Effects Of Different Treatment Modalities Research Articles

Neuropsychological short assessment of disease- and treatment-related intelligence deficits in children with brain tumours

ObjectiveThe Wuerzburger Psychologische Kurz-Diagnostik (WUEP-KD) is a short screening battery for cognitive deficits in children with brain tumour. We report on its psychometric quality and testing efficiency. Material and methodsWUEP-KD was founded on Cattell-Horn-Carroll (CHC) framework of cognitive abilities. We assessed the construct validity of the short battery by conducting factor analysis and the concurrent validity by multiple linear regressions with Kaufman Assessment Battery for Children (K-ABC). The concurrent validity was explored by multiple linear regressions with Wechsler Intelligence Scale for Children (WISC). The discriminant validity was examined by a reanalysis of harmful effects of brain tumour treatments in a medulloblastoma cohort. ResultsThe construct validity assessment revealed three neuropsychological domains: cognitive operations, executive abilities, and psychomotor abilities. The retest reliabilities for individual testing and the convergent coefficients of the WUEP-KD with K-ABC and WISC yielded satisfactory results. The cognitive effects of different treatment modalities in the medulloblastoma cohort matched exactly previously reported data on the decline of general intelligence scores and delivered the details for the harmful effects. An in-depth analysis based on Hedges' g effect sizes confirmed specific harmful late effects on all abilities of cognitive operations, on the executive ability of perceptual speed and on psychomotor ability of movement steadiness. ConclusionWUEP-KD is a valid and efficient short test instrument, which may be especially useful in larger cohorts, multicenter settings or if patients do not tolerate longer tests. Due to its foundation on the CHC framework, our findings provide a rationale to create a common data set along with scores from other factor-based tests in international studies.

Autoimmune Cytopenia in Chronic Lymphocytic Leukemia: Effect on Outcome and Survival, a Population Based Analysis in British Columbia, Canada

Background: Among Chronic Lymphocytic Leukemia (CLL) patients (pts), 4-10% are diagnosed with autoimmune cytopenias (AC) at some point during the course of their disease. This is less common than cytopenias related to bone marrow infiltration (10-20%). Infiltrative cytopenias (IC) are clearly a poor prognostic factor. However, the effect of AC on survival and prognosis of CLL pts remains understudied.Objectives: To determine the prevalence of AC and IC among CLL pts and their effect on overall survival (OS) and time to first treatment (TTFT) compared to patients without cytopenia. Furthermore, the effect of different treatment modalities including chemotherapy and chemo-immunotherapy on the disease course was evaluated in patients with AC.Methods: A population-based retrospective analysis through an electronic search of pts within the Providence Health Care CLL database between 1978 and 2013 was carried out. The diagnostic criteria for autoimmune hemolytic anemia (AIHA) were positive direct antiglobulin test and laboratory evidence of hemolysis, for immune thrombocytopenia (ITP) the exclusion of other etiologies of thrombocytopenia and for pure red cell aplasia (PRCA) anemia with low reticulocyte count and bone marrow evidence of decreased erythropoiesis. Infiltrative cytopenia diagnosis was confirmed by bone marrow biopsy based on lymphocyte percentage and cellularity. Anemia was defined as hemoglobin <100 g/L. Thrombocytopenia was defined as platelets <100 x 109/L. Baseline features of pts with AC and IC were compared using Chi-squared analysis for categorical and the Kruskal-Wallis test for continuous variables. Overall survival was calculated from the date of initial treatment to the date of death from any cause. Time to first treatment (TTFT) was defined as the time interval between the date of diagnosis and date of first CLL treatment. Survival analysis was performed by the Kaplan–Meier method using IBM SPSS statistics for windows.Results: Among 754 pts with CLL, 80 (10.6%) developed cytopenias (anemia and thrombocytopenia). Of those, 50 (6.6%) had IC and 30 (4%) had AC. There was no significant difference between the 2 groups in terms of age, gender, hemoglobin, platelets, LDH, WBC and lymphocyte count at diagnosis. The time to development of cytopenias for the IC and AC groups was similar with median of 3 and 4 years (yrs) from diagnosis, respectively. Within the AC group 16 pts had AIHA, 8 had ITP, 5 had both (Evan’s Syndrome) and 1 had PRCA. The median OS was 12.2 yrs (5.9–18.3) and 13 yrs (1.6-24.3) for IC and AC, respectively (p=0.260). However, when compared to CLL pts without cytopenias (median not reached), the AC group had worse OS (p< 0.005) (Fig 1). For the IC and AC groups, the median TTFT was 6.5 yrs (4.5-8.5) and 8.2 yrs (4.1–12.3), respectively (p=0.191). For the CLL pts without cytopenias TTFT was 8.1 yrs (2-12.2), similar to the AC group (p=0.88) (Fig 2). For AC pts, the OS was not significantly different based on treatment received: alkylator based therapy vs. chemo-immunotherapy (p= 0.885). The effect of concomitant hypo-gammaglobulinemia on OS and treatment outcome was studied.Of the 30 pts with AC, 26 had a serum protein electrophoresis done. Of those, 10 (38.5%) had normal results and 16 (61.5%) had low gammaglobulin levels (IgG< 6 g/L); the mean OS was 18.1 yrs and 15.7 yrs respectively (median not reached), (P=0.433).Conclusion: The prognosis of pts with autoimmune and infiltrative cytopenias was similar.However, CLL pts with AC had worse OS compared to those without cytopenias. There was no significant difference in TTFT between AC and IC or when compared to CLL pts without cytopenias. For the AC group, neither treatment with chemotherapy vs. chemo-immunotherapy nor having concomitant hypo-gammaglobulinemia had an effect on outcome. To our knowledge, there are limited population based studies addressing the importance of determining the etiology of cytopenias in CLL pts and the effect of AC on survival. CLL immune complications need to be studied further especially in the context of novel agents and their effects on immune reconstitution. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hemoglobin A1c Levels and risk of severe hypoglycemia in children and young adults with type 1 diabetes from Germany and Austria: a trend analysis in a cohort of 37,539 patients between 1995 and 2012.

