HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives.

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27-29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

Imaging findings of recurrent pancreatic cancer following resection.

Pancreatic cancer is a challenging malignancy to treat, largely due to aggressive regional involvement, early systemic dissemination, high recurrence rate, and subsequent low patient survival. Generally, 15-20% of newly diagnosed pancreatic cancers are candidates for possible curative resection. Eighty percent of these patients, however, will experience locoregional or distant recurrence in first 2 years. Although there is no strong evidence-based guideline for optimal surveillance after pancreatic cancer resection, careful comparison of surveillance follow-up multi-detector CT (MDCT) studies with a postoperative baseline MDCT examination aids detection of early recurrent pancreatic cancer. In this review article, we describe imaging findings suggestive of recurrent pancreatic cancer and review routine and alternative imaging options.

Meta-analysis of benefits of portal-superior mesenteric vein resection in pancreatic resection for ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma has a poor prognosis without surgery. No standard treatment has yet been accepted for patients with portal-superior mesenteric vein (PV-SMV) infiltration. The present meta-analysis aimed to compare the results of pancreatic resection with PV-SMV resection for suspected infiltration with the results of surgery without PV-SMV resection. METHODS: A systematic search was performed of PubMed, Embase and the Cochrane Library in accordance with PRISMA guidelines from the time of inception to 2013. The inclusion criteria were comparative studies including patients who underwent pancreatic resection with or without PV-SMV resection. One, 3- and 5-year survival were the primary outcomes. RESULTS: Twenty-seven studies were identified involving a total of 9005 patients (1587 in PV-SMV resection group). Patients undergoing PV-SMV resection had an increased risk of postoperative mortality (risk difference (RD) 0.01, 95 per cent c.i. 0.00 to 0.03; P = 0.2) and of R1/R2 resection (RD 0.09, 0.06 to 0.13; P < 0.001) compared with those undergoing standard surgery. One-, 3- and 5-year survival were worse in the PV-SMV resection group: hazard ratio 1.23 (95 per cent c.i. 1.07 to 1.43; P = 0.005), 1.48 (1.14 to 1.91; P = 0.004) and 3.18 (1.95 to 5.19; P < 0.001) respectively. Median overall survival was 14.3 months for patients undergoing pancreatic resection with PV-SMV resection and 19.5 months for those without vein resection (P = 0.063). Neoadjuvant therapies recently showed promising results. CONCLUSION: This meta-analysis showed increased postoperative mortality, higher rates of non-radical surgery and worse survival after pancreatic resection with PV-SMV resection. This may be related to more advanced disease in this group.

Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery.

Precise fluorescence-guided surgery (FGS) for pancreatic cancer has the potential to greatly improve the outcome in this recalcitrant disease. To achieve this goal, we have used genetic reporters to color code cancer and stroma cells in a patient-derived orthotopic xenograft (PDOX) model. The telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 was used to label the cancer cells of a pancreatic cancer PDOX. The PDOX was previously grown in a red fluorescent protein (RFP) transgenic mouse that stably labeled the PDOX stroma cells bright red. The color-coded PDOX model enabled FGS to completely resect the pancreatic tumors including stroma. Dual-colored FGS significantly prevented local recurrence, which bright-light surgery or single-color FGS could not. FGS, with color-coded cancer and stroma cells has important potential for improving the outcome of recalcitrant-cancer surgery.

HIV is hyperendemic among men who have sex with men in San Francisco: 10-year trends in HIV incidence, HIV prevalence, sexually transmitted infections and sexual risk behaviour.

OBJECTIVES: To evaluate trends in the HIV epidemic among men who have sex with men (MSM) in San Francisco and the implications for HIV prevention. METHODS: An ecological approach assessed temporal trends in sexual risk behaviour, sexually transmitted infections (STI), HIV incidence and prevalence from multiple data sources between 1998 and 2007. RESULTS: By 2007, there were over 13 000 HIV-infected MSM living in San Francisco. No consistent upward or downward temporal trends were found in HIV incidence, newly reported HIV cases, AIDS deaths, proportion of AIDS cases using antiretroviral therapy, rectal gonorrhoea or primary and secondary syphilis cases among MSM during the study period. Trends in indicators of sexual risk behaviour among MSM were mixed. Overall, unprotected anal intercourse (UAI) increased in community-based surveys. Among HIV-positive MSM, no significant trends were noted for UAI. Among HIV-negative MSM, UAI with unknown serostatus partners decreased but increased with potentially discordant serostatus partners. Among MSM seeking HIV testing, increases were noted in insertive UAI at anonymous testing sites and at the STI clinic, in receptive UAI at anonymous test sites and in receptive UAI with a known HIV-positive partner at the STI clinic. CONCLUSIONS: Temporal trends in multiple biological and behavioural indicators over the past decade describe a hyperendemic state of HIV infection among MSM in San Francisco, whereby prevalence has stabilised at a very high level. In the absence of new, effective prevention strategies this state will persist.

