Duc T.M. Nguyen

Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series

BACKGROUND At present, intrahepatic cholangiocarcinoma is a contraindication for liver transplantation. However, previous studies in this field did not preselect patients on the basis of chemosensitivity or disease trajectory after neoadjuvant therapy. Experience with hilar cholangiocarcinoma has indicated that neoadjuvant therapy followed by liver transplantation in patients without disease progression results in a long-term survival benefit. We aimed to establish the potential efficacy of liver transplantation in patients with biologically responsive intrahepatic cholangiocarcinoma who have had sustained tumour stability or regression with neoadjuvant therapy. METHODS In this prospective case-series, patients with locally advanced, unresectable intrahepatic cholangiocarcinoma, without extrahepatic disease or vascular involvement, were treated at a single liver transplant centre according to a non-randomised, centre-approved clinical management protocol with neoadjuvant chemotherapy followed by liver transplantation. Neoadjuvant therapy consisted of gemcitabine-based chemotherapy, such as gemcitabine-cisplatin or gemcitabine-capecitabine, with second-line or third-line therapies given per institutional standards. Patients with a minimum of 6 months of radiographic response or stability were listed for liver transplantation. The primary endpoints were overall survival and recurrence-free survival after liver transplantation, assessed with Kaplan-Meier analysis. This report includes interim data from the initial case-series treated under this ongoing clinical management protocol, censored on Dec 1, 2017. FINDINGS Between Jan 1, 2010, and Dec 1, 2017, 21 patients were referred for evaluation and 12 patients were accepted, of whom six patients have undergone liver transplantation for intrahepatic cholangiocarcinoma. Three patients received livers from extended criteria deceased donors that would otherwise have been discarded, two from domino living donors, and one from a standard criteria liver donor. Median duration from diagnosis to transplantation was 26 months (IQR 17-33) and median follow-up from transplantation was 36 months (29-51). All patients received neoadjuvant chemotherapy while awaiting liver transplantation. Overall survival was 100% (95% CI 100-100) at 1 year, 83·3% (27·3-97·5) at 3 years, and 83·3% (27·3-97·5) at 5 years. Three patients developed recurrent disease at a median of 7·6 months (IQR 5·8-8·6) after transplantation, with 50% (95% CI 11·1-80·4) recurrence-free survival at 1, 3, and 5 years. Adverse events after liver transplantation included one patient with postoperative ileus (grade 3) and one patient with acute kidney injury requiring temporary dialysis (grade 4). INTERPRETATION Selected patients with locally advanced intrahepatic cholangiocarcinoma who show pre-transplant disease stability on neoadjuvant therapy might benefit from liver transplantation. FUNDING None.

Intersubtype Reassortments of H5N1 Highly Pathogenic Avian Influenza Viruses Isolated from Quail

H5N1 highly pathogenic avian influenza (HPAI) viruses are considered a threat to national animal industries, causing production losses and high mortality in domestic poultry. In recent years, quail has become a popular terrestrial poultry species raised for production of meat and eggs in Asia. In this study, to better understand the roles of quail in H5N1 viral evolution, two H5N1-positive samples, designated A/quail/Vietnam/CVVI-49/2010 (CVVI-49/2010) and A/quail/Vietnam/CVVI-50/2014 (CVVI-50/2014), were isolated from quail during H5N1 outbreaks in Vietnam, and their whole genome were analyzed. The phylogenetic analysis reveals new evolutionary variation in the worldwide H5N1 viruses. The quail HA genes were clustered into clades 1.1.1 (CVVI-49/2010) and clade 2.3.2.1c (CVVI-50/2014), which may have evolved from viruses circulating from chickens and/or ducks in Cambodia, mainland of China, Taiwan, Indonesia, and South Korea in recent years. Interestingly, the M2 gene of the CVVI-49/2010 strain contained amino acid substitutions at position 26L-I and 31S-N that are related to amantadine-resistance. In particular, the CVVI-50/2014 strain revealed evidence of multiple intersubtype reassortment events between virus clades 2.3.2.1c, 2.3.2.1b, and 2.3.2.1a. Data from this study supports the possible role of quail as an important intermediate host in avian influenza virus evolution. Therefore, additional surveillance is needed to monitor these HPAI viruses both serologically and virologically in quail.

Early clearance vs persistence of de novo donor-specific antibodies following lung transplantation

The natural history of de novo donor‐specific antibodies (dnDSA) after lung transplantation is not well‐described. We sought to determine the incidence and risk factors associated with dnDSA and compare outcomes between recipients with transient (or isolated) vs persistent dnDSA after transplantation.