Severe hypoglycemia is a major complication of insulin treatment in patients with type 1 diabetes, limiting full realization of glycemic control. It has been shown in the past that low levels of hemoglobin A1c (HbA1c), a marker of average plasma glucose, predict a high risk of severe hypoglycemia, but it is uncertain whether this association still exists. Based on advances in diabetes technology and pharmacotherapy, we hypothesized that the inverse association between severe hypoglycemia and HbA1c has decreased in recent years. We analyzed data of 37,539 patients with type 1 diabetes (mean age ± standard deviation 14.4 ± 3.8 y, range 1-20 y) from the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative diabetes cohort prospectively documented between January 1, 1995, and December 31, 2012. The DPV cohort covers an estimated proportion of >80% of all pediatric diabetes patients in Germany and Austria. Associations of severe hypoglycemia, hypoglycemic coma, and HbA1c levels were assessed by multivariable regression analysis. From 1995 to 2012, the relative risk (RR) for severe hypoglycemia and coma per 1% HbA1c decrease declined from 1.28 (95% CI 1.19-1.37) to 1.05 (1.00-1.09) and from 1.39 (1.23-1.56) to 1.01 (0.93-1.10), respectively, corresponding to a risk reduction of 1.2% (95% CI 0.6-1.7, p<0.001) and 1.9% (0.8-2.9, p<0.001) each year, respectively. Risk reduction of severe hypoglycemia and coma was strongest in patients with HbA1c levels of 6.0%-6.9% (RR 0.96 and 0.90 each year) and 7.0%-7.9% (RR 0.96 and 0.89 each year). From 1995 to 2012, glucose monitoring frequency and the use of insulin analogs and insulin pumps increased (p<0.001). Our study was not designed to investigate the effects of different treatment modalities on hypoglycemia risk. Limitations are that associations between diabetes education and physical activity and severe hypoglycemia were not addressed in this study. The previously strong association of low HbA1c with severe hypoglycemia and coma in young individuals with type 1 diabetes has substantially decreased in the last decade, allowing achievement of near-normal glycemic control in these patients. Please see later in the article for the Editors' Summary.

Effect of Different Treatment Modalities on Colon Adenoma and Advanced Adenoma Among Type 2 Diabetes Mellitus Patients

Effect of Different Treatment Modalities on Colon Adenoma and Advanced Adenoma Among Type 2 Diabetes Mellitus Patients

Does treatment for cervical and vulvar dysplasia impact women’s sexual health?

