Non-Small Cell Lung Cancer Cells Expressing CD44 Are Enriched for Stem Cell-Like Properties

Background: The cancer stem cell theory hypothesizes that cancers are perpetuated by cancer stem cells (CSC) or tumor initiating cells (TIC) possessing self-renewal and other stem cell-like properties while differentiated non-stem/initiating cells have a finite life span. To investigate whether the hypothesis is applicable to lung cancer, identification of lung CSC and demonstration of these capacities is essential. Methodology/Principal Finding: The expression profiles of five stem cell markers (CD34, CD44, CD133, BMI1 and OCT4) were screened by flow cytometry in 10 lung cancer cell lines. CD44 was further investigated by testing for in vitro and in vivo tumorigenecity. Formation of spheroid bodies and in vivo tumor initiation ability were demonstrated in CD44+ cells of 4 cell lines. Serial in vivo tumor transplantability in nude mice was demonstrated using H1299 cell line. The primary xenografts initiated from CD44+ cells consisted of mixed CD44+ and CD44- cells in similar ratio as the parental H1299 cell line, supporting in vivo differentiation. Semi-quantitative Real-Time PCR (RT-PCR) showed that both freshly sorted CD44+ and CD44+ cells derived from CD44+-initiated tumors expressed the pluripotency genes OCT4/POU5F1, NANOG, SOX2. These stemness markers were not expressed by CD44- cells. Furthermore, freshly sorted CD44+ cells were more resistant to cisplatin treatment with lower apoptosis levels than CD44- cells. Immunohistochemical analysis of 141 resected non-small cell lung cancers showed tumor cell expression of CD44 in 50.4% of tumors while no CD34, and CD133 expression was observed in tumor cells. CD44 expression was associated with squamous cell carcinoma but unexpectedly, a longer survival was observed in CD44-expressing adenocarcinomas. Conclusion/Significance: Overall, our results demonstrated that stem cell-like properties are enriched in CD44-expressing subpopulations of some lung cancer cell lines. Further investigation is required to clarify the role of CD44 in tumor cell renewal and cancer propagation in the in vivo environment.© 2010 Leung et al.published_or_final_versio

Improvising hepatic venous outflow and inferior vena cava reconstruction for combined heart and liver and sequential liver transplantations

Liver transplantation is a standard treatment for patients with familial amyloidotic polyneuropathy (FAP) with disease progression. Given the multiorgan involvement by amyloidosis, the heart is often involved. When poor cardiac function becomes prohibitive to liver transplantation, a combined heart-liver transplantation (CHLT) is the only realistic treatment. This article records a CHLT for a patient with FAP whose removed liver was immediately transplanted as an amyloidotic hepatic allograft (AHA) to a patient having hepatocellular carcinoma and cirrhosis in a sequential liver transplantation. In the CHLT, the heart and liver are donated by a deceased donor. The newly implanted heart did not tolerate cross clamping of the inferior vena cava (IVC), so a side-to-side anastomosis was performed to connect the IVC and that of the liver graft. Therefore, the AHA was devoid of an IVC. The infrarenal cava procured from the deceased donor was used for reconstruction of the AHA to match a whole graft used in routine deceased-donor liver transplantation. Venoplasty was performed using the graft right hepatic vein and the middle and left hepatic vein stump to form a single cuff. The reconstructed AHA was implanted to the recipient conveniently like a usual whole graft

Improvising hepatic venous outflow and inferior vena cava reconstruction for combined heart and liver and sequential liver transplantations

Liver transplantation is a standard treatment for patients with familial amyloidotic polyneuropathy (FAP) with disease progression. Given the multiorgan involvement by amyloidosis, the heart is often involved. When poor cardiac function becomes prohibitive to liver transplantation, a combined heart-liver transplantation (CHLT) is the only realistic treatment. This article records a CHLT for a patient with FAP whose removed liver was immediately transplanted as an amyloidotic hepatic allograft (AHA) to a patient having hepatocellular carcinoma and cirrhosis in a sequential liver transplantation. In the CHLT, the heart and liver are donated by a deceased donor. The newly implanted heart did not tolerate cross clamping of the inferior vena cava (IVC), so a side-to-side anastomosis was performed to connect the IVC and that of the liver graft. Therefore, the AHA was devoid of an IVC. The infrarenal cava procured from the deceased donor was used for reconstruction of the AHA to match a whole graft used in routine deceased-donor liver transplantation. Venoplasty was performed using the graft right hepatic vein and the middle and left hepatic vein stump to form a single cuff. The reconstructed AHA was implanted to the recipient conveniently like a usual whole graft

