Advanced Clinical Disease Research Articles

Role of prophylactic central neck lymph node dissection for papillary thyroid carcinoma in the era of de-escalation.

Thyroid cancer is the most common endocrine malignancy. While there has been no appreciable increase in the observed mortality of well-differentiated thyroid cancer, there has been an overall rise in its incidence worldwide over the last few decades. Patients with papillary thyroid carcinoma (PTC) and clinical evidence of central (cN1) and/or lateral lymph node metastases require total thyroidectomy plus central and/or lateral neck dissection as the initial surgical treatment. Nodal status in PTC patients plays a crucial role in the prognostic evaluation of the recurrence risk. The 2015 guidelines of the American Thyroid Association (ATA) have more accurately determined the indications for therapeutic central and lateral lymph node dissection. However, prophylactic central neck lymph node dissection (pCND) in negative lymph node (cN0) PTC patients is controversial, as the 2009 ATA guidelines recommended that CND "should be considered" routinely in patients who underwent total thyroidectomy for PTC. Although the current guidelines show clear indications for therapeutic CND, the role of pCND in cN0 patients with PTC is still debated. In small solitary papillary carcinoma (T1, T2), pCND is not recommended unless there are high-risk prediction factors for recurrence and diffuse nodal spread (extrathyroid extension, mutation in the BRAF gene). pCND can be considered in cN0 disease with advanced primary tumors (T3 or T4) or clinical lateral neck disease (cN1b) or for staging and treatment planning purposes. The role of the preoperative evaluation is fund-amental to minimizing the possible detrimental effect of overtreatment of the types of patients who are associated with low disease-related morbidity and mortality. On the other hand, it determines the choice of appropriate treatment and determines if close monitoring of patients at a higher risk is needed. Thus, pCND is currently recommended for T3 and T4 tumors but not for T1 and T2 tumors without high-risk prediction factors of recurrence.

Sex Disparities in Infra-inguinal Vein Bypass for Peripheral Artery Disease

Although studies demonstrate sex-based differences in peripheral arterial disease (PAD), contemporary outcomes in surgically managed PAD remains largely under-characterized. We sought to discern the differences in perioperative outcomes between males and females with PAD who received infra-inguinal vein bypasses. The infra-inguinal bypass Vascular Quality Initiative (VQI) registry was queried between 2010 and 2020. We evaluated patients with infra-inguinal vein bypasses for occlusive disease, excluding non-occlusive disease, asymptomatic, acute limb ischemia, and emergent procedures. Baseline demographics, comorbidities, prior medical and surgical management, and perioperative outcomes were compared between men and women using the χ2 analysis and t test. Socioeconomic status was defined using Distressed Community Index (DCI). Bypass patency at 1 year was compared between single-segment vein bypasses of the same inflow and outflow targets, using Kaplan-Meier analysis. We identified 28,845 infra-inguinal vein bypasses; 30.6% of patients were female. Female patients were older and had a higher portion of black race, non-ambulatory status, and disadvantaged socioeconomic DCI (Table I). Males had higher rates of smoking, chronic obstructive pulmonary disease, cardiac disease, and coronary percutaneous/bypass interventions. More women were on more likely to be taking P2Y inhibitors, possibly related to a significantly higher rate of prior lower extremity endovascular interventions (P < .001). Alternatively, males had higher rates of prior ipsilateral bypass. Men presented with less clinical disease severity, with a higher proportion of claudication in men vs rest pain in women. Females had a higher rate of popliteal bypass targets suggestive of proximal disease, whereas more males had tibial bypass targets suggestive distal disease (Table II). Women had a higher utilization of non-reversed GSV compared with men (24.2% vs 22.6%; P < .001). No significant differences were seen in total procedure time, blood loss, or postoperative infection. More males underwent postoperative amputation. Fewer women returned home or were ambulatory on discharge. Males were also more likely to be on aspirin and statin both prior to intervention and on discharge (P < .001). There was no significant differences between men and women in 5-year survival (74.6% vs 74.2%; P = .98) or 1-year primary patency in femoral-above knee popliteal (58.6% vs 58.0%; P = .720), femoral-below knee popliteal (57.2% vs 56.7%; P = .816), femoral-tibial (56.5% vs 57.7%; P = .520), or popliteal-tibial (58.0% vs 55.7%; P = .950) bypass. Females present with a unique demographic, socioeconomic, and PAD disease pattern, with diminished perioperative medical management and advanced clinical disease. Acknowledgment of these differences should guide increasing attention to screening programs, medical optimization, and post intervention disposition planning. Although less women were discharged on optimal medical management, bypass patency was similar to men at 1 year.Table ICategorical variables for patients receiving infra-inguinal vein bypassMaleFemaleP-valueDemographics Age, years66 ± 1067 ± 12<.001 Body mass index, kg/m227.7 ± 5.728.0 ± 6.9.042 Race<.001White82.2%76.7%Black13.8%19.7%Others4.0%3.6% Ambulatory status<.001Ambulatory95.5%93.5%Non-ambulatory4.5%6.5% DCI<.001Prosperous23.1%20.8%Comfortable21.3%20.3%Mid-tier20.7%19.4%At-risk18.3%19.6%Distressed16.7%19.9% Smoking history87.0%76%<.001 Chronic obstructive pulmonary disease24.6%26.3%<.001 Hypertension87.8%89.6%<.001 Diabetes mellitus52.6%49.0%.008 Coronary disease31.2%27.1%<.001 Heart failure17.1%16.9%.018 Peripheral endovascular42.9%47.9%<.001 Peripheral bypass25.3%23.6%.015 Minor amputation10.7%8.6%<.001 Percutaneous coronary22.6%20.1%<.001 Coronary bypass19.1%16.9%<.001 Aspirin74.3%73%.071P2Y inhibitor28.9%32.9%<.001 Statin75.1%71.7%<.001 Claudication26.6%21.0%<.001 Rest pain24.3%28.6% Tissue loss49.2%50.4%DCI, Disadvantaged Community Index. Open table in a new tab Table IIPerioperative outcomes for patients receiving infra-inguinal vein bypassMale, %Female, %P-valueBypass category<.001 Femoral-above knee popliteal13.319.8 Femoral-below knee popliteal31.635.1 Femoral-tibial42.235.3 Popliteal-tibial12.89.8Perioperative antibiotics82.779.7<.001SSI3.03.9<.002Postoperative amputation12.111.9<.001Discharge medications Aspirin86.684.7<.001 P2Y inhibitor41.645.1<.001 Statin83.979.2<.001Discharge status<.001 Home72.364.6 Rehab16.019.8 Nursing home10.914.5 Other0.81.1Discharge graft patency.002 Primary95.093.5 Primary-assisted2.53.1 Secondary1.72.2 Occluded0.81.2SSI, Surgical site infection. Open table in a new tab

