Case report: From palliative to potentially curative – the advent of immunotherapy providing hope to advanced gallbladder adenocarcinoma

IntroductionBiliary tract cancers (BTC) are often diagnosed at an advanced stage where prognosis is poor and curative-intent surgery is infeasible. First-line cisplatin-gemcitabine chemotherapy for advanced gallbladder cancer has remained unchanged over more than a decade, but recent developments in immunotherapy such as durvalumab have highlighted promise as a combination treatment regime with current standard chemotherapy.MethodsIn this case description, we present a case of locally-advanced gallbladder adenocarcinoma involving the biliary confluence that was initially planned for an extended right hepatectomy after portal vein embolization. Interval imaging revealed peritoneal metastasis, which was confirmed on diagnostic laparoscopy and biopsy. The patient underwent 8 cycles of cisplatin 25 mg/m2 and gemcitabine 1,000 mg/m2 chemotherapy on days 1 and 8 of each 21-day cycle, with durvalumab (Imfinzi®) 1,500 mg immunotherapy on day 1 of every cycle, in accordance with the treatment protocol of the TOPAZ-1 trial. Repeat imaging demonstrated a stable primary lesion with no further evidence of peritoneal disease. The patient subsequently underwent curative-intent conversion surgery with an extended right hepatectomy and Roux-en-Y hepaticojejunostomy, which were completed through a fully minimally-invasive laparoscopic approach.ResultsFinal pathological TNM classification was ypT1aN0, with near-complete pathological response to pre-surgical therapy, uninvolved margins (R0 resection) and tumour shrinkage from 2.5 centimetres on pre-operative cross-sectional imaging to 0.5 centimetres on final histology. The patient had an uneventful post-operative course, and was fit for discharge by the fourth post-operative day. He remained well after three months of routine post-operative follow-up, with no significant post-operative complications and biochemical or radiological evidence of disease recurrence.ConclusionOur case description highlights the immense potential of combination durvalumab immunotherapy with cisplatin-gemcitabine chemotherapy in the treatment of advanced gallbladder adenocarcinoma. The patient’s locally advanced disease was initially planned for complex open surgery, prior to discovery of peritoneal metastasis rendering it inoperable. This was successfully down-staged with combination therapy to eventual R0 resection via minimally-invasive surgery. In addition, this case description demonstrates the feasibility of a fully laparoscopic approach with postulated benefits of diagnostic re-evaluation of peritoneal disease, reduced wound pain and shorter length of hospital stay

Assessment of dizziness among older patients at a family practice clinic: a chart audit study

BACKGROUND: Dizziness is a common complaint among the elderly with a prevalence of over 30% in people over the age of 65. Although it is a common problem the assessment and management of dizziness in the elderly is challenging for family physicians. There is little published research which assesses the quality of dizziness assessment and management by family physicians. METHODS: We conducted a retrospective, chart audit study of patients with dizziness attending the Sunnybrook Family Practice Center of Sunnybrook and Women's College Health Sciences Center (SWCHSC) in Toronto. We audited a random sample of 50 charts of patients from 310 eligible charts. Quality indicators across all dizziness subtypes were assessed. These quality indicators included: onset and course of symptoms; symptoms in patients' own words; number of medications used; postural blood pressure changes; symptoms of depression or anxiety; falls; syncope; diagnosis; outcome; specialty referrals. Quality indicators specific to each dizziness subtype were also audited. RESULTS: 310 charts satisfied inclusion criteria with 20 charts excluded and 50 charts were randomly generated. Documentation of key quality indicators in the management of dizziness was sub-optimal. Charts documenting patients' dizziness symptoms in their own words were more likely to have a clinical diagnosis compared to charts without (P = 0.002). CONCLUSIONS: Documentation of selected key quality indicators could be improved, especially that of patients' symptoms in their own words

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Effectiveness of career academies: A quantitative study on career academy participation and its relationship to student achievement and engagement