Human papillomavirus-associated disease represents an immense public health burden worldwide. Persistent human papillomavirus infection can lead to the development of cervical dysplasia and vulvar dysplasia, both of which have been increasing in incidence in women in recent years. Numerous studies have focused on methods for screening and diagnosis of cervical dysplasia, but few have looked at the effects of treatment on women's psychological and sexual health. Even fewer studies have addressed these issues in women with vulvar dysplasia. The aim of this article was to provide a comprehensive review of the existing evidence concerning the impact of therapy for cervical and vulvar precancers on women's sexual function and sexual relationships. We performed a search of the medical literature for the time period up to and including August 2013 on PubMed. The findings from a limited number of studies to date indicate that psychosexual vulnerability increases after diagnosis and treatment of both cervical and vulvar dysplasia. More in-depth research is needed to better understand the effects of different treatment modalities on women's sexual health and relationships during and following treatment.

Outcomes of tongue squamous cell carcinoma treated with different treatment modalities

Objective To analyze the therapeutic effects of different treatment modalities in patients with tongue squamous cell carcinoma.Methods A retrospective analysis was performed on the complete clinical and follow-up data of 132 patients with pathologically confirmed tongue squamous cell carcinoma,who were initially treated at the First Affiliated Hospital of Xinjiang Medical University from 2003 to 2011.The Kaplan-Meier method was used to calculate the overall survival (OS) rates for patients who received surgery alone (S),radiotherapy alone (R),surgery plus radiotherapy (S + R),chemotherapy plus surgery (C + S),chemotherapy plus radiotherapy (C + R),and surgery,radiotherapy,and chemotherapy (S + R + C).The OS was compared between these groups by log-rank test.Multivariate analysis was performed using the Cox proportional hazard model to establish independent treatment modalities as prognostic factors.Results The follow-up rate was 100％.The 3-year sample size was 94.The 3-year OS rate for all patients was 72.7％.The univariate analysis showed that among 70 stage Ⅰ and Ⅱ patients,the S,R,S + R,C + S,and S + R + C groups had 3-year OS rates of 86％,67％,97％,100％,and 82％,respectively (P =0.018) ;among 62 stage Ⅲ and Ⅳ patients,the S,R,S + R,C + S,C + R,and S + R + C groups had 3-year OS rates of 38％,14％,92％,40％,14％,and 67％,respectively (P =0.000).The multivariate analysis showed that S + R and S + R + C were independent prognostic factors (P =0.000 and 0.005).onclusions Surgery alone or combination therapy including surgery has a good therapeutic effect for stage Ⅰ-Ⅱ tongue squamous cell carcinoma,while S + R and S + R + C are better treatment modalities for stage Ⅲ-Ⅳ disease;however,advanced patients have a poor prognosis after being treated with R and C + R modalities. Key words: Tongue neoplasms/surgery; Tongue neoplasms/radiotherapy; Tongue neoplasms/chemotherapy; Tongue neoplasms/combined modality therapy; Prognosis

Effectiveness of different treatment modalities for the management of adult-onset granulosa cell tumours of the ovary (primary and recurrent).

