In Myanmar, 1.3 million people have been exposed to hepatitis C (HCV). However, public sector access to viral load (VL) testing for HCV diagnosis remains limited; ten near-point-of-care (POC) devices ...are available nationally. Myanmar's National Health Laboratory (NHL) has surplus capacity on centralized molecular testing platforms used for HIV diagnostics, presenting an opportunity for integrating HCV testing to expand overall testing capacity. This pilot assessed the operational feasibility and acceptability of HCV/HIV integrated testing implemented with a comprehensive package of supportive interventions.
HCV VL samples were collected prospectively from consenting participants at five treatment clinics and tested at Myanmar's NHL (October 2019-February 2020) on the Abbott m2000. To optimize integration, laboratory human resources were bolstered, staff trainings were offered, and existing laboratory equipment was serviced/repaired as needed. Diagnostics data during the intervention period were compared against HIV diagnostics data in the seven months prior. We conducted three time and motion analyses at the laboratory and semi-structured interviews with laboratory staff to assess time needs and program acceptability.
715 HCV samples were processed during the intervention period with an average test processing time of 18 days (IQR: 8-28). Despite adding HCV testing, average monthly test volumes were 2,331 for HIV VL and 232 for early infant diagnosis (EID), comparable to the pre-intervention period. Processing times were 7 days for HIV VL and 17 days for EID, also comparable to the pre-intervention period. HCV test error rate was 4.3%. Platforms utilization increased from 18.4% to 24.6%. All staff interviewed were supportive of HCV and HIV diagnostics integration; suggestions were made for broader implementation and expansion.
With a package of supportive interventions, integration of HCV and HIV diagnostics on a centralized platform was operationally feasible, did not adversely impact HIV testing, and was acceptable to laboratory staff. In Myanmar, integrated HCV VL diagnostic testing on centralized platforms may be an important addition to existing near-POC testing in expanding national testing capacity for HCV elimination.
Detection of tuberculosis disease (TB) and timely identification of Mycobacterium tuberculosis (Mtb) strains that are resistant to treatment are key to halting tuberculosis transmission, improving ...treatment outcomes, and reducing mortality. We used 332,657 Xpert MTB/RIF assay results, captured as part of the Myanmar Data Utilization Project, to characterize Mtb test positivity and rifampicin resistance by both age and sex, and to evaluate risk factors associated with rifampicin resistance. Overall, 70% of individuals diagnosed with TB were males. Test positivity was higher among males (47%) compared to females (39%). The highest positivity by age occurred among individuals aged 16-20, with test positivity for females (65%) higher than for males (57%). Although a greater absolute number of males were rifampicin resistant, a greater proportion of females (11.4%) were rifampicin resistant as compared to males (9.3%). In the multivariate model, history of previous treatment, age less than 30, testing in the Yangon region, and female sex were significantly positively associated with rifampicin resistance after adjusting for HIV status and year test was performed. Our results indicate that young adults were more likely to test positive for TB and be identified as rifampicin resistant compared to older adults.
With political will, modest financial investment and effective technical assistance, public sector hepatitis C virus (HCV) programmes can be established in low- and middle-income countries as a first ...step towards elimination. Seven countries, with support from the Clinton Health Access Initiative (CHAI) and partners, have expanded access to HCV treatment by combining programme simplification with market shaping to reduce commodity prices. CHAI has supported a multipronged approach to HCV programme launch in Cambodia, India, Indonesia, Myanmar, Nigeria, Rwanda and Vietnam including pricing negotiations with suppliers, policy development, fast-track registrations of quality-assured generics, financing advocacy and strengthened service delivery. Governments are leading programme implementation, leveraging HIV programme infrastructure/financing and focusing on higher-HCV prevalence populations like people living with HIV, people who inject drugs and prisoners. This manuscript aims to describe programme structure and strategies, highlight current commodity costs and outline testing and treatment volumes across these countries. Across countries, commodity costs have fallen from >US$100 per diagnostic test and US$750–US$900 per 12-week pan-genotypic direct-acting antiviral regimen to as low as US$80 per-cure commodity package, including WHO-prequalified generic drugs (sofosbuvir + daclatasvir). As of December 2019, 5900+ healthcare workers were trained, 2 209 209 patients were screened, and 120 522 patients initiated treatment. The cure (SVR12) rate was >90%, including at lower-tier facilities. Programmes are successfully implementing simplified, decentralised public health approaches. Combined with political will and affordable pricing, these efforts can translate into commitments to achieve global targets. However, to achieve elimination, additional investment in scale-up is required.
