Knockdown of OCT4 may sensitize NSCLC cells to cisplatin

Purpose

Cisplatin is commonly used in non-small-cell lung cancer (NSCLC) chemotherapy; however, chemoresistance to cisplatin remains a great clinical challenge. Octamer-binding protein 4 (OCT4) has been reported to be overexpressed in NSCLC. In this study, we aimed to investigate the potential role of OCT4 in NSCLC with chemoresistance to cisplatin.

Methods

Expressions of OCT4 was detected in NSCLC tissues and cell lines. We utilized siRNA to knock down OCT4 expression in human NSCLC cells and analyzed their phenotypic changes.

Results

We found that the difference of OCT4 expression between NSCLC and the adjacent non-tumourous tissues was statistically significant. Knockdown of OCT4 in NSCLC cells could decrease cell proliferation, and potentiate apoptosis induced by cisplatin, suggesting OCT4 may contribute to cisplatin resistance in NSCLC.

Conclusion

Our findings indicate that targeting OCT4 could improve cisplatin effect in NSCLC, confirming their role in modulating cisplatin sensitivity.

     

Stromal markers AKR1C1 and AKR1C2 are prognostic factors in primary human breast cancer

Background

Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo–keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism.

Methods

Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival.

Results

AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker.

Conclusion

It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status.

     

Knockdown of ST6Gal-I increases cisplatin sensitivity in cervical cancer cells

Background

Sialyltransferase I (ST6Gal-I) is an enzyme involved in tumor metastasis that processes sialic acid precursors into their mature form, enabling them to regulate gene expression. However, the effect of ST6Gal-I on the biological behavior of cancer cells remain unclear. This study was the first to demonstrate the influence of ST6Gal-I on cisplatin sensitivity in cervical cancer cells.

Methods

Knockdown of ST6Gal-I was performed by shRNA and HeLa cells combination with cisplatin were tested.

Results

We showed that down-regulation of ST6Gal-I promoted cell apoptosis and inhibited proliferation and invasion in cervical cancer cells. Knockdown of ST6Gal-I by RNA interference increased the sensitivity of HeLa cells to cisplatin in vitro, and reduced tumor volume and suppressed subcutaneous tumor growth in response to cisplatin treatment in a xenograft mouse model in vivo.

Conclusions

The results provide new information that ST6Gal-I plays an important role in several biological or pathological processes including drug resistance in cervical cancer and may be a potential therapeutic target to improve the response to chemotherapy in cervical cancer patients.

     

NFBD1/MDC1 participates in the regulation of proliferation and apoptosis in human laryngeal squamous cell carcinoma

Purpose

The objective of the study was to investigate the role of NFBD1 in the proliferation and apoptosis of laryngeal squamous cell carcinoma (LSCC) cells.

Methods

Immunohistochemistry (IHC) and qRT-PCR was employed to determine the expressions of NFBD1 protein and mRNA in LSCC tissues and adjacent noncancerous tissues. After the downregulation of NFBD1 expression, the colony formation assay, MTS assay and apoptosis assay were used to investigate the changes in the proliferation and apoptosis of Hep2 cells. The mechanisms by which silencing NFBD1 promote apoptosis of Hep2 cells were examined by western blotting. Furthermore, xenograft models were used to evaluate the proliferation of Hep2 cells in vivo.

Results

NFBD1 protein was upregulated in 55.6% of LSCC cancer tissues compared with adjacent normal tissues (26.7%). NFBD1 knockdown in Hep2 cells significantly impacted proliferation and apoptosis, and silencing NFBD1 might promote apoptosis of Hep2 cells by activating the mitochondrial apoptotic pathway. Xenograft models showed that silencing NFBD1 also significantly inhibited tumor growth.

Conclusions

Our data highlight that NFBD1 participates in the regulation of proliferation and apoptosis in LSCC, and suggest that NFBD1 could be a promising therapy target.

     

Stromal expression of JNK1 and VDR is associated with the prognosis of esophageal squamous cell carcinoma

Purpose

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, and its outcome is poor. The purpose of this study was to determine the association between JNK1 and vitamin D receptor (VDR) expression and the prognosis of ESCC.

Methods

Immunohistochemical staining was conducted on ESCC tissue microarrays (362 pairs of ESCC and normal esophagus tissues). The epithelial and stromal expression levels of c-jun NH2-terminal kinase 1 (JNK1) and VDR were scored and correlated with the ESCC characteristics. Laser-capture-based quantitative RT-PCR was performed on ESCC tissues. The effects of JNK1 and VDR on ESCC cell proliferation and migration were analyzed in vitro by transient transfection, and protein changes were evaluated by immunoblotting.