Yield of chest radiograph in tuberculosis screening for HIV-infected persons at a district-level HIV clinic

SETTING An Hoa Clinic, a district-level human immunodeficiency virus (HIV) clinic in Ho Chi Minh City, Viet Nam. OBJECTIVE To assess the performance of chest radiograph (CXR) in screening for pulmonary tuberculosis (PTB) among HIV-infected individuals and identify misdiagnosed opportunities. DESIGN This cross-sectional study was conducted in 397 HIV-infected patients consecutively enrolled at the An Hoa Clinic in Ho Chi Minh City, Viet Nam, from August 2009 to June 2010. The performance of CXR in TB screening was assessed based on its sensitivity, specificity, positive likelihood ratio and negative likelihood ratio. RESULTS Symptom screening alone missed 50% of PTB cases. The combination of CXR and symptom screening yielded an additional 28.6% (8/28) in PTB screening as compared with symptom screening alone, and should be applied routinely, especially in high TB prevalent settings. CONCLUSION CXR is a good predictor for PTB even in HIV-infected individuals. The combination of CXR and screening for common TB symptoms considerably improved the sensitivity of detecting active PTB in people living with HIV. If available, routine sputum culture and the World Health Organization-endorsed Xpert(®) MTB/RIF assay should be implemented to achieve a more accurate diagnosis.

Predictive value of serum bradykinin and desArg9-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: A retrospective case series

BACKGROUND There is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (TB) in order to predict treatment outcomes. Exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (BK) and its metabolite desArg9-bradykinin (DABK) to induce inflammation and innate immune responses. We hypothesized that serum BK and DABK levels might act as sensitive immune response signatures for changes in Mycobacterium tuberculosis (Mtb) burden, and therefore examined how serum levels of these markers corresponded with anti-TB therapy in a small cohort of active TB cases. METHODS Nanotrap Mass-Spectrometry (MS) was used to analyze serial blood specimens from 13 HIV-negative adults with microbiologically confirmed active TB who were treated with first-line anti-TB chemotherapy. MS signal for BK (m/z 1060.5) and DABK (m/z 904.5) serum peptides were evaluated at multiple time-points (before, during, and after treatment) to evaluate how BK and DABK levels corresponded with disease status. RESULTS Serum BK levels declined from pretreatment baseline levels during the early stage anti-TB therapy (induction phase) and tended to remain below baseline levels during extended treatment (consolidation phase) and after therapy completion. BK levels were consistent with induction phase sputum culture conversions indicative of decreased Mtb burden reflecting good treatment responses. Serum DABK levels tended to increase during the induction phase and decrease at consolidation and post-therapy time points, which may indicate a shift from active disease to chronic inflammation to a disease free state. Elevated BK and DABK levels after treatment completion in one patient may be related to the subsequent recurrent TB disease. CONCLUSIONS Our pilot data suggests that changes in the circulating BK and DABK levels in adult TB patients can be used as potential surrogate markers of the host response both early and late in anti-TB treatment for both pulmonary and extrapulmonary TB patients. We will further exploit these host-response signatures in the future as biomarkers in combination with other clinical and microbiologic tools which may improve treatment efficacy and facilitate the development of host-directed therapy.

Disparate rates of acute rejection and donor-specific antibodies among high-immunologic risk renal transplant subgroups receiving antithymocyte globulin induction.

Lymphocyte‐depleting induction lowers acute rejection (AR) rates among high‐immunologic risk (HIR) renal transplant recipients, including African Americans (AAs), retransplants, and the sensitized. It is unclear whether different HIR subgroups experience similarly low rates of AR. We aimed to describe the incidence of AR and de novo donor‐specific antibody (dnDSA) among HIR recipients categorized by age, race, or donor type. All received antithymocyte globulin (ATG) induction and triple maintenance immunosuppression. A total of 464 HIR recipients from 2007 to 2014 were reviewed. AR and dnDSA rates at 1 year for the entire population were 14% and 27%, respectively. AR ranged from 6.7% among living donor (LD) recipients to 30% in younger AA deceased donor (DD) recipients. De novo donor‐specific antibody at 1 year ranged from 7% in older non‐AA LD recipients to 32% in AAs. AA race remained as an independent risk factor for AR among DD recipients and for dnDSA among all HIR recipients. Development of both AR and dnDSA within the first year was associated with a 54% graft survival at 5 years and was an independent risk factor for graft loss. Despite utilization of recommended immunosuppression for HIR recipients, substantial disparities exist among subgroups, warranting further consideration of individualized immunosuppression in certain HIR subgroups.

Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections

Current immunosuppression regimens in organ transplantation primarily inhibit T cells. However, T cells are also critical in protective immunity, especially in immune‐compromised patients. In this study, we examined the association of T cell dysfunction, as marked by expression of T cell exhaustion molecules, and posttransplant infections in a cohort of liver transplant patients. We focused on Programmed Death 1 (PD‐1) and T cell Ig‐ and mucin‐domain molecule 3 (Tim‐3), which are potent co‐inhibitory receptors, and their persistent expression often leads to T cell dysfunction and compromised protective immunity. We found that patients with the highest expression of PD‐1 +Tim‐3+ T cells in the memory compartment before transplantation had increased incidence of infections after liver transplantation, especially within the first 90 days. Longitudinal analysis in the first year showed a strong association between variability of PD‐1 and Tim‐3 expression by T cells and infectious episodes in transplant patients. Furthermore, T cells that expressed PD‐1 and Tim‐3 had a significantly reduced capacity in producing interferon (IFN)‐γ in vitro, and this reduced IFN‐γ production could be partially reversed by blocking PD‐1 and Tim‐3. Interestingly, the percentage of Foxp3+ regulatory T cells in liver transplant patients was stable in the study period. We concluded that the functional status of T cells before and after liver transplantation, as shown by PD‐1 and Tim‐3 expression, may be valuable in prognosis and management of posttransplant infections.