Increases in sexually transmitted infections and sexual risk behaviour without a concurrent increase in HIV incidence among men who have sex with men in San Francisco: a suggestion of HIV serosorting?

BACKGROUND: Sexually transmitted infections (STI) and unprotected anal intercourse (UAI) have been increasing among men who have sex with men (MSM) in San Francisco. However, HIV incidence has stabilised. OBJECTIVES: To describe recent trends in sexual risk behaviour, STI, and HIV incidence among MSM in San Francisco and to assess whether increases in HIV serosorting (that is, selective unprotected sex with partners of the same HIV status) may contribute to preventing further expansion of the epidemic. METHODS: The study applies an ecological approach and follows the principles of second generation HIV surveillance. Temporal trends in biological and behavioural measures among MSM were assessed using multiple pre-existing DATA SOURCES: STI case reporting, prevention outreach programmatic data, and voluntary HIV counselling and testing data. RESULTS: Reported STI cases among MSM rose from 1998 through 2004, although the rate of increase slowed between 2002 and 2004. Rectal gonorrhoea cases increased from 157 to 389 while early syphilis increased from nine to 492. UAI increased overall from 1998 to 2004 (p<0.001) in community based surveys; however, UAI with partners of unknown HIV serostatus decreased overall (p<0.001) among HIV negative MSM, and among HIV positive MSM it declined from 30.7% in 2001 to a low of 21.0% in 2004 (p<0.001). Any UAI, receptive UAI, and insertive UAI with a known HIV positive partner decreased overall from 1998 to 2004 (p<0.001) among MSM seeking anonymous HIV testing and at the STI clinic testing programme. HIV incidence using the serological testing algorithm for recent HIV seroconversion (STARHS) peaked in 1999 at 4.1% at the anonymous testing sites and 4.8% at the STI clinic voluntary testing programme, with rates levelling off through 2004. CONCLUSIONS: HIV incidence among MSM appears to have stabilised at a plateau following several years of resurgence. Increases in the selection of sexual partners of concordant HIV serostatus may be contributing to the stabilisation of the epidemic. However, current incidence rates of STI and HIV remain high. Moreover, a strategy of risk reduction by HIV serosorting can be severely limited by imperfect knowledge of one's own and one's partners' serostatus.

Volatile anaesthetics may be the main cause of early but not delayed postoperative vomiting: a randomized controlled trial of factorial design.

BACKGROUND: Despite intensive research, the main causes of postoperative nausea and vomiting (PONV) remain unclear. We sought to quantify the relative importance of operative, anaesthetic and patient-specific risk factors to the development of PONV. METHODS: We conducted a randomized controlled trial of 1180 children and adults at high risk for PONV scheduled for elective surgery. Using a five-way factorial design, we randomly assigned subjects by gender who were undergoing specific operative procedures, to receive various combinations of anaesthetics, opioids, and prophylactic antiemetics. RESULTS: Of the 1180 patients, 355 (30.1% 95% CI (27.5-32.7%)) had at least one episode of postoperative vomiting (PV) within 24 h post-anaesthesia. In the early postoperative period (0-2 h), the leading risk factor for vomiting was the use of volatile anaesthetics, with similar odds ratios (OR (95% CI)) being found for isoflurane (19.8 (7.7-51.2)), enflurane (16.1 (6.2-41.8)) and sevoflurane (14.5 (5.6-37.4)). A dose-response relationship was present for the use of volatile anaesthetics. In contrast, no dose response existed for propofol anaesthesia. In the delayed postoperative period (2-24 h), the main predictors were being a child (5.7 (3.0-10.9)), PONV in the early period (3.4 (2.4-4.7)) and the use of postoperative opioids (2.5 (1.7-3.7)). The influence of the antiemetics was considerably smaller and did not interact with anaesthetic or surgical variables. CONCLUSION: Volatile anaesthetics were the leading cause of early postoperative vomiting. The pro-emetic effect was larger than other risk factors. In patients at high risk for PONV, it would therefore make better sense to avoid inhalational anaesthesia rather than simply to add an antiemetic, which may still be needed to prevent or treat delayed vomiting.

Postexposure prophylaxis for human immunodeficiency virus infection after sexual or injection drug use exposure: identification and characterization of the source of exposure.