Results

Both JNK1 and VDR were reduced in ESCC epithelial cells in comparison with the normal esophagus, but the expression of JNK1 and VDR in ESCC stromal tissues, not epithelial cells, was strongly associated with the survival time of ESCC patients. Functional studies showed that increased JNK1 suppressed cancer cell proliferation, mobility, and migration, which were linked to the alterations of VDR and metastasis-associated proteins.

Conclusion

JNK1 and VDR act as tumor suppressors, and their stromal expression levels are associated with prognosis in esophageal squamous cell carcinoma.

     

Body size over the life-course and the risk of endometrial cancer: the California Teachers Study

Purpose

Obesity is a public health epidemic and a major risk factor for endometrial cancer. Here, we identify key aspects of body size which jointly, over the life-course (since adolescence), are associated with endometrial cancer risk.

Methods

Among 88,142 participants in the California Teachers Study, 887 were diagnosed with invasive type 1 endometrial cancer between 1997–1998 and 2012. Multivariable Cox proportional hazards models provided estimates of hazard rate ratios (HR) and 95% confidence intervals (CI) for endometrial cancer associated with life-course body size phenotypes, which incorporated validated measures.

Results

Among women currently using hormone therapy, endometrial cancer risk was only associated with height (HR 1.78, 95% CI 1.32–2.40 for ≥67 vs. <67 inches). Among women not using hormone therapy, tall women who were overweight/obese in adolescence (HR 4.33, 95% CI 2.51–7.46) or who became overweight/obese as adults (HR 4.74, 95% CI 2.70–8.32) were at greatest risk.

Conclusions

Considering absolute body mass, changes in adiposity over time, and body fat distribution together, instead of each measure alone, we identified lifetime obesity phenotypes associated with endometrial cancer risk. These results more clearly define specific risk groups, and may explain inconsistent findings across studies, improve risk prediction models, and aid in developing targeted interventions for endometrial cancer.

     

The functional status of DNA repair pathways determines the sensitization effect to cisplatin in non-small cell lung cancer cells

Purpose

Cisplatin can cause a variety of DNA crosslink lesions including intra-strand and inter-strand crosslinks (ICLs), which are associated with the sensitivity of cancer cells to cisplatin. Here, we aimed to assess the contribution of the Fanconi anemia (FA), homologous recombination (HR) and nucleotide excision repair (NER) pathways to cisplatin resistance in non-small cell lung cancer (NSCLC)-derived cells.

Methods

The expression of FA, HR and NER pathway-associated genes was assessed by RT-qPCR and Western blotting. siRNAs were used to knock down the expression of these genes. CCK-8 and flow cytometry assays were used to assess the viability and apoptotic rate of NSCLC-derived cells, respectively. Immunofluorescence and alkaline comet assays were used to assess the repair of ICLs.

Results

We found that acquired cisplatin-resistant NSCLC-derived A549/DR cells exhibited markedly enhanced FA and HR repair pathway capacities compared to its parental A549 cells and another independent NSCLC-derived cell line, Calu-1, which possesses a moderate innate resistance to cisplatin. siRNA-mediated silencing of the FA-associated genes FANCL and RAD18 and the HR-associated genes BRCA1 and BRCA2 significantly potentiated the sensitivity of A549/DR cells to cisplatin compared to A549 and Calu-1 cells, suggesting that the acquired cisplatin resistance in A549/DR cells may be attributed to enhanced FA and HR pathway capacities responsible for ICL repair. Although we found that expression knockdown of the NER-associated genes XPA and ERCC1 sensitized the three NSCLC-derived cell lines to cisplatin, the sensitization effect was more significant in Calu-1 cells than in A549 and A549/DR cells, implying that the innate cisplatin resistance in Calu-1 cells may result from an increased NER activity.

Conclusions

Our results indicate that the functional status of DNA repair pathways determine the sensitivity of NSCLC cells to cisplatin. Direct targeting of the pathway that is involved in cisplatin resistance may be an effective strategy to surmount cisplatin resistance in NSCLC.

     

Supernormal Electro-Oculograms in Patients with Neurofibromatosis Type 1

Purpose

To asses the retinal pigment epithelium (RPE) function measured by EOG testing in patients with neurofibromatosis type 1 (NF-1). Our preliminary EOG results suggested dysfunction of the RPE in individuals with NF-1. In order to confirm our initial results we performed EOG examination on a larger group of NF-1 patients.