Bone sialoprotein promotes lung cancer osteolytic bone metastasis via MMP14-dependent mechanisms

Bone metastases during lung cancer are common. Bone sialoprotein (BSP), a non-collagenous bone matrix protein, plays important functions in bone mineralization processes and in integrin-mediated cell-matrix interactions. Importantly, BSP induces bone metastasis in lung cancer, but the underlying mechanisms remain unclear. This study therefore sought to determine the intracellular signaling pathways responsible for BSP-induced migration and invasion of lung cancer cells to bone. Analyses of the Kaplan-Meier, TCGA, GEPIA and GENT2 databases revealed that high levels of BSP expression in lung tissue samples were associated with significantly decreased overall survival (hazard ratio = 1.17; p = 0.014) and with a more advanced clinical disease stage (F-value = 2.38, p < 0.05). We also observed that BSP-induced stimulation of matrix metalloproteinase (MMP)-14 promoted lung cancer cell migration and invasion via the PI3K/AKT/AP-1 signaling pathway. Notably, BSP promoted osteoclastogenesis in RAW 264.7 cells exposed to RANKL and BSP neutralizing antibody reduced osteoclast formation in conditioned medium (CM) from lung cancer cell lines. Finally, at 8 weeks after mice were injected with A549 cells or A549 BSP shRNA cells, the findings revealed that the knockdown of BSP expression significantly reduced metastasis to bone. These findings suggest that BSP signaling promotes lung bone metastasis via its direct downstream target gene MMP14, which reveals a novel potential therapeutic target for lung cancer bone metastases.

Penile cancer: 20 years of experience in a reference oncology center in Mexico.

6 Background: Penile cancer is a rare neoplasm (&lt;1%), being more common in underdeveloped countries, 10-20% of male neoplasms, with a mean age at diagnosis of 60 years. The number of annual cases in Mexico is only 660 cases, 0.35% of all neoplasms. Its initial symptomatology as a palpable or ulcerated lesion must be differentiated from infectious processes. From 30 to 60% of cases debut with inguinal lymphadenopathies and distant metastases in 1 to 10%. Methods: Cross-sectional, retrospective cohort study of patients diagnosed with penile cancer, who received medical care at the medical oncology service of the University Cancer Center from January 1, 1999 to December 31, 2019. Results: Of the 103 patients analyzed in this study, the mean age was 55 years (27-91 years), the highest level of schooling obtained was primary in 18.5%, being mostly from the state of Nuevo León in 61.1%. of the cases. The duration of symptoms was 17 months on average, and the time interval between diagnosis and receiving medical or surgical treatment was 97 days. Regarding the pathological characteristics of penile cancer, the average tumor size was 41.4mm, the most frequent histological type was squamous in 91.3%. Regarding the classification by clinical stages, patients in clinical stage I was 8%, II 10.6%, III 26.2% and IV 32%, not being recorded accurately in 23.3% of cases. The initial medical treatment was surgical in 81.5% of the cases, with partial phallectomy being the procedure of choice in 57.2% of the patients, with the presence of positive margins in 9.5% of the patients. Lymph node involvement was 71.2% of the cases and lymph node dissection was only performed in 31% of the patients. Those who received chemotherapy were 27.1% of the patients, the majority, 57.1% in the adjuvant setting, the most commonly used scheme was cisplatin with 5-fluoroacyl in 60.7%. Radiotherapy was used in 25.2% of the patients, being the adjuvant modality in 65.4% and in the palliative context in 34.6%, with an average dose of 46.5 Gy and 8 fractions. Conclusions: A diagnosis at an earlier age was observed in our court, being 55 years old vs 60 years old reported in the literature. A delay in diagnosis of up to 12 months has been reported in 15-50% in the literature, being higher in our population with a mean of 17.7 months. Poor adherence to treatment and clinical follow-up was observed, since one in 4 patients only goes to oncology once and loses follow-up. Penile cancer is a rare, psychologically devastating neoplasm with delayed diagnosis, advanced clinical disease, decreased survival, and high recurrence rates despite bimodal or trimodal treatment. A multidisciplinary team approach should be sought to achieve better oncological results and timely detection of cancer in earlier stages.

