When comparing a macroscopic selective strategy with no histological assessment, 50 life-years would be saved and the ICER was estimated to be €20 708 in a cohort of 10 000 patients undergoing cholecystectomy. CONCLUSION: A macroscopic selective strategy appears to be the most cost-effective approach.

Quantitative determination of airborne respirable non-fibrous alpha-silicon carbide by x-ray powder diffractometry.

OBJECTIVES: The purpose of the present investigation was to establish a method for the determination of airborne respirable non-fibrous silicon carbide (SiC). The main application is within the industrial production of SiC. METHODS: Due to the complex airborne aerosol mixture of crystalline compounds in the SiC industry, X-ray powder diffractometry was selected as the most appropriate method. Without any international standard material for the respirable fraction of non-fibrous SiC, pure and suitable products from three SiC plants in Norway were selected. These products have a median particle diameter in the range 4.4-5.1 mum. The method is based on thin sample technique, with the dust deposited on a polycarbonate filter. Absorption correction is done by standard procedures with the use of a silver filter, situated below the polycarbonate filter. RESULTS: The diffraction line used for quantitative determination was selected carefully. This was done to avoid interferences from quartz, cristobalite, and graphite, which all are airborne components present in the atmosphere during the industrial process. The instrumental limit of detection for the method is 12 microg. CONCLUSIONS: This method has been used to determine airborne non-fibrous SiC in a comprehensive ongoing project in the Norwegian SiC industry for further epidemiological studies. The method is fully applicable for compliance work.

A Personal Computer Freeware as a Tool for Surgeons to Plan Liver Resections.

BACKGROUND AND AIMS: The increase in liver surgery and the proportion of resections done on the margin to postoperative liver failure make preoperative calculations regarding liver volume important. Earlier studies have shown good correlation between calculations done with ImageJ and specimen weight as well as volume calculations done with more robust systems. The correlation to actual volumes of resected liver tissue has not been investigated, and this was the aim of this study. MATERIAL AND METHODS: A total of 30 patients undergoing well-defined liver resections were included in this study. Volumes calculated with ImageJ were compared to volume measurements done after the retrieval of resected liver tissue. RESULTS AND CONCLUSIONS: A strong correlation between calculated and measured liver volume was found with sample concordance correlation coefficient (ρc) = 0.9950. The knowledge on the nature of liver resections sets liver surgeons in a unique position to be able to accurately predict the volumes to be resected and, therefore, also the volume that will remain after surgery. This becomes increasingly important with the evolvement of methods to extend the boundaries of liver surgery. ImageJ is a reliable tool to preoperatively assess liver volume.

Pseudomalignant spindle cell proliferations of the urinary bladder.

Twelve cases of polypoid, nonrecurrent, pseudomalignant spindle cell proliferations of the urinary bladder (eight women and four men) were analyzed. Two patients had a simultaneous urinary bladder carcinoma. The lesions were characterized by proliferating spindle- or strap-shaped cells, which on electron microscopic examination (performed in all 12 cases) revealed characteristics of fibroblasts and myofibroblasts. The cells showed immunoreactivity for vimentin in all cases, for alpha-smooth muscle-specific and muscle-specific actin in six cases, for cytokeratins in five cases, and for CD 34 in one case. No immunoreactivity was observed for desmin, myoglobin, epithelial membrane antigen, S-100 protein, endothelial cell antigen (H and Y), CD 68, or factor VIII RAG. Immunoreactivity for Ki-67 and proliferating cell nuclear antigen was detected in up to 30% of the spindle cell nuclei. The static cytometric DNA analysis revealed a diploid, or in two cases a hyperdiploid, stem cell line. An awareness of this type of spindle cell lesion and its immunophenotypic characteristics and diversity is of importance to avoid an erroneous diagnosis of spindle cell sarcoma (in particular leiomyosarcoma and embryonal rhabdomyosarcoma) or spindle cell carcinoma.

Infantile rhabdomyofibrosarcoma: a high-grade sarcoma distinguishable from infantile fibrosarcoma and rhabdomyosarcoma.