Patients

Studies were performed on 36 patients with clinically diagnosed NF-1 and compared to normal healthy controls.

Methods

Standard EOG recordings were performed in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standards.

Results

In NF-1 patients the Arden indexes of the EOG test were significantly higher primarily due to the lower values of dark troughs. Supernormal EOGs (exceeding the value of the mean + 2 SD from the control group) were present in 58% of NF-1 patients.

Conclusions

Dysfunction of the RPE is a characteristic feature of individuals with NF-1.

     

Multicenter phase II study of trastuzumab plus S-1 alone in elderly patients with HER2-positive advanced gastric cancer (JACCRO GC-06)

Background

S-1 plus cisplatin is a standard regimen for advanced gastric cancer (AGC) in Asia. The ToGA trial established a fluoropyrimidine plus cisplatin and trastuzumab as a standard treatment for human epidermal growth factor receptor 2 (HER2)-positive AGC. In the HERBIS-1 trial, trastuzumab combined with S-1 plus cisplatin showed promising antitumor activity in patients with HER2-positive AGC. However, cisplatin has several important drawbacks, including vomiting and renal toxicity. These disadvantages of cisplatin are prominent in elderly patients. Therefore, we conducted a prospective phase II study of trastuzumab plus S-1 without cisplatin in elderly patients with HER2-positive AGC.

Methods

Patients 65 years or older who had HER2-positive AGC received S-1 orally on days 1–28 of a 42-day cycle and trastuzumab intravenously on day 1 of a 21-day cycle.

Results

A total of 51 patients were enrolled. Two patients were ineligible. The full analysis set thus comprised 49 patients. The median age was 71 years (range 65–85). The confirmed response rate was 40.8% (95% CI 27.1–54.6%), and the null hypothesis was rejected. The median follow-up period was 10.6 months. Median overall survival was 15.8 months. Median progression-free survival was 5.1 months, and time to treatment failure was 4.0 months. Major grade 3 or 4 adverse events included neutropenia (12.0%), anemia (24.0%), diarrhea (10.0%), and anorexia (12.0%). There was one treatment-related death.

Conclusions

Trastuzumab in combination with S-1 alone demonstrated promising antitumor activity and manageable toxic effects as well as promising survival results in elderly patients with HER2-positive AGC.

Clinical trials registration

UMIN000007368.

     

Les tumeurs endocrines rectocoliques: particularités anatomocliniques et thérapeutiques

Background

Endocrine tumours of the gastro-intestinal tract are rare and predominate in the small intestine and in the appendix, less commonly in the colon and the rectum.

Aim

The aim of this study is to analyze clinical and pathologic features of an endocrine tumour of the colon and the rectum diagnosed in the Department of Pathology (Sousse, Tunisia).

Methods

Five cases were diagnosed between 1992 and 2006 in our hospital unit. The medical records of the affected patients were analyzed. The pathological material was reviewed and the tumours were classified according to 2000 WHO classification.

Results

The study population consisted of 2 male and 3 female patients. Their median age was 55 years. Two poorly differentiated endocrine carcinomas of the colon, and one colic and two rectal well differentiated endocrine carcinoma were identified.

Conclusion

This study illustrates the importance of adequately diagnosing endocrine tumours because their treatment and prognosis are different from those of conventional carcinoma.

     

Atypical presentation of hepatocellular carcinoma: a mass on the left thoracic wall

Background

Hepatocellular carcinoma is a common malignancy for which chronic hepatitis B infection has been defined as the most common etiologic factor. The most frequent metastatic sites are the lung, bone, lymphatics, and brain, respectively. Metastases to the chest wall have been reported only rarely.

Case presentation

We report a patient with hepatocellular carcinoma who presented with an isolated metastatic mass on the left anterolateral chest wall in the axillary region.

Conclusions

Metastasis of HCC should be included in the differential diagnosis of rapidly growing lesions in unusual localizations, particularly in patients with chronic liver disease even if a primary tumor can not be radiologically identified.

     

Platinum-based neoadjuvant chemotherapy in BRCA1-positive breast cancer: a retrospective cohort analysis and literature review

Background

There is increasing evidence of high platinum sensitivity in BRCA-associated breast cancer. However, evidence from randomized trials is lacking. The aim of this study was to analyze the results of platinum-based chemotherapy for BRCA1-positive breast cancer in a neoadjuvant setting.