The academic demands of No Child Left Behind have narrowed the curriculum and much of the teaching and learning is centered around performing on standardized tests. Many students are meeting these demands while others are slowly disengaging from the school creating the potential for dropping out. A curricular reform, called the career academy, was introduced in the 1970s to help keep students in school by focusing on vocational education and preparing students for entry-level jobs and skilled labor. Over the years, these entry-level jobs have evolved to include technical skills, and many require more than a high school diploma. The career academy model has evolved to incorporate an integrated vocational and academic curriculum, small learning community structure, and partnerships with local businesses to help students make the transition from school to work. Review of the literature on career academy effectiveness suggested positive effects on student engagement and mixed effects on academic achievement for students participating in career academies. The purpose of this study is to examine differences in student achievement and engagement between career academy and non-academy students. This quasi-experimental study utilized statistical controls for prior academic achievement in order to estimate the effects of academy participation with greater precision. Therefore, the statistical control will account for the varying initial achievements of students and the removal of the variance attributed to initial achievement allows the researcher to estimate the impact of career academy participation. The findings in this study suggest that low achieving students participating in career academies have significantly higher academic achievement than low achieving non-academy students. These results suggest the career academy model is beneficial to some students. Career academies can appeal to a wide variety of student interests and provide an alternative to the traditional academic curriculum by allowing students to integrate their learning of vocational skills with academic content. Additionally, students participating in career academies have the opportunity to complete the academic requirements needed to graduate from high school and qualify for postsecondary education

Study of serum inhibin levels in two in-vitro fertilization protocols

In order to characterize and compare the pattern of inhibin production in the follicular phase between patients of the clomiphene citrate/human menopausal gonadotropin (hMG) and Buserelin/hMG protocols in in-vitro fertilization, serum inhibin levels from 20 patients in each protocol were measured. The patients were matched for age and had tubal diseases only. It was hypothesized that the serum inhibin levels would be different in these two groups due to possible local actions of clomiphene citrate and Buserelin (a GnRH agonist) on the ovary. Serum inhibin levels were measured using an immunoenzymatic assay kit, with the mean interassay and intraassay coefficients of variation being 14.1% and 8.9% respectively. This assay did not cross-react with folliclestimulating hormone, luteinizing hormone, transforming growth factor β, activin A, insulin-like growth factor-1, seminal inhibin like peptide and human chorionic gonadotropin (hCG), but it could detect free a subunits of inhibin in addition to dimric inhibin. Apart from inhibin, serum estradiol-17/3 levels in patients from the two protocols were compiled from patient records. Serum inhibin was found to correlate significantly with serum estradiol-17/3 in the follicular phase (r= 0.844; P< 0.0001). In the clomiphene citrate/HMG protocol, on day 0 (day of ovulation trigger with hCG), day -1 (one day before hCG administration) and day -2 (two days before hCG administration), the serum inhibins were 6.84 +/- 0.76, 5.11 +/- 0.61, and 3.55 +/- 0.31 U/ml respectively; the serum estradiol-170 levels were 5141 +/- 353.6, 3332.7 +/- 192.6, and 2112.5 +/- 117.3 pmol/1 respectively. In the Buserelin/HMG protocol, on days 0, -1, and -2, the serum inhibin levels were 6.48 +/- 0.71, 5.47 +/- 0.49, and 4.0 +/- 0.35 U/ml respectively; the serum estradiol-17/3 levels were 4287.8 +/- 409.4, 2991.7 +/- 259.8, and 2093.5 +/- 151.3 pmol/1 respectively. Serum inhibin and estradiol-17/3 levels in these two protocols were compared by the unpaired t-test. No significant differences were found in serum inhibin and estradiol-17/3 levels on days 0, -1 and -2 between these two groups of patients (inhibin: P= 0.73, 0.639, and 0.37, respectively; estradiol-17/3: P= 0.123, 0.298 and 0.93, respectively). With respect to follicular growth as assessed by ultrasonography, the Buserelin/HMG protocol resulted in significantly greater number of large follicles with diameter greater than or equal to 17 mm on day 0 (2.45 +/- 0.28), compared with that in the corresponding size category of the clomiphene citrate/HMG protocol (1.50+/- 0.21) (P=0.0095). Whereas, in the size category of 10 to 13mm in follicular diameter on day 0, the number of follicles in the Buserelin/HMG protocol (4.7 + /- 0.7) was significantly smaller than that in the clomiphene citrate/HMG protocol (7.1 +/- 0.8) (P= 0.0306). Nevertheless, no significant differences were found in the number of oocytes retrieved, mature and total, between the two groups of patients. In summary, the clomiphene citrate/HMG and "ultra-short" Buserelin/HMG protocols resulted in similar ovarian responses as reflected by serum inhibin and estradiol-17/3 levels. Therefore, the data of the present study did not support the proposed hypothesis, despite the observation that the Buserelin/HMG protocol produced larger follicles.Medicine, Faculty ofObstetrics and Gynaecology, Department ofGraduat