B cell phenotypes and maturation states in cows naturally infected with Mycobacterium avium subsp. Paratuberculosis.

Little is known about the role that B cells play in immune responses to infection with the intracellular pathogen, Mycobacterium avium subsp. paratuberculosis (MAP). Traditionally, the role of B cells has been constrained to their function as antibody-producing cells, however, antibodies are not thought to play a protective role in mycobacterial infections. The present study was designed to characterize B cell subpopulations as well as activation/maturation states in cattle with paratuberculosis. Peripheral blood mononuclear cells (PBMCs) were isolated from noninfected control cows (n = 8); as well cattle naturally infected with MAP in the subclinical (n = 8) and clinical (n = 7) stage of infection and stimulated with MAP antigen for 6 days. MAP infection resulted in greater numbers of total B cells for clinical cows compared to control noninfected cows. The major subpopulation in freshly isolated PBMCs in clinical cows was B-1a B cells, but this shifted to a composite of both B-1a and B-2 B cells upon stimulation of PBMCs with either MAP antigen or pokeweed mitogen, with higher numbers of B-2 B cells. Early B cells were observed to predominate the population of B cells in PBMCs, with lesser populations of germinal B cells, memory B cells and plasma cells. These subpopulations were elevated in clinical cows upon stimulation of PBMCs with MAP antigen, except for plasma cells which were lower compared to control noninfected cows. Increased numbers of B cells in clinical cows aligned with higher expression of B cell markers such as MAPK1/3, BTG1, Bcl2, CD79A and SWAP70, depending upon in vitro stimulation with either mitogen or antigen. This would indicate that the B cells were capable of activation but were anti-apoptotic in nature. The shift to B-2 B cells in the periphery of clinical cows seems to be indicative of an expansion of memory B cells, rather than plasma cells. This may be a last attempt by the host to control the rampant inflammatory state associated with advanced clinical disease.

Antiretroviral choice and severe disease predict poorer neuropsychological outcomes in HIV+ children from Africa.

BackgroundThe International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1104s study evaluated neuropsychological outcomes over 96 weeks in children living with HIV (CLHIV) aged 5–11 years at 6 Sub-Saharan African sites to explore associations between HIV-illness related biomarkers and neuropsychological outcomes.MethodsChildren living with HIV had participated in IMPAACT P1060, which compared efficacy of nevirapine versus lopinavir/ritonavir in children initiating ART at <3 years of age. At age 5–11, neuropsychological evaluations of KABC cognitive ability, TOVA attention-impulsivity and BOT-2 motor domains were assessed and repeated after 48 and 96 weeks. Clinical, antiretroviral therapy (ART) and laboratory (immunological and virological) parameters were used to predict neuropsychological outcomes using linear mixed-effects multivariable regression models, controlling for child and caregiver characteristics.Results246 CLHIV (45% male, mean age at initial neuropsychological evaluation 7.1 yrs [SD 1.2]) began ART at a median age 14.9 months (IQR 8.2, 25.2). Nadir CD4 percentage was 14.7% (IQR 11.0, 19.5); the median peak viral load (VL) was 750 000 copies/ml (IQR 366 000, 750 000) and 63% had ≥WHO stage 3 clinical disease; 164 (67%) were on lopinavir/ritonavir, 71 (29%) were on nevirapine and 7 (3%) were on efavirenz. Other antiretrovirals were similar. Nevirapine at P1104s study start or later was associated with poorer neuropsychological scores across all domains except Global Executive Composite, even when controlling for nadir CD4 percent and time-varying HIV VL. Other predictors of poorer scores in KABC domains included low birth weight, WHO stage 4 disease and serious illness history and elevated VL was associated with worse BOT-2 scores.ConclusionChildren receiving nevirapine had poorer neuropsychological scores than those on lopinavir/ritonavir. Antiretroviral choice might adversely impact neuropsychological performance. In addition, low birth weight and markers of severe HIV disease: advanced WHO clinical HIV disease, history of serious illness and an elevated VL, were associated with lower neuropsychological scores.