Methods

A retrospective study was performed by obtaining information from patient files. The results were compared with the available data from a literature review.

Results

Twelve female patients with BRCA1 gene mutations who had stage I to III breast cancers were eligible for evaluation. They received platinum-based neoadjuvant chemotherapy between 2011 and 2016. Eleven patients received a combination of cisplatin and doxorubicin, and one patient received carboplatin and docetaxel. All patients underwent mastectomy after chemotherapy. Ten patients (83%) achieved pathological complete remission (pCR). The observed pCR rate was comparable to existing results found in similar studies.

Conclusion

The results of the study confirm the high pCR rate in BRCA1-positive breast cancer after platinum-based neoadjuvant chemotherapy. Larger randomized studies and longer follow-up times are necessary to evaluate the role of platinum-based therapies in BRCA1-positive breast cancer.

     

Phenotype plasticity rather than repopulation from CD90/CK14+ cancer stem cells leads to cisplatin resistance of urothelial carcinoma cell lines

Background

Tumour heterogeneity and resistance to systemic treatment in urothelial carcinoma (UC) may arise from cancer stem cells (CSC). A recent model describes cellular differentiation states within UC based on corresponding expression of surface markers (CD) and cytokeratins (CK) with CD90 and CK14 positive cells representing the least differentiated and most tumourigenic population. Based on the fact that this population is postulated to constitute CSCs and the origin of cisplatin resistance, we enriched urothelial carcinoma cell lines (UCCs) for CD90 and studied the tumour-initiating potential of these separated cells in vitro.

Methods

Magnetic- and fluorescence-activated- cell sorting were used for separation of CD90⁺ and CD90^? UCCs. Distribution of cell surface markers CD90, CD44, and CD49f and cytokeratins CK14, CK5, and CK20 as well as the effects of short- and long-term treatment with cisplatin were assessed in vitro and measured by qRT-PCR, immunocytochemistry, reporter assay and flow cytometry in 11 UCCs.

Results

We observed cell populations with surface markers according to those reported in tumour xenografts. However, expression of cytokeratins did not concord regularly with that of the surface markers. In particular, expression of CD90 and CK14 diverged during enrichment of CD90⁺ cells by immunomagnetic sorting or following cisplatin treatment. Enriched CD90⁺ cells did not exhibit CSC-like characteristics like enhanced clonogenicity and cisplatin resistance. Moreover, selection of cisplatin-resistant sublines by long-term drug treatment did not result in enrichment of CD90⁺ cells. Rather, these sublines displayed significant phenotypic plasticity expressing EMT markers, an altered pattern of CKs, and WNT-pathway target genes.

Conclusions

Our findings indicate that the correspondence between CD surface markers and cytokeratins reported in xenografts is not maintained in commonly used UCCs and that CD90 may not be a stable marker of CSC in UC. Moreover, UCCs cells are capable of substantial phenotypic plasticity that may significantly contribute to the emergence of cisplatin resistance.

     

Mutation spectrum in South American Lynch syndrome families

Background

Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system.

Methods

We compiled data from publications and hereditary cancer registries to characterize the Lynch syndrome mutation spectrum in South America. In total, data from 267 families that fulfilled the Amsterdam criteria and/or the Bethesda guidelines from Argentina, Brazil, Chile, Colombia and Uruguay were included.

Results

Disease-predisposing mutations were identified in 37% of the families and affected MLH1 in 60% and MSH2 in 40%. Half of the mutations have not previously been reported and potential founder effects were identified in Brazil and in Colombia.

Conclusion

The South American Lynch syndrome mutation spectrum includes multiple new mutations, identifies potential founder effects and is useful for future development of genetic testing in this continent.

     

A phase II study of combination therapy with oral S-1 and cisplatin in elderly patients with advanced gastric cancer

Background

A combination of S-1 and cisplatin is recognized as one of the standard first-line chemotherapy regimens for patients with advanced gastric cancer. However, demographic analyses of pivotal phase III studies have showed that only a minority of treated patients were aged 76 years or older. The purpose of this phase II study was to evaluate the safety and efficacy of combination therapy with S-1 and cisplatin in elderly patients with chemotherapy-naive advanced gastric cancer.

Methods

Patients aged 76 years or older received S-1 40 mg/m² orally twice daily for 21 days and cisplatin 60 mg/m² intravenously infused at day 8 of each 35-day cycle. Dose modification was performed according to creatinine clearance. The primary endpoint was overall survival (OS). Secondary endpoints included response rate, progression-free survival (PFS), time to treatment failure (TTF), and adverse events.