Granulosa cell tumour is a rare gynaecological tumour of the ovary with recurrences many years after initial diagnosis and treatment. Evidence-based management of granulosa cell tumour of the ovary is limited, and treatment has not been standardised. Surgery, including fertility-sparing procedures for young women, has traditionally been the standard treatment. Adjuvant treatments following surgery have been based on non-randomised trials. A combination of bleomycin, etoposide and cisplatin (BEP) has traditionally been used for treatment of advanced and/or recurrent disease that cannot be optimally managed surgically. To evaluate the effectiveness and safety of different treatment modalities offered in current practice for the management of primary, residual and recurrent adult-onset granulosa cell tumours (GCTs) of the ovary. We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to December 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. We searched for randomised controlled trials (RCTs), quasi-RCTs and observational studies that examined women with adult-onset granulosa cell tumours of the ovary (primary and recurrent). For non-randomised studies, we included studies that used multivariate analysis to adjust for baseline characteristics. Two review authors independently abstracted data and assessed risk of bias. Studies were heterogeneous with respect to treatment comparisons, so data were not synthesised in meta-analyses, and methods for assessing heterogeneity were not needed. Risk of bias in included studies was assessed by using the six core items used to assess RCTs and by evaluating four additional criteria specifically addressing risk of bias in non-randomised studies. Five retrospective cohort studies (535 women with a diagnosis of GCT) that used appropriate statistical methods for adjustment were included in the review.Two studies, which carried out multivariate analyses that attempted to identify factors associated with better outcomes (in terms of overall survival), reported no apparent evidence of a difference in overall survival between surgical approaches, whether a participant underwent lymphadenectomy or received adjuvant chemotherapy or radiotherapy. Only percentage of survival for all participants combined was reported in two trials and was not reported at all in one study.One study showed that women who received postoperative radiotherapy had lower risk of disease recurrence compared with those who underwent surgery alone (adjusted hazard ratio (HR) 0.3, 95% confidence interval (CI) 0.1 to 0.6, P value 0.04). Three studies reportedthat there was no evidence of differences in disease recurrence based on execution and type of adjuvant chemotherapy or on type of surgery or surgical approach, other than that surgical staging may be important. One study described no apparent evidence of a difference in disease recurrence between fertility-sparing surgery and conventional surgery. Recurrence-free survival was not reported in one study.Toxicity and adverse event data were incompletely reported in the five studies. None of the five studies reported on quality of life (QoL). All studies were at very high risk of bias. One study showed a lower recurrence rate with the use of adjuvant radiotherapy, although this study was at high risk of bias and the results should be interpreted with caution. After evaluating the five small retrospective studies, we are unable to reach any firm conclusions as to the effectiveness and safety of different types and approaches of surgery, including conservative surgery, as well as adjuvant chemotherapy or radiotherapy, for management of GCTs of the ovary. The available evidence is very limited, and the review provides only low-quality evidence. Further research is very likely to have an important impact on our confidence in the estimate of effect and may alter our findings.Ideally, multinational RCTs are needed to answer these questions. The disease is relatively rare and generally has a good prognosis. RCTs are challenging to conduct, but three ongoing trials have been identified, demonstrating that they are feasible, although two of these studies are single-arm trials. The study that may be able to provide answers to the question of which chemotherapeutic regimen should be selected for management of sex cord stromal tumours is an ongoing, randomised, phase 2 study, led by the Gynaecological Oncology Group to compare the efficacy of carboplatin and paclitaxel versus standard BEP. These investigators are also looking into the value of inhibin A and inhibin B as predictive biomarkers. Additional trials are required to assess toxicity and QoL associated with different treatment regimens as well as the safety of conservative surgical options.

The effectiveness of different treatment modalities for the rehabilitation of unilateral neglect in stroke patients: A systematic review

Patients suffering from unilateral neglect syndrome (UNS) are not able to respond to stimuli administered to the side of the body opposite to the lesion. UNS is most commonly seen after right-hemisphere lesions. Patients with UNS experience more problems with activities of daily living and recovery after stroke is delayed. To investigate which treatment modalities can alleviate the symptoms of UNS after stroke and to determine their effectiveness. Databases PubMed, Web of knowledge and PEDro have been searched. Quality assessment was conducted using the 9-item Delphi list. Data extraction was performed by the first author. Effect sizes have been calculated using Cohen's d. 15 RCT's have been included. Most studies used add-on therapies. Almost all studies found improvements in both groups, but only 7 trials showed statistically significant between group differences in favor of the experimental group. Large effect sizes were found in only four studies. All the interventions discussed in this review can reduce the symptoms of UNS. However, TENS, optokinetic stimulation, somatosensory electrostimulation, mirror therapy and virtual reality training seem to be the most effective treatment methods (d > 0,80). Future research should focus on producing studies of higher methodological quality with larger sample sizes.

The Natural History of Esophagogastric Junction Outflow Obstruction and Treatment Outcomes

Purpose: Esophagogastric junction outflow obstruction (EGJOO) is a diagnosis made by high resolution manometry (HRM) that represents a heterogeneous group of disorders that cause dysphagia. Potential causes of EGJOO include evolving achalasia, strictures, extrinsic compression by tumors or the aorta, and functional obstruction where no cause is found. The focus after encountering EGJOO should be in determining the cause of the obstruction, then treating the cause. Little is known about the natural history of EGJOO. Methods: We conducted a retrospective chart review and cross sectional phone survey of patients (25-92 years old) with a diagnosis of EGJOO by HRM between June 2010 to June 2012. EGJOO was defined as a minimum integrated relaxation pressure (IRP) of 15 mmHg as well as at least one normal or weak swallow on HRM. Exclusion criteria included diagnosis other than EGJOO on HRM and a history of prior surgical procedure causing the EGJOO. Chart review measures included patient demographic and clinical characteristics (documented symptoms, prior endoscopies, endoscopic ultrasound, and treatments). Patients were contacted via telephone between November 2012 and April 2013 and asked to rate specific symptoms on a severity scale both before and after diagnosis with manometry, and whether improvement in symptoms had been achieved. Results: Ninety-four patients with EGJOO based on HRM data were initially included in the analysis. 16 patients that had a surgical cause of the EGJOO were excluded, and 21 patients were unable to complete the phone survey for various reasons. Dysphagia was the predominant symptom that initiated HRM testing (46%), followed by chest pain (32%), heartburn (20%), or nausea and vomiting (19%). Of the patients contacted by phone (N=57), 61.4% reported overall improvement in their symptoms; however, many of these patients did not receive treatment for EGJOO (54.4%). There were proportionally more patients reporting improvement in symptoms who received treatment (69.2%) compared to those who did not (54.8%), but this did not reach statistical significance (P=0.115). Conclusion: Dysphagia is the most common presenting symptom in patients with a diagnosis of EGJOO, although other atypical symptoms such as heartburn, regurgitation, and nausea and vomiting may be present, likely due to the diversity of causes. The majority of patients reported improvement in symptoms over time. Future research should involve prospective, well designed studies with a greater number of patients to evaluate the effect of different treatment modalities on patient outcomes.Table: Table. Demographics, swallow characteristics, and treatmentsTable: Table. Improvement by treatment status