Tuberculosis and isoniazid prophylaxis among adult HIV positive patients on ART in Northwest Ethiopia.

Although antiretroviral therapy (ART) can avert tuberculosis (TB) incidence among human immunodeficiency virus (HIV) infected patients, the concomitant use of ART with isoniazid (INH) has a paramount effect. Despite this evidence, there is a paucity of data regarding TB incidence among HIV patients on ART with and without isoniazid prophylaxis and its predictors. Thus, this study sought to assess the incidence and predictors of TB among adult HIV positive patients on ART. This was a hospital based retrospective study including 368 adult HIV positive patients on ART in Gondar comprehensive specialized hospital between January 1, 2016, and April 30, 2019. Data was extracted from clinical laboratory and HIV care ART follow up clinic. The bi-variable and multivariable regression models were used to ascertain predictors of incident TB. Data was analyzed using SPSS version 20 software. A total of 335 adult HIV positive patients were included in the analysis, of whom, 56 (16.7%) were developed incident TB. Being ambulatory and bedridden (AOR: 2.2, 95% CI: 1.1, 4.6), advanced WHO clinical HIV disease stage (III and IV) (AOR: 3.2, 95% CI: 1.6, 6.1), not taking INH (AOR: 2.8, 95% CI: 1.3, 5.9), and baseline CD4+ T cell count ≤ 200 cell/mm3 (AOR: 3.6, 95% CI: 1.8, 7.2) were found to be the predictors of tuberculosis incidence. The study indicated a high TB incidence among HIV positive patients in Gondar. Therefore, scaling up the isoniazid preventive therapy program and its strict compliance is necessary to avert HIV fueled tuberculosis in HIV endemic areas.

Prevalence and Predictors of Cytopenias in HIV-Infected Adults at Initiation of Antiretroviral Therapy in Mehal Meda Hospital, Central Ethiopia

BackgroundHematologic abnormalities are common complications of patients infected with HIV associated with accelerated deterioration in CD4+ cell counts, disease progression, poor quality of life and death. Few studies have evaluated the magnitude of cytopenias at the initiation of antiretroviral therapy (ART) in sub-Saharan Africa. The aim of this study was to determine the prevalence and predictors of cytopenias among HIV-infected adults at initiation of ART in a resource-limited setting in Ethiopia.MethodsA cross-sectional study was conducted among HIV-infected adults initiating ART at the HIV care and treatment clinic of Mehal Meda Hospital between September 2008 and June 2019. Demographic, clinical and laboratory data of patients were collected from medical records. Anemia was defined according to WHO guidelines as hemoglobin concentration <12 g/dl for non-pregnant females and <13 g/dl for males. Leucopenia was defined as total white blood cell count <4.0 × 103 cells/μL and thrombocytopenia as platelet count <150 × 103 cells/μL. Logistic regression analysis was used to determine factors associated with the presence of cytopenias.ResultsOut of the total 566 patients included, 36.6% (95% CI 32.7–40.6%) had anemia, 17.1% (95% CI 14.2–20.4%) had leucopenia and 14.5% (95% CI 11.8–17.6%) had thrombocytopenia. A total of 53.2% (95% CI 49.1–57.3%) of patients had at least one form of cytopenia, 14.1% (95% CI 11.4–17.2%) had bicytopenia, and only 0.5% had pancytopenia. Factors associated with the presence of any cytopenia in multivariable analysis were male sex, advanced clinical disease stage, low CD4+ cell count, low BMI, and decreased renal function.ConclusionA substantial burden of cytopenias was detected among HIV-infected adults enrolled for care and treatment services in our setting. Patients with HIV infection should be screened for hematological abnormalities at initiation of ART because of its potential for morbidity and mortality during ART.

Synergistic and Detrimental Effects of Alcohol Intake on Progression of Liver Steatosis.

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma.

Intermediate-term survival of robot-assisted versus open radical cystectomy for muscle-invasive and high-risk non-muscle invasive bladder cancer in The Netherlands.