Helicobacter pylori is the major triggering factor for gastric carcinoma, but only a small proportion of infected patients develop this disease. Differences in virulence observed among H. pylori ...strains, namely in the vacuolating cytotoxin vacA gene, may contribute to this discrepancy. Infection with vacA s1, i1 and m1 strains increases the risk for progression of gastric premalignant lesions and for gastric carcinoma. However, in East Asian countries most of the H. pylori strains are vacA s1, regardless of the patients' clinical status, and the significance of the vacA i1 and m1 genotypes for gastric carcinoma in this geographic area remains to be fully elucidated. The aim of the present study was to investigate this relationship in 290 patients from Macau, China. Using very sensitive and accurate genotyping methods, we detected infection with vacA i1 and with vacA m1 strains in, respectively, 85.2% and 52.6% of the patients that were infected with single genotypes. The prevalence of cagA-positive strains was 87.5%. No significant associations were observed between vacA genotypes or cagA and gastric carcinoma. It is worth noting that 37.5% of the infected patients had coexistence of H. pylori strains with different vacA genotypes. Additional studies directed to other H. pylori virulence factors should be performed to identify high risk patients in East Asia.
Background
The presence of tumor infiltrating lymphocytes (TIL) is associated with favorable prognosis. Recent evidence suggested that not only their density, but also the spatial organization as ...tertiary lymphoid structures (TLS), play a key role in determining patient survival.
Materials and Methods
In a cohort of 248 breast cancers, the clinicopathologic association and prognostic role of TLS was examined.
Results
Tertiary lymphoid structures were associated with higher tumor grade, apocrine phenotype, necrosis, extensive in situ component, lymphovascular invasion (LVI), and high TIL. For biomarkers, TLS were associated with hormone receptors negativity, HER2 positivity, and c‐kit expression. Tertiary lymphoid structures were significantly related to better disease‐free survival (DFS) in HER2 positive (HER2+) breast cancers (log‐rank = 4.054), which was not dependent on high TIL status. The combined TLS and TIL status was an independent favorable factor associated with DFS in those cases. Interestingly, tumor cell infiltration into the TLS was found in 41.9% of TLS positive cases. It was associated with LVI in HER2 negative (HER2−) TLS positive (particularly estrogen receptor positive ER+ HER2−) cases. In the ER+ HER2− cases, tumor cell infiltration into TLS was also associated with increased pathologic nodal stage (pN) stage and nodal involvement.
Conclusion
Tertiary lymphoid structures showed a similar relationship with clinicopathologic features and biomarkers as TIL. The presence of TLS, irrespective of TIL level, could be an important favorable prognostic indicator in HER2+ breast cancer patients. Given the significance of TLS in promoting effective antitumor immunity, further understanding of its organization and induction may provide new opportunities to improve the current immunotherapy strategies.
Implications for Practice
Despite recent interest on the clinical value of tumor infiltrating lymphocyte (TIL), little was known on the clinical significance on their spatial organization as tertiary lymphoid structures (TLS). Although TLS showed similar relationships with clinicopathologic features and biomarkers as TIL, the prognostic value of TLS, particularly in HER2 positive cancers, was independent of TIL. Moreover, tumor infiltration could be present in TLS which appears to be related to tumor invasion in HER2 negative cancers. Overall, the results demonstrated the additional value for TLS in HER2 cancer subtypes. Further investigations and its standardized evaluation will enhance its use as standard practice.
摘要
背景.肿瘤浸润淋巴细胞（TIL）与良好的预后有关。最新证据表明, TIL的密度和空间组织, 如三级淋巴结构（TLS）, 在决定患者生存方面均具有关键作用。
材料与方法.在一个包含248名乳腺癌患者的队列中检查了TLS的临床病理学相关性和预后作用。
结果.三级淋巴结构与较高的肿瘤分级、顶浆分泌表型、坏死、广泛的原位癌成分、淋巴管浸润（LVI）和高TIL相关。对于生物标志物, TLS与激素受体阴性、HER2阳性和c‐kit表达相关。三级淋巴结构与HER2阳性（HER2+）乳腺癌（log‐rank=4.054）患者的无病生存期（DFS）更长显著相关, 而这与高TIL水平无关。在HER2+乳腺癌患者中, TLS和TIL状态是与DFS相关的独立有利因素。有趣的是, 在41.9％的TLS阳性患者中发现了肿瘤细胞浸润到TLS中的情况, 这与HER2阴性（HER2‐）TLS阳性 特别是雌激素受体阳性（ER+）HER2‐患者中的LVI相关。在ER+ HER2‐病例中, 肿瘤细胞浸润到TLS也与病理淋巴结分期（pN）升高和淋巴结受累有关。
结论.三级淋巴结构的临床病理特征和生物标志物的关系与TIL相似。无论TIL水平如何, TLS可能是HER2+乳腺癌患者的重要且有利的预后指标。考虑到TLS在促进有效的抗肿瘤免疫方面的重要性, 进一步了解其组织和诱导作用可能为改善目前的免疫疗法策略提供新机会。
Tumor infiltrating lymphocytes are associated with good clinical outcome in many types of cancer, including breast cancer. Tertiary lymphoid structures are associated with anti‐tumor immune responses and prolonged patient survival. This study analyzed characteristics of tertiary lymphoid structures and their prognostic value related to different invasive breast cancer molecular subgroups.