Severe renal tubulopathy in a newborn due to BCS1L gene mutation: Effects of different treatment modalities on the clinical course

Very early onset Toni–Debré–Fanconi Syndrome, a disorder of proximal renal tubules of the kidney which results in the increased urinary excretion of glucose, amino acids, uric acid, phosphate and bicarbonate, could be the manifestation of various inborn errors. Defects of oxidative phosphorylation are a heterogeneous group of disorders with various clinical presentations. Recently, patients with early liver failure, renal tubulopathy and encephalopathy due to the mutations in the BCS1L gene coding for a structural protein in mitochondrial complex III have been described.Ten-day-old female newborn was referred to our clinic because of intractable acidosis. Physical examination revealed severe hypotonia, and hepatomegaly. The laboratory examinations revealed lactic acidosis, increased blood alanine, alanine aminotransferase and aspartate aminotransferase levels, generalized aminoaciduria and glucosuria. The tubular reabsorption of phosphate was reduced. Because of multisystem involvement, mitochondrial disease was suspected and the mutational analysis of the BCS1L gene revealed homozygous P99L mutation. As the patient was unresponsive to bicarbonate replacement, oral dichloroacetate and peritoneal dialysis, continuous high dose intravenous sodium bicarbonate therapy with a dose up to 1.25mEq/kg/h was started. The patient got on well until the age of 9months when she died of sepsis.It was stressed that high dose intravenous continuous sodium bicarbonate therapy could be an alternative treatment option in patients with severe acidosis and renal tubulopathy resistant to dichloroacetate and peritoneal dialysis. Patients with BCS1L mutations should be considered in the differential diagnosis of severe tubulopathy in the newborn period.

FRI0428 Anti –tnf-a therapy and arterial stiffness in anklosing spondylitis; results with long-term 2 year- follow-up

BackgroundAnti-TNF-α are effectively used in management of AS, a chronic disease with increased risk of future cardiovascular events, but influence and additional benefit of these agents on arterial stiffness, a...

Abstract 82: Comparison of Outcomes by Type of Treatment for Patients with ST-Elevation Myocardial Infarction (STEMI) who presented to Hospitals without Percutaneous Coronary Intervention (PCI) Facilities in Quebec, Canada

BACKGROUND: Guidelines recommend that STEMI patients who present to non-PCI centers generally be treated with fibrinolysis instead of untimely transfer for primary PCI (i.e., first medical contact [FMC] to device ≥120 min). Little real-world evidence exists for this recommendation since transfer patients are often excluded from clinical registries. A provincial field evaluation of the whole system of STEMI care in Quebec (Canada) provided the opportunity to compare the effectiveness of different treatment modalities, including, importantly, inter-hospital transfer for primary PCI. METHODS: All STEMI patients who presented to non-PCI hospitals during two 6-month periods in 2006-7 and 2008-9 were identified (N=2623) and followed up to one year. Detailed information on patient risk factors and treatment delays was extracted from medical charts. We used a multivariate Cox proportional hazards model with time-dependent treatment modelling to assess the hazard ratio of death for 5 treatment modalities: on-site fibrinolysis without later transfer to a PCI center; on-site fibrinolysis with subsequent transfer; timely transfer for primary PCI; untimely transfer for primary PCI; no reperfusion therapy. RESULTS: Median FMC-to-device delay for transfer primary PCI patients was 131 min (interquartile range, IQR: 107-166) and only 29% had timely treatment. Median door-to-needle delay was 30 min (IQR: 20-48) with 70% being transferred, after fibrinolysis, to a PCI center (81% subsequently received PCI). Median time to transfer after fibrinolysis was 17.8 hours (IQR: 3.3-77.3). Compared with untimely transfer for primary PCI, the adjusted hazard ratio was 0.29 (95% CI: 0.15-0.56) for timely primary PCI transfer, 0.52 (95% CI: 0.29-0.95) for fibrinolysis with subsequent transfer, 1.18 (95% CI: 0.75-1.84) for fibrinolysis alone and 1.74 (95% CI: 1.31-2.31) for no reperfusion therapy. CONCLUSION: Timely treatment delay is associated with improved STEMI survival. These results also provide real-world evidence to support the guideline recommendation to prioritize on-site treatment with fibrinolysis (with consideration of subsequent transfer to a PCI center) over untimely transfer for primary PCI. Transfer to a PCI center after fibrinolysis mostly occurred the following day, suggesting that transfer need not necessarily be immediate.