Radical cystectomy with pelvic lymph node dissection is the recommended treatment in non-metastatic muscle-invasive bladder cancer (MIBC). In randomised trials, robot-assisted radical cystectomy (RARC) showed non-inferior short-term oncological outcomes compared with open radical cystectomy (ORC). Data on intermediate and long-term oncological outcomes of RARC are limited. To assess the intermediate-term overall survival (OS) and recurrence-free survival (RFS) of patients with MIBC and high-risk non-MIBC (NMIBC) who underwent ORC versus RARC in clinical practice. A nationwide retrospective study in 19 Dutch hospitals including patients with MIBC and high-risk NMIBC treated by ORC (n = 1086) or RARC (n = 386) between January 1, 2012 and December 31, 2015. Primary and secondary outcome measures were median OS and RFS, respectively. Survival outcomes were estimated using Kaplan-Meier curves. A multivariable Cox regression model was developed to adjust for possible confounders and to assess prognostic factors for survival including clinical variables, clinical and pathological disease stage, neoadjuvant therapy and surgical margin status. The median follow-up was 5.1 years (95% confidence interval ([95%CI] 5.0-5.2). The median OS after ORC was 5.0 years (95%CI 4.3-5.6) versus 5.8 years after RARC (95%CI 5.1-6.5). The median RFS was 3.8 years (95%CI 3.1-4.5) after ORC versus 5.0 years after RARC (95%CI 3.9-6.0). After multivariable adjustment, the hazard ratio for OS was 1.00 (95%CI 0.84-1.20) and for RFS 1.08 (95%CI 0.91-1.27) of ORC versus RARC. Patients who underwent ORC were older, had higher preoperative serum creatinine levels and more advanced clinical and pathological disease stage. ORC and RARC resulted in similar intermediate-term OS and RFS in a cohort of almost 1500 MIBC and high-risk NMIBC.

Impact of COVID-19 on presentation, staging, and treatment of head and neck mucosal squamous cell carcinoma

ObjectivesDuring the COVID-19 pandemic, maintenance of safe and timely oncologic care has been challenging. The goal of this study is to compare presenting symptoms, staging, and treatment of head and neck mucosal squamous cell carcinoma during the pandemic with an analogous timeframe one year prior. Materials and methodsRetrospective cohort study at a single tertiary academic center of new adult patients evaluated in a head and neck surgical oncology clinic from March -July 2019 (pre-pandemic control) and March - July 2020 (COVID-19 pandemic). ResultsDuring the pandemic, the proportion of patients with newly diagnosed malignancies increased by 5%, while the overall number of new patients decreased (n = 575) compared to the control year (n = 776). For patients with mucosal squamous cell carcinoma (SCC), median time from referral to initial clinic visit decreased from 11 days (2019) to 8 days (2020) (p = 0.0031). There was no significant difference in total number (p = 0.914) or duration (p = 0.872) of symptoms. During the pandemic, patients were more likely to present with regional nodal metastases (adjusted odds ratio (OR) 2.846, 95% CI 1.072-3.219, p = 0.028) and more advanced clinical nodal (N) staging (p = 0.011). No significant difference was seen for clinical tumor (T) (p = 0.502) or metastasis (M) staging (p = 0.278). No significant difference in pathologic T (p = 0.665), or N staging (p = 0.907) was found between the two periods. ConclusionHead and neck mucosal SCC patients presented with more advanced clinical nodal disease during the early months of the COVID-19 pandemic despite no change in presenting symptoms.

Modelling human liver fibrosis in the context of non-alcoholic steatohepatitis using a microphysiological system

Non-alcoholic steatohepatitis (NASH) is a common form of chronic liver disease characterised by lipid accumulation, infiltration of immune cells, hepatocellular ballooning, collagen deposition and liver fibrosis. There is a high unmet need to develop treatments for NASH. We have investigated how liver fibrosis and features of advanced clinical disease can be modelled using an in vitro microphysiological system (MPS). The NASH MPS model comprises a co-culture of primary human liver cells, which were cultured in a variety of conditions including+/− excess sugar, fat, exogenous TGFβ or LPS. The transcriptomic, inflammatory and fibrotic phenotype of the model was characterised and compared using a system biology approach to identify conditions that mimic more advanced clinical disease. The transcriptomic profile of the model was shown to closely correlate with the profile of patient samples and the model displayed a quantifiable fibrotic phenotype. The effects of Obeticholic acid and Elafibranor, were evaluated in the model, as wells as the effects of dietary intervention, with all able to significantly reduce inflammatory and fibrosis markers. Overall, we demonstrate how the MPS NASH model can be used to model different aspects of clinical NASH but importantly demonstrate its ability to model advanced disease with a quantifiable fibrosis phenotype.

Comparative Effectiveness of a Complex Care Program for High-Cost/High-Need Patients: a Retrospective Cohort Study.