In a nonrandomized study of nonoccupational postexposure prophylaxis (PEP), a cross-sectional evaluation of subjects who were the source of human immunodeficiency (HIV) exposure was performed to characterize partners of index subjects seeking nonoccupational PEP against HIV. Among 401 index subjects, 64 (16%) recruited a source subject. Those in a steady relationship and those who knew that the source subject was HIV antibody positive were more likely to recruit their source subject. Source subjects reported high rates of past (78%) and current (69%) antiretroviral use; 46% of those using antiretroviral drugs had detectable plasma HIV-1 RNA levels. Antiretroviral resistance was detected in many source subjects who reported any use of antiretrovirals and was rare among source subjects who reported no history of antiretroviral use. Clinicians often make treatment decisions on the basis of incomplete knowledge of the source subject's HIV status or antiretroviral treatment history. The treatment history, particularly nonuse of a class of antiretroviral drugs, can be used to predict drug resistance.

Predictors of use of highly active antiretroviral therapy (HAART) among persons with AIDS in San Francisco, 1996-1999.

Highly active antiretroviral therapy (HAART) has contributed to a decrease in AIDS-related morbidity and mortality. This study used population-based AIDS surveillance data to evaluate the prevalence and predictors of HAART use among persons with AIDS in San Francisco. Use of HAART among persons living with AIDS increased from 41% in 1996 to 72% in 1999. Fourteen percent of persons diagnosed with AIDS between 1996 and 1999 initiated HAART before their AIDS diagnosis. Use of HAART before an AIDS diagnosis increased from 5% in 1996 to 26% in 1999. In the multivariable analysis, African Americans, injection drug users, and those without insurance at the time of AIDS diagnosis were less likely to use HAART before AIDS diagnosis. Delayed initiation of HAART after AIDS was more likely to occur among African Americans, injection drug users, homeless persons, those with public insurance, and those with higher CD4 counts. Although the overall prevalence of HAART use was high, disparity in use of HAART existed by race and risk group, patient's insurance status, and facility of diagnosis. Barriers in use of treatment should be identified so all persons with AIDS can benefit from improved therapies.

Incidence of human immunodeficiency virus among male-to-female transgendered persons in San Francisco.

OBJECTIVE: To estimate HIV incidence among male-to-female transgendered persons (MtF transgendered persons) who repeatedly tested for HIV antibodies at public San Francisco counseling and testing sites between July 1997 and June 2000. METHODS: HIV seroconversions were identified and person-time of observation were estimated using the date and result of the current test and the self-reported date and result of the previous test. Factors independently associated with HIV seroconversion were determined using multivariable proportional hazard analysis. RESULTS: HIV incidence was 7.8 per 100 person-years (95% confidence intervals [CI], 4.6-12.3) based on 13 seroconversions among 155 repeat testers with 167.7 person-years of observation. African-American race/ethnicity (adjusted relative hazard ratio [HR], 5.0; 95% CI, 1.5-16.2) and unprotected receptive anal intercourse (HR, 3.9; 95% CI, 1.2-13.1) were independent predictors of HIV seroconversion. CONCLUSIONS: HIV is currently spreading at an extremely high rate among MtF transgendered persons in San Francisco, especially those who are African Americans.

HIV incidence among repeat HIV testers at a county hospital, San Francisco, California, USA.

OBJECTIVES: To estimate HIV incidence, characterize correlates of HIV seroconversion, and monitor temporal trends in HIV transmission among patients repeatedly tested for HIV by a county hospital in San Francisco. DESIGN: Retrospective longitudinal study. METHODS: HIV incidence was retrospectively calculated among persons voluntarily tested for HIV antibody more than once at San Francisco's county hospital or one of its affiliated satellite community clinics between 1993 and 1999. Linkage of HIV test results in computerized databases identified "seroconverters" as individuals who had a negative antibody test followed by a positive test. The interval between tests was used as the person-time at risk. Cox proportional hazards analysis identified correlates of HIV seroconversion. RESULTS: A total of 84 HIV seroconversions were identified among 2893 eligible patients repeatedly tested for HIV antibody over a cumulative 5860 person-years (PYs) (incidence of 1.4 per 100 PYs, 95% confidence interval [CI]: 1.2-1.7). The majority of seroconversions (71 [84.5%]) were among injection drug users (IDUs) (incidence of 2.0 per 100 PYs, CI: 1.6-2.4). HIV incidence was highest among men who have sex with men (MSM) who were also IDUs (incidence of 3.8 per 100 PYs, CI: 2.7-5.1) and lowest among non-IDUs, heterosexual men, and non-IDU women (incidence of 0.3 per 100 PYs, CI: 0.1-0.6). In multivariate analysis, correlates of HIV seroconversion were age 25 to 29 years (hazard ratio [HR] = 3.9, CI: 2.4-6.3), MSM (HR = 2.9, CI: 1.9-4.4), and IDU (HR = 3.2, CI: 1.8-5.8). Overall, no temporal trend in annual HIV incidence was noted during the study period; however, HIV incidence among MSM IDUs increased from 2.9 per 100 PYs in 1996 to 4.7 per 100 PYs in 1998. CONCLUSIONS: The rate of seroconversion in this hospital and affiliated clinic population is unexpectedly high. Moreover, HIV transmission among IDU patients has not decreased over the last several years. The San Francisco county hospital provides a high-risk sentinel population to monitor emerging trends in HIV transmission, especially among IDUs, and presents multiple opportunities for prevention interventions, because these patients are being seen repeatedly by clinicians.