Nonsarcoid granulomatous myopathy: two cases and a review of literature

Granulomatous myopathy is an uncommon skeletal muscles disorder. It can develop in association with other granuloma-forming diseases and is then considered a secondary myopathy or, less frequently, a primary disorder for which no etiology is identified. Studies of granulomatous myopathies have focused on examining the differences between primary and secondary diseases. Herein, we describe two cases of nonsarcoid granulomatous myopathies, for which diagnostic work-up did not reveal an underlying granuloma-causing pathology. The patients exhibited similar histopathological characteristics in skeletal muscle biopsies. However, they had different clinical presentations and therapeutic responses. Specifically, one patient had distal muscle weakness with a poor response to immunosuppressive treatment, whereas the other had a more proximal muscle weakness distribution and a very good response to treatment with corticosteroids and azathioprine, resulting in remission. More studies are warranted to further characterize the clinical course and effect of different treatment modalities on nonsarcoid granulomatous myopathy.

Abstract IA5: Genetics of clonal progression in pancreatic cancer

Abstract The goal of our laboratory is to understand the extent to which genetic features of a neoplasm influence its metastatic progression. Towards this goal we have focused on human pancreatic ductal adenocarcinoma (PDAC) as it represents an ideal tumor type for study of the metastatic process. For example, the precursor lesions that give rise to PDAC have been described in detail (pancreatic intraepithelial neoplasia, or PanIN), exomic sequencing has elucidated the major genetic alterations of this tumor type, and the accumulation of these genetic alterations during PanIN formation underlies the well accepted genetic progression model of pancreatic ductal carcinogenesis. Finally, PDAC is a tumor type that is often diagnosed in the advanced stages of disease and thus most patients have their primary carcinoma in situ for comparison to matched metastatic disease. Such is not the case for many other common human tumor types. We have taken the unique approach of performing rapid autopsies for acquisition of primary and metastatic cancer tissues from a large number of individuals, and have used this resource to make several novel observations related to the timing of acquisition of metastatic traits. First, not all pancreatic cancers are metastatic; of those that do form metastases the range of deposits seen at autopsy ranges from few (&amp;lt;10, oligometastatic disease) to &amp;gt;100 (widely metastatic). Moreover, loss of the SMAD4 tumor suppressor gene that occurs during carcinogenesis is highly correlated with widespread metastatic disease. Second, using a whole exome sequencing approach we have defined the clonal evolution of PDAC. This has shown that the majority of genetic alterations are founder mutations in that they are encompassed with the parental clone of cells that give rise to PDAC, upon which are superimposed additional genetic alterations that accumulate during subclonal evolution. Geographic mapping of subclones based on their unique genetic signatures indicates that metastatic subclones originate within the primary carcinoma; moreover, several years are required for development of metastatic subclones beyond initiation of the infiltrating carcinoma by the parental clone. Thus, even in carcinomas with SMAD4 loss additional events are needed for successful metastasis to occur. Most recently, we have investigated pancreatic cancer progression by utilizing a mathematical framework of metastasis formation together with comprehensive data of PDAC patients obtained at autopsy. This work indicates that primary and metastatic PDAC growth is initially exponential, and that patients with seemingly early stage disease likely harbor metastases at diagnosis. Furthermore, based on the estimating rates of PDAC growth and dissemination, we analyzed the effects of different treatment modalities and found that therapies which efficiently reduce the growth rate of cells earlier in the course of treatment appear to be superior to upfront tumor resection. These lines of investigation not only shed light on this difficult tumor type but also have implications for most other major tumor types for which metastatic progression is common. Citation Format: Christine A. Iacobuzio-Donahue. Genetics of clonal progression in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA5.