Background
Immune checkpoint blockades are currently actively investigated in invasive breast cancers. Given the complexity of immune regulation, multiple inhibitory molecules within the immune ...checkpoint framework would be involved in tumor immune escape. Evaluation of the components within the framework is a prerequisite for not only identification of additional treatment targets and optimization of immunotherapeutic strategies but also understanding the prognostic value of these molecules.
Methods and Results
We examined a recently described component, herpes virus entry mediator (HVEM), in a large cohort of invasive breast cancers using immunohistochemistry, and evaluated its clinical relevance. HVEM expression was associated with aggressive tumor features, namely high grade (
p
< 0.001), high pT (
p
= 0.001) and pN stage (
p
= 0.008), and was most prevalently found in human epidermal growth factor receptor 2-overexpressed subtype (67%). Interestingly, a negative association with programmed death-ligand 1 (
p
= 0.021) has been observed. The prognostic impact of HVEM depended on the level of tumor-infiltrating lymphocytes (TILs), with the worst outcome occurring in patients with low TIL, HVEM-positive tumors.
Conclusion
HVEM plays significant oncogenic roles in breast carcinogenesis, and may also be a tumor-specific target.
•The clinico-pathological features of the unusual ISH groups 2 and 4 were more similar to typical non-amplified HER2 cases than amplified HER2 cases while vice versa was found with group 3.•Group 4 ...cases showed similar survival to those typical non-amplified HER2 cases, but differed significantly from the amplified cases.•The data supported the re-categorization of group 2 and 4 as HER2 non-amplified and group 3 as HER2 amplified.
The latest American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline has updated the interpretation of uncommon human epidermal growth factor receptor 2 (HER2) in situ hybridization (ISH) patterns (groups 2-4) with concomitant HER2 immunohistochemistry, leading to changes in the diagnosis of these subgroups. We sought to assess the clinicopathological features and outcomes in these subgroups in detail with our local cohort.
Clinicopathologic features of groups 2 to 4 were compared to the typical amplified group (group 1: HER2/CEP17 ≥ 2, HER2 ≥ 4) and non-amplified group (group 5: HER2/CEP17 < 2, HER2 < 4).
Group 2 (HER2/CEP17 ≥ 2, HER2 < 4) cases showed lower Ki67 expression and grade (P ≤ .002) than group 1 but no differences compared with group 5. Group 4 (HER2/CEP17 < 2, HER2 = 4-6) cases were associated with less necrosis, more estrogen receptor positivity, lower grade, more nodal metastases, and more special histotypes (P ≤ .037) than group 1, but higher grade and more nodal metastases (P ≤ .021) than group 5. Except for presenting as a larger tumor and of special histotypes, group 3 (HER2/CEP17 < 2, HER2 ≥ 6) cases showed no other significant differences from group 1, but were of higher grade and Ki67 level than groups 2, 4, and 5. Group 4, similar to group 5, showed worse survival than group 1 (disease-free survival: log-rank = 5.547, P = .019; overall survival: log-rank = 4.678, P = .031). The rate of relapse was similar in group 4 with and without anti-HER2 therapy, albeit with limited cases.
Our findings indicate more similarities among groups 2, 4, and 5 than between groups 1 and 3, supporting the HER2 categorization in the latest guideline. Additional studies may be warranted to assess the outcomes of these patients with different management approaches.
The latest American Society of Clinical Oncology/College of American Pathologists update re-categorized the diagnosis of uncommon HER2 in situ hybridization categories. Despite that, there is no robust clinical evidence to support this categorization. In this study, we sought to compare the clinicopathological characteristics and outcomes of these groups with typical amplified and non-amplified cases to gain further insights into their biology and the relevance of this revised classification.
Abstract
Background
Tuberculosis (TB) is the most common co-infection among people living with HIV, but HIV positivity is associated with a lower Mycobacterium tuberculosis (MTB) bacillary load in ...sputum, making TB often difficult to diagnose with current diagnostic solutions. GeneXpert MTB/RIF (Cepheid, USA), a rapid, molecular diagnostic assay, has transformed the TB diagnostic landscape and can be used to diagnose TB and limited drug resistance in HIV patients from direct clinical samples in < 2 hours, but results can be significantly affected by sample bacterial load, which is quantified by the GeneXpert MTB/RIF (Xpert) instrument using Ct values. Our primary objective was to assess how a patient’s HIV status affected their MTB bacterial load in sputum vs. saliva samples submitted for Xpert diagnosis of TB.