Effect of case management on unmet needs and utilization of medical care and medications among HIV-infected persons.

BACKGROUND: Although case management has been advocated as a method for improving the care of chronically ill persons, its effectiveness is poorly understood. OBJECTIVE: To assess the effect of case managers on unmet need for supportive services and utilization of medical care and medications among HIV-infected persons. DESIGN: Baseline and follow-up interview of a national probability sample. SETTING: Inpatient and outpatient medical facilities in the United States. PARTICIPANTS: 2437 HIV-infected adults representing 217 081 patients receiving medical care. MEASUREMENTS: Outcomes measured at follow-up were unmet need for supportive services, medical care utilization (ambulatory visits, emergency department visits, and hospitalizations), and use of HIV medication (receipt of antiretroviral therapy and prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis). RESULTS: At baseline, 56.5% of the sample had contact with a case manager in the previous 6 months. In multiple logistic regression analyses that adjusted for potential confounders, contact with a case manager at baseline was associated with decreased unmet need for income assistance (odds ratio [OR], 0.57 [95% CI, 0.36 to 0.91]), health insurance (OR, 0.54 [CI, 0.33 to 0.89]), home health care (OR, 0.29 [CI, 0.15 to 0.56]), and emotional counseling (OR, 0.62 [CI, 0.41 to 0.94]) at follow-up. Contact with case managers was not significantly associated with utilization of ambulatory care (OR, 0.77 [CI, 0.57 to 1.04]), hospitalization (OR, 1.13 [CI, 0.84 to 1.54]), or emergency department visits (OR, 1.30 [CI, 0.97 to 1.73]) but was associated with higher utilization of two-drug (OR, 1.58 [CI, 1.23 to 2.03]) and three-drug (OR, 1.34 [CI, 1.00 to 1.80]) antiretroviral regimens and of treatment with protease inhibitors or non-nucleoside reverse transcriptase inhibitors (OR, 1.29 [CI, 1.02 to 1.64]) at follow-up. CONCLUSIONS: Case management appears to be associated with fewer unmet needs and higher use of HIV medications in patients receiving HIV treatment.

Cost-effectiveness of prevention referrals for high-risk HIV-negatives in San Francisco.

We retrospectively assessed the cost-effectiveness of providing prevention referrals to high-risk seronegatives at HIV test sites in San Francisco. We examined the costs and effects from the perspectives of society and the San Francisco Department of Public Health (SFDPH). Cost categories assessed included referral materials, counsellor training and time required to make referrals, prevention services and the value of client time. Effect data are drawn from a study of 289 high-risk seronegatives and the published literature, and are applied to a city-wide caseload of 6,626 high-risk seronegatives. We estimate that a city-wide programme in San Francisco averts two HIV infections per year and yields net savings to society of $43,765, with a cost to the SFDPH of $20,738 per HIV infection averted. We conclude that providing HIV prevention referrals to high-risk seronegatives receiving antibody testing imposes significant costs, but has attractive cost-effectiveness when applied to a large high-risk population.

Risk of infection from needle reuse at a phlebotomy center.

OBJECTIVES: This study determined infection risk for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) from needle reuse at a phlebotomy center that possibly exposed 3810 patients to infection. METHODS: We used a model for the risk of infection per blood draw, supplemented by subsequent testing results from 1699 patients. RESULTS: The highest risk of transmission was for HBV infection: 1.1 x 10(-6) in the best case and 1.2 x 10(-3) in the (unlikely) worst case. Subsequent testing yielded prevalence rates of 0.12%, 0.41%, and 0.88% for HIV, HBV, and HCV, respectively, lower than National Health and Nutrition Examination Survey III prevalence estimates. CONCLUSIONS: The infection risk was very low; few, if any, transmissions are likely to have occurred.