Physical and Psychological Effects of Treatment on Sexual Functioning in Colorectal Cancer Survivors

As a result of advances in surgical techniques and (neo)adjuvant therapy, mortality rates for colorectal cancer (CRC) have declined significantly in the last two decades. In general, CRC survivors report good health-related quality of life in survivorship. However, many survivors, including those who describe their quality of life as good, also report sexual problems that persist long after treatment is completed. In this article, we review the effects of different treatment modalities for CRC on sexual functioning in men and women. We highlight both the physical and psychological aspects of CRC treatment and discuss the management of common sexual problems in CRC survivors. The authors reviewed the existing available published articles regarding this topic. Our review of the evidence suggests that surgical treatment and (neo)adjuvant therapy for CRC are commonly associated with a wide range of sexual problems. Sexual functioning is an important functional outcome after CRC treatment and is influenced by a myriad of clinical and patient factors, including an individual's physical and psychological well-being after a diagnosis of CRC. As such, the assessment and management of sexual functioning in men and women with CRC should begin prior to the initiation of treatment and continue throughout treatment and survivorship.

Abstract 3961: Computational modeling of pancreatic cancer reveals growth and dissemination kinetics and suggests optimum treatment strategies

Abstract Pancreatic cancer is a leading cause of cancer-related death, largely due to metastatic dissemination. We investigated pancreatic cancer progression by utilizing a mathematical framework of metastasis formation together with comprehensive data of 228 patients, 101 of whom had autopsies. We found that pancreatic cancer growth is initially exponential. After estimating the rates of pancreatic cancer growth and dissemination, we determined that patients likely harbor metastases at diagnosis and predicted the number and size distribution of metastases as well as patient survival. These findings were validated in an independent database. Finally, we analyzed the effects of different treatment modalities, finding that therapies which efficiently reduce the growth rate of cells earlier in the course of treatment appear to be superior to upfront tumor resection. These predictions can be validated in the clinic. Our interdisciplinary approach provides insights into the dynamics of pancreatic cancer metastasis and identifies optimum therapeutic interventions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3961. doi:1538-7445.AM2012-3961

Abstract SY30-01: Evolution and dynamics of pancreatic cancer progression

Abstract The goal of our laboratory is to understand the extent to which genetic features of a neoplasm influence its metastatic progression. Towards this goal we have focused on human pancreatic ductal adenocarcinoma (PDAC) as it represents an ideal tumor type for study of the metastatic process. For example, the precursor lesions that give rise to PDAC have been described in detail (pancreatic intraepithelial neoplasia, or PanIN), exomic sequencing has elucidated the major genetic alterations of this tumor type, and the accumulation of these genetic alterations during PanIN formation underlies the well accepted genetic progression model of pancreatic ductal carcinogenesis. Finally, PDAC is a tumor type that is often diagnosed in the advanced stages of disease. We have taken the unique approach of performing rapid autopsies for acquisition of primary and metastatic cancer tissues from a large number of individuals, and have used this resource to make several novel observations. First, not all pancreatic cancers are metastatic; of those that do form metastases the range of deposits seen at autopsy ranges from few (&amp;lt;10, oligometastatic disease) to &amp;gt;100 (widely metastatic). Moreover, loss of the DPC4/SMAD4 tumor suppressor gene that occurs during PanIN formation is highly correlated with widespread metastatic disease. Second, using a whole exome sequencing approach we have defined the clonal evolution of PDAC. This has shown that the majority of genetic alterations are founder mutations in that they are encompassed with the parental clone of cells that give rise to PDAC, upon which are superimposed additional genetic alterations that accumulate during subclonal evolution. Geographic mapping of subclones based on their unique genetic signatures indicates that metastatic subclones originate within the primary carcinoma; moreover, several years are required for development of metastatic subclones beyond initiation of the infiltrating carcinoma by the parental clone. Most recently, we have investigated pancreatic cancer progression by utilizing a mathematical framework of metastasis formation together with comprehensive data of PDAC patients obtained at autopsy. This work indicates that primary and metastatic PDAC growth is initially exponential, and that patients with seemingly early stage disease likely harbor metastases at diagnosis. Furthermore, based on the estimating rates of PDAC growth and dissemination, we analyzed the effects of different treatment modalities and found that therapies which efficiently reduce the growth rate of cells earlier in the course of treatment appear to be superior to upfront tumor resection. These lines of investigation not only shed light on this difficult tumor type but also have implications for other major tumor types for which metastatic progression and treatment failure are common. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY30-01. doi:1538-7445.AM2012-SY30-01