Systematic review on volume-outcome relationship in radical prostatectomy

Background: Radical prostatectomy (RP) is one of the most complex urological procedures performed. A 2013 systematic review demonstrated that higher annual volume of cases undertaken by both surgeons and hospitals is associated with better short- and long-term outcomes. Objectives: To provide an updated systematic review of the association of hospital and surgeon volume on outcomes after RP. Search strategy: A systematic review of literature was undertaken, searching PubMed (1959-2016) for original articles. Selection criteria consisted RP, hospital and/or surgeon volumes as predictor variables, categorisation of hospital and/or surgeon volumes and measurable end-points. Evidence synthesis: The search terms used yielded 3,859 results, from which 49 publications were included. Most studies were retrospective and done using population-based or institutional databases. 11 studies examined both hospital and surgeon volumes, while the remainder investigated either in isolation. Most studies supported the association of increasing hospital or surgeon volume with improved RP outcomes, such as mortality, complications, costs and length-of-stay. A small proportion of studies did not show any significance between the two. Large variation existed between the studies with regard to volume cut-offs for evaluation of the volume-outcome relationship. Conclusion: Contemporary evidence continues to support the volume-outcome relationship for RP. Increasing studies outside of the US suggest reproducibility of this volume-outcome relationship around the world.Bachelor of Medicine and Bachelor of Surger

Accuracy of Perceived Estimated Travel Time by EMS to a Trauma Center in San Bernardino County, California

Introduction: Mobilization of trauma resources has the potential to cause ripple effects throughout hospital operations. One major factor affecting efficient utilization of trauma resources is a discrepancy between the prehospital estimated time of arrival (ETA) as communicated by emergency medical services (EMS) personnel and their actual time of arrival (TOA). The current study aimed to assess the accuracy of the perceived prehospital estimated arrival time by EMS personnel in comparison to their actual arrival time at a Level II trauma center in San Bernardino County, California.Methods: This retrospective study included traumas classified as alerts or activations that were transported to Arrowhead Regional Medical Center in 2013. We obtained estimated arrival time and actual arrival time for each transport from the Surgery Department Trauma Registry. The difference between the median of ETA and actual TOA by EMS crews to the trauma center was calculated for these transports. Additional variables assessed included time of day and month during which the transport took place.Results: A total of 2,454 patients classified as traumas were identified in the Surgery Department Trauma Registry. After exclusion of trauma consults, walk-ins, handoffs between agencies, downgraded traumas, traumas missing information, and traumas transported by agencies other than American Medical Response, Ontario Fire, Rialto Fire or San Bernardino County Fire, we included a final sample size of 555 alert and activation classified traumas in the final analysis. When combining all transports by the included EMS agencies, the median of the ETA was 10 minutes and the median of the actual TOA was 22 minutes (median of difference=9 minutes, p&lt;0.0001). Furthermore, when comparing the difference between trauma alerts and activations, trauma activations demonstrated an equal or larger difference in the median of the estimated and actual time of arrival (p&lt;0.0001). We also found month and time of day to be associated with variability in the difference between the median of the estimated andactual arrival time (p=0.0082 and p=0.0005 for month and time of the day, respectively).Conclusion: EMS personnel underestimate their travel time by a median of nine minutes, which may cause the trauma team to abandon other important activities in order to respond to the emergency department prematurely. The discrepancy between ETA and TOA is unpredictable, varying by month and time of day. As such, a better method of estimating patient arrival time is needed