High-cost/high-need (HCHN) adults and the healthcare systems that provide their care may benefit from a new patient-centered model of care involving a dedicated physician and nurse team who coordinate both clinical and social services for a small patient panel. Evaluate the impact of a Complex Care Program (CCP) on likelihood of patient survival and hospital admission in 180 days following empanelment to the CCP. Retrospective cohort study using a quasi-experimental design with CCP patients propensity score matched to a concurrent control group of eligible but unempaneled patients. Kaiser Permanente Mid-Atlantic States (KPMAS) during 2017-2018. Nine hundred twenty-nine CCP patients empaneled January 2017-June 2018, 929 matched control patients for the same period. The KPMAS CCP is a new program consisting of 8 teams each staffed by a physician and nurse who coordinate care across a continuum of specialty care, tertiary care, and community services for a panel of 200 patients with advanced clinical disease and recent hospitalizations. Time to death and time to first hospital admission in the 180 days following empanelment or eligibility. Compared to matched control patients, CCP patients had prolonged time to death (hazard ratio [HR]: 0.577, 95% CI: 0.474, 0.704), and CCP decedents had longer survival (median days 69.5 vs. 53.0, p=0.03). CCP patients had similar time to hospital admission (HR: 1.081, 95% CI: 0.930, 1.258), with similar results when adjusting for competing risk of death (HR: 1.062, 95% CI: 0.914, 1.084). Non-randomized intervention; single healthcare system; patient eligibility limited to specific conditions. The KPMAS CCP was associated with significantly reduced short-term mortality risk for eligible patients who volunteered to participate in this intervention.

KIM-1 (kidney injury molecule 1) in the urine of renal cell carcinoma patients

Objective: to assess the potential clinical significance of KIM-1 (kidney injury molecule 1) as a urinological marker for kidney cancer.Materials and methods. An enzyme-linked immunosorbent assay was used to assess urinary KIM-1 (uKIM-1 — kidney injury molecule 1) levels in 67 patients with renal cell carcinoma (RCC) and 36 healthy volunteers (a control group).Results. Both in patients and in healthy individuals, uKIM-1 levels were age independent. A difference between mean uKIM-1 values in RCC patients (2.4 ± 0.2 ng/ml) and the control group (0.7 ± 0.1 ng/ml) was statistically significant (p &lt;0.0001). In RCC patients the higher uKIM-1 level was observed at more advanced clinical disease stages: the values increasedfrom 2.0 ± 0.2 ng/ml at the stage I and 3.0 ± 0.5 ng/ml at the stage II—III to 4.4 ± 1.2 ng/ml at the stage IV. In the group of patients with stage IRCC, most representative by the number of cases (n = 44) the uKIM-1 levels correlated with the tumor size and were increased in patients with different histological subtypes of the tumor, including clear cell, papillary and chromophobe RCC. After nephrectomy, a monotonous decrease in uKIM-1 level was observed, and after 6 days its values approached the mean value in the control group. Two days after kidney resection, uKIM-1 increased and then decreased, remaining elevated after 6 days.Conclusion. This study demonstrates that uKIM-1 can be attributed to potentially significant urine tumor-associated markers of RCC.

Survival and Predictors of Mortality Among Adult HIV/AIDS Patients Initiating Highly Active Antiretroviral Therapy in Debre-Berhan Referral Hospital, Amhara, Ethiopia: A Retrospective Study.

BackgroundAcquired immune deficiency syndrome is one of the most destructive epidemics the world has ever witnessed. An estimated 36.9 million people were living with HIV in 2017. HIV/AIDS is the major contributing factor for morbidity and mortality in low- and middle-income countries. Although different studies on survival and predictors of mortality among HIV/AIDS patients after initiation of antiretroviral therapy were conducted, there are inconsistencies in the findings of those studies. Furthermore, to the authors’ knowledge, there was a dearth of studies conducted in this study area.PurposeThe purpose of this study was to assess the survival and predictors of mortality among adult patients starting highly active antiretroviral therapy at Debre Berhan Referral Hospital, North Showa, Amhara, Ethiopia.Patients and MethodsAn institution-based retrospective study was conducted among the medical records of 447 study subjects’ selected using simple random sampling from January 1t, 2013 to December 30, 2018. The data was collected using a structured data abstraction checklist and analyzed using Kaplan–Meier statistics and Cox regression models.ResultsAmong 447 adult patients, 54 patients (12.1%) had died, giving a crude death rate of 4.18 per 100 person years (95% CI=3.20–5.45). The overall estimated survival rate after initiation of antiretroviral therapy was 81.7% (95% CI=75.36–86.54%) at 72 months of follow-up. The independent predictors of mortality were clinical stage IV (HR=15.6, 95% CI=6.609–36.948), baseline opportunistic infections (HR=1.86, 95% CI=1.048–3.330), baseline Hgb<10 mg/dL (HR=4.655, 95% CI=2.253–9.619), baseline CD4<200 cells/µL (HR=4.71, 95% CI=2.275–9.751), the presence of comorbidity (HR=2.56 95% CI=1.391–4.740), being widowed (HR=3.475, 95% CI=1.412–8.550), and bedridden functional status (HR=3.069, 95% CI=1.111–8.480).ConclusionPatients with opportunistic infections, advanced clinical stage disease, bedridden functional status, baseline Hgb<10 mg/dL, baseline CD4<200 cells/µL, and comorbidity should be given special care.