The effect of different treatment modalities on the calcification potential and cross-linking stability of bovine pericardium

Porcine heart valves and bovine pericardium exhibit suitable properties for use as substitutes in cardiothoracic surgery, but must meet several requirements to be safe and efficient. Treatment with glutaraldehyde (GA) render some of these requirements, but calcification and degradation post-implant remain a problem. This study aimed to identify additional biochemical treatments that will minimize calcification potential without compromising the physical properties of pericardium. Pericardium treated with GA calcified severely after 8 weeks in the subcutaneous rat model, compared to tissue treated with higher concentrations of glycosaminoglycans (GAG) and commercial Glycar patches. GA, lower concentrations GAG and Glycar pericardium had high denaturation temperatures due to enhanced cross-linking. Tensile strength of GA tissue was significantly lower than GAG-treated or Glycar tissues, due to lower water content with resultant lower flexibility and suppleness. Pericardium treated with 0.01 M GAG gave acceptable denaturation temperatures, tensile strength and reduced calcification potential. All tissue treatments evoked comparable host immune responses, and no significant difference in resistance to enzymatic degradation. Ineffective stabilization and fixation of cross-links following GAG treatment, as well as limited penetration into the pericardium, resulted in GAG leaching out into the surrounding host tissue or storage medium, and prohibits safe clinical use of such tissue.

Brain functional connectivity of male patients in remission after the first episode of schizophrenia

Abnormal task-related activation and connectivity is present in schizophrenia. The aim of this study was the analysis of functional networks in schizophrenia patients in remission after the first episode. Twenty-nine male patients in remission after the first episode of schizophrenia and 22 healthy controls underwent examination by functional magnetic resonance during verbal fluency tasks (VFT). The functional connectivity of brain networks was analyzed using independent component analysis. The patients showed lower activation of the salience network during VFT. They also showed lower deactivation of the default mode network (DMN) during VFT processing. Spectral analysis of the component time courses showed decreased power in slow frequencies of signal fluctuations in the salience and DMNs and increased power in higher frequencies in the left frontoparietal cortex reflecting higher fluctuations of the network activity. Moreover, there was decreased similarity of component time courses in schizophrenia—the patients had smaller negative correlation between VFT activated and deactivated networks, and smaller positive correlations between DMN subcomponents. There is still an abnormal functional connectivity of several brain networks in remission after the first episode of schizophrenia. The effect of different treatment modalities on brain connectivity, together with temporal dynamics of this functional abnormality should be the objective of further studies to assess its potential as a marker of disease stabilization.

Biomechanical effects of different treatment modalities used in knee pain during cycling

Background: Little work has been undertaken on the biomechanical effects of patellofemoral taping and bracing in cycling. Objective: The purpose of the study was to assess the three-dimensional movement of the knee joint at different levels of resistance, across four treatment conditions, in experienced cyclists and discuss the clinical implications of the findings. Method: 15 healthy male subjects were asked to conduct four separate tests at three separate resistances on a static trainer. Each test used a different treatment modality. The order of testing was randomised a) no intervention, b) placebo patella taping, c) a patellofemoral brace, d) McConnell patella taping. Kinematic data were collected using a 10 camera ProReflex motion analysis system. Reflective markers were placed on the foot, shank, thigh and pelvis using the CAST technique. Results: A repeated measures two-way ANOVA test was performed together with posthoc Pairwise comparison with Bonferroni adjustment to examine the difference in three dimensional movement under the different conditions. Results (small significant differences) were presented in ROM tables for clinical application and relevance. Extension (1-2 p=0.002, 1-3 p= 0.003, 2-3 p= 0.004). Coronal plane between brace and neutral taping (p= 0.033) also between resistances 1 & 3 and 2 & 3 (p= 0.035, p=0.011). Transverse plane (p= 0.028) between Brace and McConnell taping. Conclusion: If changes in the cycling movement patterns are required in clinical treatment, then taping or bracing may possibly affect this. However, a full understanding of an individual’s biomechanical movement and cycling position is required as generic adaptations that do not take into account position, cadence, skin/fabric movement and power, and may be counterproductive. This study provides some initial understanding of the possible effects of bracing and taping in experienced cyclists, the application of taping may alter the biomechanics of the cycling action. Taping seems to initiate changes in ROM but as yet it is unclear as to its implication with respect to pain reduction. This study also helps us to understand that bracing is both impractical and any resultant changes during cycling are unlikely to be measurable.