The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS

Background: The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4- ALK) fusion gene resulting from the chromosome inversion inv(2)(p21;p23) recently was identified in non- small cell lung cancer (NSCLC). The authors of this study investigated the frequency, genetic and clinicopathologic profiles of EML4-ALK in Chinese patients with NSCLC. Methods: EML4-ALK was investigated in 266 resected primary NSCLC, including adenocarcinomas (AD), lymphoepithelioma-like carcinomas, squamous cell carcinomas, mucoepidermoid carcinomas, and adenosquamous carcinomas, by reverse transcriptase-polymerase chain reaction and was verified by sequencing. EML4-ALK protein expression was studied by immunohistochemistry. Results: Thirteen tumors (4.9%) had EML4-ALK comprising 4 fusion transcript variants with fusion of the variable segments from 5' EML4 to 3' ALK and with preservation of the ALK kinase domain. The most common variant consisted of 8 tumors with variant 3 that involved EML4 exon 6. The others included 2 tumors with variant 1 (exon 13), 2 tumors with variant 2 (exon 20), and 1 tumor with the novel variant 5 (exon 18). There were 11 ADs and 2 unusual carcinomas with mixed squamous and glandular components. Immunohistochemistry demonstrated diffuse ALK fusion proteins in the tumor cell cytoplasm. EML4-ALK was associated with nonsmokers (P = .009). Tumors with the fusion gene had the wild-type epidermal growth factor receptor (EGFR)(P = .001) and v-Ki-ras2/Kirsten rat sarcoma viral oncogene homolog (KRAS) genes. Patients who had EML4-ALK-positive AD had a younger median age (P = .018) compared with patients who did not have the fusion gene. Conclusions: The EML4-ALK fusion gene was present in various histologic types of NSCLC. It occurred in mutual exclusion to EGFR and KRAS mutations and was associated with nonsmokers. The authors concluded that EML4-ALK may be useful for predicting the potential response to ALK inhibitors as a therapeutic option for patients with lung cancer. © 2009 American Cancer Society.link_to_subscribed_fulltex

Trends in contemporary advanced heart failure management: an in-depth review over 30 years of heart transplant service in Hong Kong

Background : The year 2022 marks the 30th anniversary of heart transplant service in Hong Kong (HK). In this study, we describe prevailing trends and outcomes of advanced heart failure (AHF), including heart transplantations (HTx), in HK over the past 30 years. Methods : Trends in heart failure prevalence in HK from 1993 to 2021 were analyzed based on data from the Hospital Authority Clinical Data and Reporting System. All AHF patients referred for HTx consideration between 1992 and 2021 were reviewed. The bridge-to-transplant (BTT) utilization of short-term mechanical circulatory support (ST-MCS) devices, including venoarterial extracorporeal membrane oxygenation (VA-ECMO) and durable left ventricular assist devices (LVADs), from 2010 to 2021 was reviewed. Results : Overall, 237 heart transplants were performed in HK, with 10-year posttransplant and median survival of 68.1% and 18.7 years, respectively. An increase in AHF clinic referrals was correlated with increasing heart failure prevalence (R2=0.635, P<0.001). In total, 146 referrals were made for ST-MCS, and an observed increase in ST-MCS referrals was correlated with increasing VA-ECMO utilization (R2=0.849, P<0.001). Among 62 patients accepted for AHF therapy, those with durable LVAD implementation had better 1-year survival (71.5%) than those receiving an extracorporeal CentriMag (Levitronix) device as BTT (40%, P=0.008). In total, 143 LVADs were implanted, with 130 as BTT or bridge-to-candidacy (BTC) methods. The survival rate among the 130 BTT/BTC LVAD patients resembled that of HTx recipients (73.8% vs. 69.8% at 9 years, P=0.296). Conclusions: The burden of AHF management has increased and gained complexity over the past 30 years in Hong Kong