Methods
We completed a retrospective analysis of >4,000 patient records from the Myanmar National TB Program captured as part of a nation-wide electronic reporting system developed with the assistance of FIND (Geneva). De-identified records included HIV status, Xpert testing results, and for a subset of patients, specimen type. With this diagnostic information, we compared the distribution of MTB load (quantified by Xpert Ct values) in sputum and saliva in HIV positive vs. HIV negative patients using STATA.
Results
Based on mean Ct value comparison independent of HIV status, saliva samples (mean Ct = 22.7) contained a significantly lower bacterial load of MTB as compared to sputum samples (mean Ct=19.2, p < .001).Within saliva samples, a lower bacterial load was also detected in HIV positive patients (mean Ct = 26.9) compared to HIV negative patients (mean Ct = 22.3, p< .05). Similarly, in sputum samples, a lower bacterial load was detected in HIV positive patients (mean Ct = 21.6) compared to HIV negative patients (mean Ct = 19.0, p < .001) (Figure 1).
Figure 1. Ct Values by HIV Status and Specimen Type
Conclusion
Sputum samples have a significantly higher bacterial load on average compared to saliva samples independent of HIV status. Additionally, when looking at both saliva and sputum as sample types, HIV positive patients have significantly lower bacterial load than individuals who are HIV negative. Based on these results, sputum is the optimal sample type for Xpert TB detection, especially in people living with HIV.
Disclosures
All Authors: No reported disclosures
Doublecortin-like kinase 1 (DCLK1), a microtubule associated kinase, has recently been proposed to be a putative marker for stemness and adverse prognosis in gastrointestinal cancers. However, it is ...not clear whether the protein also plays similar roles in breast cancer. Here, the expression of DCLK1 was analyzed in a large cohort of invasive breast cancers (IBC) by immunohistochemistry. DCKL1 was associated with favorable clinico-pathologic features, namely lower histologic grade, absence of lymphovascular invasion, fibrotic focus, necrosis and lower pN stage (p≤0.045). Additionally, independent significant correlations were found with estrogen receptor and neuroendocrine markers (p ≤0.019), implicating its relationship with IBC with neuroendocrine differentiation (IBC-NED). In the current cohort, IBC-NED showed worse outcome than luminal cancers without NED (hazard ratio=1.756, p=0.041). Interestingly, within the IBC-NED group, DCLK1 was found to be a good prognostic factor (hazard ratio =0.288, p=0.011). These findings were in contrast to those in gastrointestinal cancers, suggesting different functional roles of DCLK1 in different types of cancers. In clinical practice, NED is not routinely assessed; thus IBC-NED are not well studied. Its poor outcome and significant heterogeneity warrants more attention. DCLK1 expression could aid in the prognostication and management of this special cancer subtype.
Macao is a densely populated city situated in East Asia where a relatively high prevalence of human papillomavirus (HPV) types 52 and 58 has been reported in women with invasive cervical cancer. To ...provide data for a population-specific estimation on the impact of HPV vaccines, paraffin-embedded tissues collected from women with invasive cervical cancer or cervical intrapeitheilal neoplasia grade 2 or 3 confirmed histologically were examined for HPV using the INNO-LiPa kit. Of the 35 HPV-positive patients with invasive cancer, one HPV type was detected in 68.6%, and 31.4% were co-infected with more than one HPV type. Overall, HPV 16, HPV 18, HPV 52, and HPV 54 were the most common types found respectively in 57.1%, 17%, 11.4%, and 8.5% of patients with invasive cervical cancer. Among the 59 HPV-positive patients with cervical intraepithelial neoplasia grade 2/3, 55.9% hardbored one HPV type, and 44.1% had co-infections. The common HPV types found included HPV 16 (52.5%), HPV 52 (23.7%), HPV 58 (18.7%), and HPV 33 (17%). Although HPV 11 (a low-risk type) was also found commonly in invasive cervical cancers (14.3%) and cervical intraepithelial neoplasia grade 2/3 (15.3%), the fact that they all existed as co-infections with another high-risk type suggested HPV 11 was not the cause of the lesion. The current vaccines targeting HPV 16/18 are expected to cover 62.9-74.3% of invasive cervical cancers and 32.2-55.9% of cervical intraepithelial neoplasia 2/3 in Macao. Widespread HPV vaccination is expected to reduce substantially the disease burden associated with cervical neoplasia in Macao. J. Med. Virol. 82:1600-1605, 2010.
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