Image_2_Case report: From palliative to potentially curative – the advent of immunotherapy providing hope to advanced gallbladder adenocarcinoma.jpg

IntroductionBiliary tract cancers (BTC) are often diagnosed at an advanced stage where prognosis is poor and curative-intent surgery is infeasible. First-line cisplatin-gemcitabine chemotherapy for advanced gallbladder cancer has remained unchanged over more than a decade, but recent developments in immunotherapy such as durvalumab have highlighted promise as a combination treatment regime with current standard chemotherapy.MethodsIn this case description, we present a case of locally-advanced gallbladder adenocarcinoma involving the biliary confluence that was initially planned for an extended right hepatectomy after portal vein embolization. Interval imaging revealed peritoneal metastasis, which was confirmed on diagnostic laparoscopy and biopsy. The patient underwent 8 cycles of cisplatin 25 mg/m2 and gemcitabine 1,000 mg/m2 chemotherapy on days 1 and 8 of each 21-day cycle, with durvalumab (Imfinzi®) 1,500 mg immunotherapy on day 1 of every cycle, in accordance with the treatment protocol of the TOPAZ-1 trial. Repeat imaging demonstrated a stable primary lesion with no further evidence of peritoneal disease. The patient subsequently underwent curative-intent conversion surgery with an extended right hepatectomy and Roux-en-Y hepaticojejunostomy, which were completed through a fully minimally-invasive laparoscopic approach.ResultsFinal pathological TNM classification was ypT1aN0, with near-complete pathological response to pre-surgical therapy, uninvolved margins (R0 resection) and tumour shrinkage from 2.5 centimetres on pre-operative cross-sectional imaging to 0.5 centimetres on final histology. The patient had an uneventful post-operative course, and was fit for discharge by the fourth post-operative day. He remained well after three months of routine post-operative follow-up, with no significant post-operative complications and biochemical or radiological evidence of disease recurrence.ConclusionOur case description highlights the immense potential of combination durvalumab immunotherapy with cisplatin-gemcitabine chemotherapy in the treatment of advanced gallbladder adenocarcinoma. The patient’s locally advanced disease was initially planned for complex open surgery, prior to discovery of peritoneal metastasis rendering it inoperable. This was successfully down-staged with combination therapy to eventual R0 resection via minimally-invasive surgery. In addition, this case description demonstrates the feasibility of a fully laparoscopic approach with postulated benefits of diagnostic re-evaluation of peritoneal disease, reduced wound pain and shorter length of hospital stay.</p

Identification of Tropical Plant Extracts That Extend Yeast Chronological Life Span

Certain plant extracts (PEs) contain bioactive compounds that have antioxidant and lifespan-extending activities on organisms. These PEs play different roles in cellular processes, such as enhancing stress resistance and modulating longevity-defined signaling pathways that contribute to longevity. Here, we report the discovery of PEs that extended chronological life span (CLS) in budding yeast from a screen of 222 PEs. We identified two PEs, the leaf extracts of Manihot esculenta and Wodyetia bifurcata that extended CLS in a dose-dependent manner. The CLS-extending PEs also conferred oxidative stress tolerance, suggesting that these PEs might extend yeast CLS through the upregulation of stress response pathways