Three patients with a predominantly fibrosarcomatous, desmoplastic, and fascicular spindle-cell sarcoma, resembling that of infantile fibrosarcoma but with ultrastructural and immunocytochemical evidence of rhabdomyoblastic differentiation, are described. The tumors were compared light and electron microscopically and immunocytochemically with six classical cases of infantile fibrosarcoma of the desmoplastic type. The three tumors occurred in two girls and one boy who were between 1 and 3 years of age. Ultrastructurally, the tumor cells primarily demonstrated fibroblastic and myofibroblastic features, but there were also tumor cells with sarcomere-like structures. The spindle-shaped, fibroblast-like tumor cells expressed vimentin, desmin, and smooth muscle-specific and sarcomere-specific actins. In one tumor peculiar intracytoplasmic inclusions were observed by light and electron microscopy. The immunocytochemical analysis indicated that these bodies contained all types of thin and intermediate filaments. In short-term cell cultures the tumor cells of two examined tumors revealed immunoreactivity for vimentin, smooth muscle-specific actin, and desmin. Cytogenetically, both tumors displayed a similar chromosomal pattern. One tumor contained two abnormal clones with monosomy 19 and monosomy 22, respectively, and the other tumor revealed a single clone with monosomy 19. In addition, both tumors contained clones with a normal karyotype. Two of the patients with metastatic spread died within 2 years of the primary operation. The third patient is alive with a local recurrence. The three tumors described here deviate from infantile fibrosarcoma in terms of their clinical, ultrastructural, immunocytochemical, and cytogenetic characteristics. The descriptive term "infantile rhabdomyofibrosarcoma" is suggested. The present investigation calls for detailed studies of tumors diagnosed as infantile fibrosarcomas that have metastasized and followed a fatal course.

Proliferative myositis and fasciitis. A light and electron microscopic, cytologic, DNA-cytometric and immunohistochemical study.

Two cases of proliferative myositis, four cases of proliferative fasciitis and one mixed form of proliferative myositis and fasciitis have been analyzed in terms of cell differentiation and DNA content. Light microscopically, the lesions were characterized by a mixture of proliferating spindle-shaped cells and uni-, bi- or occasionally multinucleated ganglion cell-like cells. The spindle cells showed ultrastructural features and immunohistochemical properties, including an immunoreactivity for smooth muscle-specific actin, indicative of a myofibroblastic differentiation. The ganglion cell-like cells displayed some resemblance to active osteoblasts ultrastructurally and differed immunohistochemically from the spindle cells by being non-immunoreactive for smooth muscle-specific actin. None of the two cell types showed immunoreactivity for desmin, myoglobin or factor VIII RAG. It is suggested that the two cell types represent different lines of cell differentiation. The cytologic features in smears, as seen in two cases of proliferative fasciitis and one case of proliferative myositis, are considered to be characteristic of these lesions and to permit the diagnosis to be made by fine-needle aspiration. In two of the cases, the lesion was diagnosed only cytologically and thereafter disappeared spontaneously within a month. Cytometric DNA measurements, using two different image analysis systems on Feulgen-stained sections and smears, revealed a "diploid" spindle-shaped cell population with a variable proportion of cells with scattered DNA values. The ganglion cell-like cells differed from the spindle cells by having a broad DNA peak in the diploid region and additional peaks in the tetraploid region, as well as a higher proportion of cells with scattered DNA values compared with those of the spindle-shaped cells. The results of the quantitative DNA analysis are well in keeping with the benign and proliferative nature of these lesions. However, with the technique used here, quantitative DNA analysis, does not distinguish these pseudosarcomatous fibrous lesions from diploid and tetraploid soft tissue sarcomas.

Intermediate and fine cytofilaments in cutaneous and subcutaneous leiomyosarcomas.

The expression of fine and intermediate cytofilaments in 10 cutaneous and seven subcutaneous leiomyosarcomas was studied immunohistochemically. All the tumors contained tumor cells which showed a positive immunoreactivity for desmin in formaldehyde-fixed and paraffin-embedded sections, but none of the seven anti-desmin antibodies used alone produced a distinct positive staining in all the tumors. A lack of correspondence in terms of immunoreactivity between tumor cells and the supposed muscle of origin was observed, especially in the subcutaneous leiomyosarcomas. In all cases, antibodies to muscle-specific and smooth muscle-specific actin were found to produce a positive staining in both the tumors and the supposed muscle of origin. Vimentin was detected in 8/10 cutaneous and 4/7 subcutaneous leiomyosarcomas, while the supposed muscle of origin was positive in 3/10 and 7/7 cases, respectively. Four of the cutaneous and three of the subcutaneous leiomyosarcomas contained tumor cells which stained positively for cytokeratins, while the supposed muscle of origin showed no positivity. It thus appears that a phenotypic shift in terms of vimentin and cytokeratin expression occurs in the tumor cells of cutaneous and subcutaneous leiomyosarcomas compared with the supposed muscle of origin. It is recommended that more than one monoclonal anti-desmin antibody is used to characterize these tumor entities. It is also concluded that the immunoreactivity for muscle-specific actins in superficial leiomyosarcomas is more constant, although less specific, than that of desmin and that the demonstration of the simultaneous expression of muscle-specific actins and desmin is helpful.