Results

A total of 40 patients were enrolled. Median OS was 12.3 months, PFS was 7.8 months, and TTF was 4.3 months. The response rate was 54%. The most common grade 3–4 adverse events were anorexia (25%), neutropenia (23%), hyponatremia (20%), anemia (18%), and febrile neutropenia (8%). No treatment-related death occurred.

Conclusions

Combination chemotherapy with S-1 and cisplatin is an effective and well-tolerated regimen for elderly patients with advanced gastric cancer when the dose is adjusted according to renal function.

     

Vitamin D Deficiency has a Negative Impact on Cetuximab-Mediated Cellular Cytotoxicity against Human Colon Carcinoma Cells

Background

Hypovitaminosis D is associated with an adverse prognosis in colon cancer patients, possibly due to the effects of the vitamin on the immune system. Antibody-dependent cell-mediated cytotoxicity (ADCC) significantly contributes to the anti-tumor effects of monoclonal antibodies, including cetuximab, an epidermal growth factor receptor (EGFR)-targeted monoclonal antibody that is frequently added to chemotherapy in the treatment of colon cancer.

Objective

The present study evaluates the association between vitamin D serum levels and the ability of ex vivo NK cells to support cetuximab-mediated ADCC in colon cancer cell lines.

Methods

Blood samples were obtained from 124 healthy volunteers and serum vitamin D was determined by RIA. NK cells were isolated from each sample and added to human colorectal carcinoma cells with or without cetuximab, and ADCC was assessed using a colorimetric lactate dehydrogenase assay.

Results

Correlation analysis indicates a significant, gender- and age-independent association between vitamin D levels and cetuximab-induced ADCC on HT29 cells, where NK cells from samples with vitamin D?<?20 ng/mL are significantly less efficient in inducing ADCC. A confirmatory study on two additional colon cancer cell lines yielded similar results.

Conclusions

These data suggest that vitamin D supplementation in vitamin-deficient/insufficient colorectal cancer patients could improve cetuximab-induced ADCC.

     

Retrospective comparison of S-1 plus cisplatin versus S-1 monotherapy for the treatment of advanced gastric cancer patients with positive peritoneal cytology but without gross peritoneal metastasis

Background

Peritoneal cytology positive for carcinoma cells (CY+) is an independent poor prognostic factor in gastric cancer, and patients with CY+ are diagnosed with stage IV disease. However, there is no standard treatment strategy for CY+ gastric cancer, whereas combination chemotherapy with fluoropyrimidine and platinum has been established as the standard treatment for unresectable advanced gastric cancer or after R2 resection. Herein, we assessed whether adding cisplatin to S-1 (SP) could improve the outcome of CY+ gastric cancer patients, as compared to S-1 monotherapy.

Methods

This retrospective study was conducted at a single Japanese institute between June 2005 and March 2014. Patients diagnosed with CY+ advanced gastric cancer and treated with S-1-based therapy were enrolled. Patients with incurable factors other than CY+ were excluded.

Results

Forty-four patients were enrolled; 25 and 19 were administered S-1 and SP, respectively. The 2-year survival rates were 52.0% [95% confidence interval (CI), 31.2–69.2%] and 52.6% (28.7–71.9%) in the S-1 and SP groups, respectively. The median overall survival (OS) and progression-free survival (PFS) were 28.2 and 15.6 months in the S-1 group and 24.0 and 18.8 months in the SP group, respectively; they were not significantly different. The relative dose intensities were 0.79 (S-1) in the S-1 group and 0.69 (S-1)/0.70 (cisplatin) in the SP group.

Conclusion

Adding cisplatin to long-term S-1 monotherapy did not significantly improve the outcome of CY+ advanced gastric cancer patients.

     

The effect of EGB on proliferation of gastric carcinoma SGC7901 cells

Objective

To investigate the effect of Ginkgo biloba extract (EGB) on the proliferation and cell cycles of gastric carcinoma SGC7901 cells, and make a preliminary exploration on possible molecular mechanisms associated with its inhibitory effect.

Methods

Human gastric carcinoma SGC7901 cells were cultured in vitro, and treated with various concentrations (100, 200, 300, 400 mg/L) of EGB for different incubation periods (24, 48 and 72 h). CCK-8 assay was used to detect cell proliferation and flow cytometry was performed to analyze the effect of EGB on cell cycles. In addition, mRNA and protein level of two cell cycle regulators cyclin D1 and c-myc in SGC7901 cells treated with EGB were determined using PCR and Western blot. And subcutaneous xenograft model of gastric carcinoma in nude mice was established to evaluate the anti-cancer effect of EGB in vivo.