White Blood Cell Counts, Alcoholism, and Cirrhosis in Pneumococcal Pneumonia

Abstract Background An elevated white blood cell (WBC) count is a characteristic finding in pneumococcal pneumonia. Very low WBC counts, occurring in some cases, are often associated with overwhelming pneumonia and have been attributed to alcohol-induced suppression of bone marrow. However, a systematic study of neutropenia, leukocytosis, alcohol ingestion, and cirrhosis in pneumococcal pneumonia has not been previously reported. Methods Using a database of patients with pneumococcal pneumonia at our medical center, we extracted data on WBC counts at admission, differential counts, alcohol ingestion, and cirrhosis, and we related these to 7-day and 30-day mortality. Results White blood cell counts were <6000/mm3 in 49 of 481 patients (10.2%) with pneumococcal pneumonia and >25000/mm3 in 40 (8.3%). Mortality at 7 days was 18.4% and 12.5%, respectively, 5-fold and 3-fold greater in patients with WBC <6000 or >25000 than in those with WBC counts between 6000 and 25000 (P < .001). Increased band forms were not associated with a worse outcome (P = .12). Alcohol use and cirrhosis were not associated with WBC counts <6000 (P = .63 and P = .41, respectively). Conclusions In a large series of cases of pneumococcal pneumonia, WBC counts <6000 or >25000 correlated significantly with increased 7-day mortality. More than 10% band forms was not associated with a poor outcome. Alcohol abuse was not associated with low WBC or increased mortality. Our findings suggest that greater consideration be given to more intense care for patients with bacterial pneumonia who have very high or very low WBC counts at the time of hospital admission.

Characteristics associated with negative interferon-γ release assay results in culture-confirmed tuberculosis patients, Texas, USA, 2013–2015

Interferon-γ release assays (IGRAs) are the preferred diagnostic test for tuberculosis (TB) infection in at-risk populations in developed countries. However, IGRAs have high false-negative rates in patients with TB disease. Population-based studies assessing the factors associated with negative IGRA results in TB patients have not been performed. Using statewide TB surveillance data of culture-confirmed TB patients in Texas, USA, during 2013–2015, we describe the patient characteristics and treatment outcomes associated with false-negative IGRA results. Among 2,854 TB patients, 1,527 (53.5%) had an IGRA result; 97.4% (1,487/1,527) of those had a positive (87.7%) or negative (12.3%) result. Older age, HIV co-infection, non-Hispanic white race/ethnicity, and being tested with T-SPOT.TB were associated with negative IGRA results. TB patients with negative IGRA results had a higher mortality, potentially due to delayed treatment. Healthcare providers should consider these risk factors when making decisions for patients with suspected TB and negative IGRA results and potentially provide treatment.

Novel Reassortant H5N6 Highly Pathogenic Influenza A Viruses in Vietnamese Quail Outbreaks

Avian influenza A H5N6 virus is a highly contagious infectious agent that affects domestic poultry and humans in South Asian countries. Vietnam may be an evolutionary hotspot for influenza viruses and therefore could serve as a source of pandemic strains. In 2015, two novel reassortant H5N6 influenza viruses designated as A/quail/Vietnam/CVVI01/2015 and A/quail/Vietnam/CVVI03/2015 were isolated from dead quails during avian influenza outbreaks in central Vietnam, and the whole genome sequences were analyzed. The genetic analysis indicated that hemagglutinin, neuraminidase, and polymerase basic protein 2 genes of the two H5N6 viruses are most closely related to an H5N2 virus (A/chicken/Zhejiang/727079/2014) and H10N6 virus (A/chicken/Jiangxi/12782/2014) from China and an H6N6 virus (A/duck/Yamagata/061004/2014) from Japan. The HA gene of the isolates belongs to clade 2.3.4.4, which caused human fatalities in China during 2014-2016. The five other internal genes showed high identity to an H5N2 virus (A/chicken/Heilongjiang/S7/2014) from China. A whole-genome phylogenetic analysis revealed that these two outbreak strains are novel H6N6-like PB2 gene reassortants that are most closely related to influenza virus strain A/environment/Guangdong/ZS558/2015, which was detected in a live poultry market in China. This report describes the first detection of novel H5N6 reassortants in poultry during an outbreak as well as genetic characterization of these strains to better understand the antigenic evolution of influenza viruses.