Intermediate and fine filaments of vascular leiomyomas (angiomyoma), leiomyoma and leiomyosarcomas of large veins.

The expression of fine and intermediate filaments in 10 cases of leiomyosarcoma originating from a large vein, 9 cases of vascular leiomyoma (angiomyoma) and one case of a leiomyoma originating from the wall of the saphena magna vein was studied immunohistochemically by using 6 different anti-desmin antibodies, one anti-vimentin antibody and 2 antibodies to muscle-specific isoforms of actin. All the benign tumors and all the leiomyosarcomas of a large vein as well as the vein of origin were positively stained for desmin. The staining results obtained using the different anti-desmin antibodies varied considerably, however, and formaldehyde-fixed tissues were apparently inappropriate for some of them. No single anti-desmin antibody produced a positivity in all cases, and the extent and distribution of the positivity varied by being irregular and patchy in the leiomyosarcomas and in the muscle walls of the veins, while the benign tumors generally revealed a more uniform and strong positivity. Antibodies to muscle-specific and smooth muscle-specific actin produced a positive staining in all the benign tumors, as well as all the leiomyosarcomas and the veins from which they originated. A strong and uniform positivity was observed in the benign tumors and muscle walls of the veins, while the positivity in the leiomyosarcomas was more irregular, as it was for desmin. Vimentin was constantly expressed in the benign tumors and in the veins of origin, but only in 5/10 of the leiomyosarcomas. It is concluded from this study that the immunohistochemical demonstration of desmin, utilizing a monoclonal antibody appropriate to the type of fixation used, and muscle specific isoforms of actin, provide strong support to the light-microscopic diagnosis of leiomyosarcoma of venous origin.

Phenolic extractives from root bark of Picea abies.

Five new compounds, viz. 3,4-dimethoxyphenyl 2-O-(3-O-methyl-alpha-L-rhamnopyranosyl)-beta-D-glucopyranoside, 4'-hydroxyphenacyl beta-D-glucopyranoside, (2R,3R)-2,3-dihydro-7-hydroxy-2-(4'- hydroxy-3'-methoxyphenyl)- 3-hydroxymethyl-5-benzofuranpropanol 4'-O-(3-O-methyl-alpha-L-rhamnopyranoside), 1-(4'-hydroxy-3'-methoxyphenyl)-2-[4"-(3-hydroxypropyl)-2"-methoxyphe noxy]-1,3-propanediol 4'-O-beta-D-xylopyranoside and 3'-O-methylcatechin 7-O-beta-D-glucopyranoside, together with several known compounds were isolated from the root bark of Picea abies. The structures were elucidated on the basis of chemical and spectroscopic evidence.

Pyrone and pyridone compounds in the liquid culture of Physisporinus sanguinolentus.

Chromatographic separation of the liquid culture filtrate of the basidiomycete fungus Physisporinus sanguinolentus has yielded three new compounds viz., 2-methyl-4-pyrone, 2-methyl-5,6-dihydro-4-pyrone and the pyridone form of 4-hydroxy-2-methylpyridine, together with the known triacetic acid lactone, the sesquiterpene dialdehyde merulidial and a derivative of merulidial. Their structures were elucidated by spectroscopic analysis and by comparison to literature data and a synthetic sample. One of the compounds, merulidial, was shown to inhibit the germination of spores and the hyphal growth of the wood-rotting basidiomycete Heterobasidion annosum and the saprophytic mould Cladosporium cucumerinum.

Triterpenoid saponins from Quillaja saponaria.