Results

The proliferation of gastric carcinoma SGC7901 cells was inhibited by EGB in dose- and time-dependent manner. Flow cytometry showed cell cycle arrest in EGB-treated cells, with increased percentage of cells in G1 phase and decreased percentage in S stage. In addition, the mRNA and protein level of cyclin D1 and c-myc genes were significantly down-regulated in cells with EGB treatment with the concentration increasing.

Conclusion

EGB conferred an inhibitory effect on the proliferation of gastric carcinoma SGC7901 cells both in vitro and in vivo. The inhibitory effect was dose dependent and possibly depended on inhibiting cell cycle through G1 arrest induction by suppressing cyclin D1 and c-myc expression.

     

Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours

Background

Testicular germ cell tumours (TGCT) are highly sensitive to cisplatin-based chemotherapy, but patients with tumours containing differentiated teratoma components are less responsive to this treatment. The cisplatin sensitivity in TGCT has previously been linked to the embryonic phenotype in the majority of tumours, although the underlying mechanism largely remains to be elucidated. The aim of this study was to investigate the role of the DNA mismatch repair (MMR) system in the cisplatin sensitivity of TGCT.

Methods

The expression pattern of key MMR proteins, including MSH2, MSH6, MLH1 and PMS2, were investigated during testis development and in the pathogenesis of TGCT, including germ cell neoplasia in situ (GCNIS). The TGCT-derived cell line NTera2 was differentiated using retinoic acid (10 μM, 6 days) after which MMR protein expression and activity, as well as cisplatin sensitivity, were investigated in both undifferentiated and differentiated cells. Finally, the expression of MSH2 was knocked down by siRNA in NTera2 cells after which the effect on cisplatin sensitivity was examined.

Results

MMR proteins were expressed in proliferating cells in the testes, while in malignant germ cells MMR protein expression was found to coincide with the expression of the pluripotency factor OCT4, with no or low expression in the more differentiated yolk sac tumours, choriocarcinomas and teratomas. In differentiated NTera2 cells we found a significantly (p < 0.05) lower expression of the MMR and pluripotency factors, as well as a reduced MMR activity and cisplatin sensitivity, compared to undifferentiated NTera2 cells. Also, we found that partial knockdown of MSH2 expression in undifferentiated NTera2 cells resulted in a significantly (p < 0.001) reduced cisplatin sensitivity.

Conclusion

This study reports, for the first time, expression of the MMR system in fetal gonocytes, from which GCNIS cells are derived. Our findings in primary TGCT specimens and TGCT-derived cells suggest that a reduced sensitivity to cisplatin in differentiated TGCT components could result from a reduced expression of MMR proteins, in particular MSH2 and MLH1, which are involved in the recognition of cisplatin adducts and in activation of the DNA damage response pathway to initiate apoptosis.

     

A retrospective analysis of 5-fluorouracil plus cisplatin as first-line chemotherapy in the recent treatment strategy for patients with metastatic or recurrent esophageal squamous cell carcinoma

Background

Patients with metastatic or recurrent esophageal squamous cell carcinoma (ESCC) have a poor prognosis. For decades, the most widely used first-line chemotherapy regimen for these patients has been the combination of 5-fluorouracil + cisplatin (CF). However, prognostic factors of CF as first-line chemotherapy for ESCC have not been clarified.

Methods

A total of 187 patients with metastatic or recurrent esophageal ESCC treated with CF at the National Cancer Center Hospital between January 2001 and December 2012 were enrolled in the study. The CF regimen comprised cisplatin (80 mg/m²) administered on day 1 and 5-fluorouracil (800 mg/m²) administered continuously on days 1–5, every 4 weeks. Multivariate Cox regression analysis was used to determine the potential prognostic factors.

Results

The median age of the patients was 62 (range 34–84) years. Metastasis and recurrence occurred in 116 and 71 of these patients, respectively. The overall response rate was 37.2%, with median progression-free and overall survival times of 4.8 and 10.4 months, respectively. In the multivariate analysis, higher serum C-reactive protein level and lower serum albumin level at the time of CF treatment initiation and number of metastatic sites were identified as independent prognostic factors for survival.

Conclusions

The results of this study corroborate previous findings on the efficacy of CF and will aid physicians in clinical decision-making and individual patient risk stratification, as well as in the further development of chemotherapy regimens.