Barriers to getting needed services for Ryan White CARE clients.

To determine why HIV-infected persons do not access needed services, we interviewed clients of Ryan White CARE-funded agencies in San Francisco, San Mateo and Marin Counties. From July to September 1996, we interviewed 519 clients receiving services at 65 CARE-funded sites. Just over half the clients (54.5%) had at least one unmet service need in the previous four months; persons in an unstable living situation and those with lower perceived health status were significantly more likely to have an unmet need. For persons with unmet needs, agency barriers were most common (54.0%), followed by emotional issues (44.8%), lack of information (44.0%) and financial/practical barriers (19.4%). None of the client characteristics (sex, race/ethnicity, age, living situation, perceived health status and risk group) were consistently or significantly (p < 0.05) associated with specific barriers. We believe that the similarity between clients with and without unmet needs reflects the success of CARE in eliminating many barriers. However, the persistence of certain barriers and lack of sub-group-specific barriers suggests the need for individualized interventions to improve service delivery, publicize service availability and address the emotional barriers to accessing HIV-related care.

Effect of highly active antiretroviral therapy on diagnoses of sexually transmitted diseases in people with AIDS.

BACKGROUND: There has been an increase in high-risk sexual behaviour and sexually transmitted diseases (STD) during the time period when highly active antiretroviral therapy (HAART) became widely available. We examined whether taking HAART increased the risk of acquiring an STD--an epidemiological marker of unsafe sex--in people with AIDS. METHODS: We did a computerised match of people in the San Francisco STD and AIDS registries. People with AIDS who were diagnosed before 1999 and alive in November, 1995, or later, were classified as having had an STD after AIDS diagnosis or not having had an STD after AIDS diagnosis. We used a Cox proportional hazards model to see whether use of antiretroviral therapy was associated with acquiring an STD after AIDS, after adjustment for sex, age, race, HIV-1 risk category, and CD4 count at AIDS diagnosis. FINDINGS: People with AIDS who had had HAART showed an independent increase in the risk of developing an STD (hazard ratio 4.10; 95% CI 2.84-5.94). Americans of African origin, younger age, and higher CD4 count at AIDS diagnosis were also associated with acquiring an STD after AIDS. The number of people living with AIDS who acquired an STD increased over time from 60 (0.66%) in 1995 to 113 (1.32%) in 1998 (p<0.001). INTERPRETATION: We have shown that people on HAART are more likely to develop an STD, an epidemiological marker of unsafe sex. More intensive risk-reduction counselling and STD screening for people with AIDS is needed.

Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug use exposure: the San Francisco PEP Study.

The feasibility of providing postexposure prophylaxis (PEP) after sexual or injection drug use exposures to human immunodeficiency virus (HIV) was evaluated. PEP was provided within 72 h to individuals with exposures from partners known to have or to be at risk for HIV infection. PEP consisted of 4 weeks of antiretroviral medications and individually tailored risk-reduction and medication-adherence counseling. Among 401 participants seeking PEP, sexual exposures were most common (94%; n=375). Among sexual exposures, receptive (40%) and insertive (27%) anal intercourse were the most common sexual acts. The median time from exposure to treatment was 33 h. Ninety-seven percent of participants were treated exclusively with dual reverse-transcriptase inhibitors, and 78% completed the 4-week treatment. Six months after the exposure, no participant developed HIV antibodies, although a second PEP course for a subsequent exposure was provided to 12%. PEP, after nonoccupational HIV exposure, is feasible for persons at risk for HIV infection.

Postexposure prophylaxis for HIV after sexual assault.

PIP: This paper presents the findings of a retrospective review of charts of sexual assault survivors who were offered postexposure prophylaxis (PEP) between April 1998 and November 1999 at San Francisco General Hospital. The total cost of PEP medications was also computed. Overall, it is noted that one-third of the 367 sexual assault survivors chose to initiate PEP. Men who were anally raped are at the highest risk for HIV transmission and were most likely to initiate PEP. Among women, on the other hand, those who were non-White and homeless were less likely to accept PEP. In the context of cost, the total per-person cost of medication dispensed during the study period (US$65 per person offered PEP) is comparable to other medications offered routinely following sexual assault, such as azithromycin for chlamydia prophylaxis (US$43 per treatment). However, there is no definitive evidence that PEP is effective in preventing HIV seroconversion after sexual assault. It is suggested that in developing rational policy recommendation offering HIV PEP after sexual assault, further studies are needed to better delineate the rates of HIV seroprevalence among sexual assailants, the efficacy of PEP after sexual exposure, and the psychological benefits or harm incurred by the sexually assaulted patients.^ieng