Three new saponins were isolated from a commercial bark extract of Quillaja saponaria Molina. These compounds were also obtained as degradation products from larger saponins in this extract when treated with strong alkali. The compounds were characterized, using mainly NMR spectroscopy, mass spectrometry and chemical methods, as quillaic acid 3-O-¿beta-D-galactopyranosyl-(1-->2)-beta-D-glucopyranosiduronic acid¿, 3-O-¿alpha-L-rhamnopyranosyl-(1-->3)-[beta-D-galactopyranosyl-(1-->2)] -beta-D-glucopyranosiduronic acid¿ and 3-O-¿beta-D-xylopyranosyl-(1-->3)-[beta-D-galactopyranosyl -(1-->2)]-beta-D-glucopyranosiduronic acid¿, respectively.

Identification of a sucrose diester of a substituted beta-truxinic acid in oats.

A novel compound, 4,4'-dihydroxy-3,3'-dimethoxy-beta-truxinic acid esterified to sucrose through the fructosyl 3-and 6-carbons (1), was isolated from oat grains (Avena sativa L.). Its structure was determined by a combination of mass spectrometry and 1-D and 2-D NMR. The amounts of 1 in groats of six different oat cultivars ranged from 101 to 150 microg g(-1) (dry wt). None was detected in the hulls. The free diacid, 4,4'-dihydroxy-3,3'-dimethoxy-beta-truxinic acid (2), could not be detected in groats nor in hulls.

An oligomer from flaxseed composed of secoisolariciresinoldiglucoside and 3-hydroxy-3-methyl glutaric acid residues.

A straight-chain oligomeric structure composed of five secoisolariciresinoldiglucoside (SDG) residues interconnected by four 3-hydroxy-3-methyl glutaric acid (HMGA) residues (molecular weight ca. 4000 Da) was assigned to the main lignan of flaxseed on the basis of nuclear magnetic resonance spectroscopy (NMR).

HPLC method for analysis of secoisolariciresinol diglucoside in flaxseeds.

A method was developed for the analysis of secoisolariciresinol diglucoside (SDG) in flaxseeds. The analytical method involves extraction of defatted flaxseed flour with dioxane/ethanol, aqueous base-hydrolysis, solid-phase purification of an SDG-containing fraction, and quantitative analysis by high-performance liquid chromatography (HPLC). Pure SDG was isolated from flaxseed using different column chromatographic methods and used, as external standard, for the calibration of the method and for quantification. The method was then applied to study the variation in SDG content in flaxseeds from 14 cultivars grown in Sweden and 15 cultivars grown in Denmark. The SDG content varied between 11.7 and 24.1 mg/g in defatted flaxseed flour and between 6.1 and 13.3 mg/g in whole flaxseeds.

Racial and ethnic differences in drug treatment entry of injection drug users in Massachusetts.

This article examines patterns of drug treatment entry among 28,000 adult injection drug users (IDUs), with special attention to racial and ethnic differences. The data analyzed originates from a statewide drug-treatment database covering four years. Through the use of logistic regression analysis, the study identified significant population differences between those who used detoxification only, those who used residential treatment and those who used methadone maintenance. Latino IDUs were approximately a third less likely than Caucasian IDUs to enter residential treatment and African American IDUs were half as likely as Caucasian IDUs to enter methadone maintenance treatment. This article discusses specific programmatic and research implications including the need to determine whether differential entry rates are due to access, client awareness, cultural, referral or other factors.

African-American injection drug users: association between pre-treatment services and entry into and completion of detoxification.

Research suggests that African-American injection drug users, when compared with other ethnic and racial groups of injection drug users, are more likely to have no history of substance abuse treatment. The project evaluated was designed to attract African-American injection drug users to treatment by providing comprehensive pre-treatment services including street outreach, drop-in center services, case management, and motivational counseling. The overall program goal was to facilitate clients' acceptance of referral to treatment and readiness to utilize treatment. The evaluation described here examines whether, for this African-American population of hard-core drug users, utilization of pre-treatment services improved the intermediary treatment outcomes of entry into and completion of detoxification. Findings showed that high utilization of drop-in center services increased the frequency of entrance into detoxification programs. Entrance into detoxification has been shown to be significantly correlated with (a) entrance into further treatment, (b) reduced HIV/AIDS risk, and (c) successful linkage with health care and social services. Contrary to expectations, high utilization of pre-treatment services was not significantly correlated to increased completion of detoxification.