HL-323: Outcomes of First-Line Treatment in Patients with Advanced Clinical Stage Classic Hodgkin Lymphoma and Human Immunodeficiency Virus Infection

Context Patients with human immunodeficiency virus (HIV) have a higher incidence of advanced-stage classic Hodgkin lymphoma (cHL) than those without HIV. Outcomes with first-line ABVD chemotherapy in these patients have yet to be well defined. Objective To determine the outcomes of advanced-stage HIV-cHL and compare them with those of non-HIV-cHL. Design Observational, descriptive study from August 2004 to December 2018. Clinical features were compared by standard statistical methods. Overall survival (OS) and relapse-free survival (RFS) were calculated with Kaplan-Meier methodology. Setting Studied population comes from a national reference center. Patients or other participants Twenty-one patients with HIV-cHL (based on the 2016 WHO criteria), all male with advanced clinical stage disease, were compared with 58 non-HIV-cHL patients with the same characteristics. Interventions All patients received ABVD chemotherapy. Main outcome measures Complete response (CR), OS, and RFS were determined. Results The mean age was 42.9 (± 10.88) years in HIV-cHL and 45.1 (± 17.56) years in non-HIV-cHL (p = 0.50). There was a significantly lower leucocyte count in HIV-cHL (4.6×103 cells/mL) compared with non-HIV-cHL (6.7×103 cells/mL) (p = 0.02). In the monocyte line, HIV-cHL had lower absolute counts (340 cells/mL) than non-HIV-cHL (708 cells/mL) (p = 0.01). In HIV-positive patients, 40 months was the median time for cHL diagnosis. The median CD4 cell count was 109 cells/mL. The median follow-up time for HIV-cHL was 10 months, shorter than the median follow-up time for non-HIV-cHL (45 months) (p = 0.01). CR was documented in 61.1% of HIV-cHL and in 66.1% of non-HIV-cHL (p = 0.77). RFS was 36.5 months for all patients, being less for HIV-cHL (24 months) compared with non-HIV-cHL (51 months) (p = 0.03). The OS median at the time of last follow-up had not yet been reached in all patients. At last follow-up, 22 (27.8%) patients had died, 6 (28.6%) HIV-cHL and 16 (27.6%) non-HIV-cHL (p = 1.00). Conclusions Outcomes were similar in both groups. There was no difference observed in the likelihood of achieving CR. Hence, the prognosis of advanced clinical stage HIV-cHL is similar to non-HIV-cHL patients treated with first-line ABVD chemotherapy.

LINC00511 as a prognostic biomarker for human cancers: a systematic review and meta-analysis

BackgroundLong intergenic non-coding RNA 00511 (LINC00511) is highly expressed in diverse cancers and has a correlation with poor clinical outcomes for cancer patients. In view of contradictory data among published data, we aim to evaluate the prognostic role of LINC00511 for cancer patients.MethodsIn the present study, a meta-analysis of related studies has been performed to investigate the prognostic significance of LINC00511 in cancer patients. Relevant studies published before December 22, 2019 were systematically searched online in PubMed, EMBASE, Web of Science, and the Cochrane Library databases. The relationship between LINC00511 expression and cancer patients’ survival, including overall survival (OS), disease-free survival (DFS)/relapse-free survival (RFS) and progression-free survival (PFS), was evaluated using pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs). The association between LINC00511 expression and clinicopathological features was assessed using odd ratios (ORs) and their corresponding 95% CIs.ResultsA total of 14 eligible studies with 1883 patients were enrolled in the present meta-analysis. The results demonstrated that elevated expression of LINC00511 was significantly associated with poor OS (HR = 2.62; 95% CI: 2.00–3.45; p < 0.001), PFS (HR = 1.80; 95% CI: 1.29–2.51; p = 0.001) and DFS/RFS (HR = 2.90; 95% CI: 1.04–8.12; p = 0.04). Additionally, High LINC00511 expression was associated with large tumor size (OR = 3.10; 95% CI: 1.97–4.86; p < 0.00001), lymph node metastasis (OR = 3.11; 95% CI: 2.30–4.21; p < 0.00001), advanced clinical stage (OR = 3.95; 95% CI: 2.68–5.81; p < 0.00001), distant metastasis (OR = 2.39; 95% CI: 1.16–4.93; p = 0.02), and disease recurrence (OR = 4.62; 95% CI: 2.47–8.65; p < 0.00001). Meanwhile, no correlation was found between LINC00511 expression and age, gender, and histological grade. These findings were consolidated by the results of bioinformatics analysis.ConclusionsBased on our findings, LINC00511 may serve as a novel prognostic biomarker for cancer patients.

Echocardiographic Findings in a Cohort of Perinatally HIV-Infected Adolescents Compared with Uninfected Peers from the Cape Town Adolescent Antiretroviral Cohort

Little is known about the cardiac health of perinatally HIV-infected (PHIV+) adolescents on antiretroviral therapy (ART) in sub-Saharan Africa. The authors examined cardiac structure and function in PHIV+adolescents on ART compared with HIV-uninfected (HIV-) adolescents. Echocardiography was performed on PHIV+ and age- and sex-frequency-matched HIV- adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort. Participants were eligible if they were 9 to 14years of age and had been on ART for ≥6months. Overall, 474 PHIV+adolescents (median age, 12years; 51% boys; mean age at ART initiation, 5years) and 109 HIV- adolescents (median age, 11.8years; 45% boys) were included. The mean duration on ART was 7years, with 37% starting treatment before 2years of age. Compared with HIV- adolescents, PHIV+adolescents had higher median Z scores for left ventricular (LV) internal end-diastolic dimension, LV end-systolic posterior wall thickness, and end-systolic interventricular septal thickness. PHIV+adolescents had a lower median Z score for right ventricular internal end-diastolic dimension as compared with HIV- adolescents. There was no difference in ejection fraction or diastolic function between groups. Later initiation of ART (after 6years) was associated with increased risk for LV hypertrophy (odds ratio, 2.9; 95% CI, 1.3-6.6; P=.01) compared with those who started ART earlier. PHIV+adolescents with World Health Organization stage IV HIV infection were at increased risk (odds ratio, 2.2; 95% CI, 1.0-4.6; P=.05) of having LV diastolic dysfunction compared with those with less advanced clinical disease. This study revealed subtle differences in echocardiographic parameters between PHIV+ and HIV- adolescents. Although these were not clinically significant, starting ART at an older age was a significant risk factor for LV hypertrophy, while more advanced clinical disease was associated with LV diastolic dysfunction.

Same-day antiretroviral therapy initiation for HIV-infected adults in South Africa: Analysis of routine data.

Same-day initiation (SDI) of antiretroviral therapy (ART) has been recommended to improve ART programme outcomes in South Africa since August 2017. This study assessed implementation of SDI over time in two South African districts, describing the characteristics of same-day initiators and evaluating the impact of SDI on retention in ART care. Routine data were analysed for HIV-infected adults who were newly initiating ART in Johannesburg or Mopani Districts between October 2017 and June 2018. Characteristics of same-day ART initiators were compared to later initiators, and losses to follow-up (LTFU) to six months were assessed using Kaplan Meier survival analysis and multivariate logistic regression. The dataset comprised 32 290 records (29 964 from Johannesburg and 2 326 from Mopani). The overall rate of SDI was 40.4% (n = 13 038), increasing from 30.3% in October 2017 to 54.2% in June 2018. Same-day ART initiators were younger, more likely to be female and presented with less advanced clinical disease than those initiating treatment at later times following diagnosis (p<0.001 for all). SDI was associated with disengagement from care: LTFU was 30.1% in the SDI group compared to 22.4%, 19.8% and 21.9% among clients initiating ART 1–7 days, 8–21 days and ≥22 days after HIV diagnosis, respectively (p<0.001). LTFU was significantly more likely among clients in Johannesburg versus Mopani (adjusted odds ratio (aOR) = 1.43, p<0.001) and among same-day versus later initiators (aOR = 1.45, p<0.001), while increasing age reduced LTFU (aOR = 0.97, p<0.001). In conclusion, SDI has increased over time as per national guidelines, but there is serious concern regarding the reduced rate of retention among same-day initiators. Nevertheless, SDI may result in a net programmatic benefit provided that interventions are implemented to support client readiness for treatment and ongoing engagement in ART care, particularly among younger adults in large ART programmes such as Johannesburg.

Divergent Antigen-Specific Cellular Immune Responses during Asymptomatic Subclinical and Clinical States of Disease in Cows Naturally Infected with Mycobacterium avium subsp. paratuberculosis.

Infection of the host with Mycobacterium avium subsp. paratuberculosis results in chronic and progressive enteritis that traverses both subclinical and clinical stages. The mechanism(s) for the shift from an asymptomatic subclinical disease state to advanced clinical disease is not fully understood. In the present study, naturally infected dairy cattle were divided into subclinical and clinical infection groups, along with noninfected control cows of similar parity, to study host immune responses in different stages of infection. Both infection groups had higher levels of secretion of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) than control cows, whereas only clinical cows had increased secretion of IL-10, IL-12, and IL-18 upon stimulation of peripheral blood mononuclear cells (PBMCs) with antigen. Conversely, secretion of IL-17Α was decreased for clinical cows compared to subclinical and control cows. Proinflammatory cytokine genes were upregulated only for subclinical cows, whereas increased IL-10 and IL-17 gene expression levels were observed for both infection groups. Increased CD4+, CD8+, and γδ T cell receptor-positive (TCR+) T cells were observed for subclinical cows compared to clinical cows. Although clinical cows expressed antigen-specific immune responses, the profile for subclinical cows was one of a dominant proinflammatory response to infection. We reason that a complex coordination of immune responses occurs during M. avium subsp. paratuberculosis infection, with these responses shifting as the host transitions through the different stages of infection and disease (subclinical to clinical). A further understanding of the series of events characterized by Th1/Th2/Th17 responses will provide mechanisms for disease progression and may direct insightful intervention strategies.