Is There a Benefit in Receiving Concurrent Chemoradiotherapy for Elderly Patients with Inoperable Thoracic Esophageal Squamous Cell Carcinoma?

Background and purpose

The benefit of concurrent chemoradiotherapy (CCRT) in elderly patients with inoperable esophageal squamous cell carcinoma (SCC) is controversial. This study aimed to assess the efficiency and safety of CCRT in elderly thoracic esophageal cancer patients.

Methods and materials

Between January 2002 and December 2011, 128 patients aged 65 years or older treated with CCRT or radiotherapy (RT) alone for inoperable thoracic esophageal SCC were analyzed retrospectively (RT alone, n = 55; CCRT, n = 73).

Results

No treatment-related deaths occurred and no patients experienced any acute grade 4 non-hematologic toxicities. Patients treated with CCRT developed more severe acute toxicities than patients who received RT alone. The 3-year overall survival (OS) rate was 36.1% for CCRT compared with 28.5% following RT alone (p = 0.008). Multivariate analysis identified T stage and treatment modality as independent prognostic factors for survival. Further analysis revealed that survival was significantly better in the CCRT group than in the RT alone group for patients ≤ 72 years. Nevertheless, the CCRT group had a similar OS to the RT group for patients > 72 years.

Conclusion

Our results suggest that elderly patients with inoperable thoracic esophageal SCC could benefit from CCRT, without major toxicities. However, for patients older than 72 years, CCRT is not superior to RT alone in terms of survival benefit.     

Predictive and Prognostic Value of Metabolic Tumor Volume (MTV) in Patients with Laryngeal Carcinoma Treated by Radiotherapy (RT) / Concurrent Chemoradiotherapy (CCRT)

PurposeTo evaluate the predictive and prognostic value of pretreatment metabolic tumor volume (MTV) in patients with treated by radiotherapy (RT) or concurrent chemoradiotherapy (CCRT).MethodsWe reviewed the records of 118 patients with newly diagnosed laryngeal carcinoma, who had been treated by RT or CCRT. Pretreatment positron emission tomography (PET) was performed, and MTV values were obtained by contouring margins of standardized uptake value. Clinical factors and MTV were analyzed for their association with survival.ResultsPatients with residual disease showed a significantly higher MTV than those with a complete response (CR) after primary treatment. Univariate analysis showed that the patients with a high MTV had a significantly lower disease-free survival (DFS) (p < 0.001). Subsite (p = 0.010), T-stage (p < 0.001), nodal metastasis (p < 0.001) and clinical stage (p < 0.001) also correlated significantly with DFS. In the multivariate analysis, MTV and clinical stage were both found to be independent prognostic factors for DFS (p = 0.001, p = 0.034, respectively). The 3-year DFS for patients with a high MTV were significantly poorer than those with a low MTV (p < 0.001).ConclusionsMTV of the primary tumor is a significant prognostic factor for DFS in patients with laryngeal carcinoma treated by RT or CCRT. The results imply that MTV could be an important factor when planning treatment and follow-up for patients with laryngeal carcinoma.     

The Effect of Adjuvant Chemotherapy on Survival in Patients with Residual Nasopharyngeal Carcinoma after Undergoing Concurrent Chemoradiotherapy

Background

Guidelines from the U.S. National Comprehensive Cancer Network have recommended use of concurrent chemoradiotherapy (CCRT), followed by a 3-cycles combination of platinum and 5-fluorouracil chemotherapy as standard treatment for nasopharyngeal carcinoma (NPC). The benefits of CCRT for treatment of locally advanced NPC have been established. Whether platinum and 5-fluorouracil chemotherapy should be routinely added to locally advanced NPC after CCRT is still open to debate. Whether adjuvant chemotherapy provides an additional survival benefit for the subgroup of patients with residual nasopharyngeal carcinoma who have undergone CCRT is also unclear. This retrospective study was initiated to determine the survival benefit of adjuvant chemotherapy (AC) in residual NPC patients who have undergone concurrent chemoradiotherapy.

Methods

The retrospective study included 155 nasopharyngeal carcinoma patients who had local residual lesions after the platinum-based CCRT without or with AC. Kaplan-Meier analysis and the log-rank test were used to estimate overall survival (OS), failure-free survival (FFS), local relapse-free survival (LRFS) and distant metastasis-free survival (DMFS).

Results

Median follow-up was 47 months. Adjuvant cisplatin or nedaplatin plus 5-fluorouracil chemotherapy did not significantly improve 3-year OS, LRFS, FFS, and DMFS for patients with residual nasopharyngeal carcinoma after undergoing CCRT. The 3-year OS rates for the no-AC group and AC group were 71.6% and 73.7%, respectively (P= 0.44). The 3-year FFS rates for no-AC group and AC group were 57.5% and 66.9%, respectively ((P= 0.19). The 3-year LRFS rates for no-AC group and AC group were 84.7% and 87.9%, respectively ((P= 0.51). The 3-year DMFS rates for no-AC group and AC group were 71.4% and 77.4%, respectively ((P= 0.23).

Conclusions

Since we did not find sufficient data to support significant survival in 3-year OS, LRFS, FFS, and DMFS, whether Adjuvant cisplatin or nedaplatin and 5-fluorouracil chemotherapy should be routinely added to residual nasopharyngeal carcinoma patients after undergoing CCRT remain uncertain.     

The Effect of Adding Neoadjuvant Chemotherapy to Concurrent Chemoradiotherapy in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma and Undetectable Pretreatment Epstein-Barr Virus DNA

PURPOSE: To assess the effect of adding neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and undetectable pretreatment Epstein-Barr virus (pEBV) DNA. MATERIALS AND METHODS: We enrolled 639 NPC patients with stage II to IVB and undetectable pEBV DNA to receive CCRT with or without NACT. Radiotherapy was 2.0 to 2.27 Gy per fraction with five daily fractions per week for 6 to 7 weeks to the primary tumor and 62 to 70 Gy to the involved neck area. NACT was cisplatin (80-100 mg/m² day 1) and 5-fluorouracil (800-1000 mg/m², 120-hour continuous intravenous infusion) every 3 weeks for two or three cycles. CCRT was cisplatin (80-100 mg/m² day 1) every 3 weeks for three cycles. RESULTS: For all patients, the 5-year overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) rates were 91.9%, 92.2%, 95.0%, and 86.4%, respectively. There was no significant difference in OS (5-year OS 90.8% [NACT + CCRT group] vs 92.7% [CCRT alone]; hazard ratio [HR] 1.24; P = .486), LRFS (HR 1.13, 95% confidence interval [CI] 0.59-2.14, P = .715), DMFS (HR 0.78, 95% CI 0.34-1.78, P = .554), or PFS (HR 1.21, 95% CI 0.75-1.95, P = .472). CONCLUSION: CCRT with or without NACT produced a good treatment outcome in patients with locoregionally advanced NPC and undetectable pEBV DNA, but NACT before CCRT did not significantly improve survival rates.     

Downregulation of HIPK2 Increases Resistance of Bladder Cancer Cell to Cisplatin by Regulating Wip1

Cisplatin-based combination chemotherapy regimen is a reasonable alternative to cystectomy in advanced/metastatic bladder cancer, but acquisition of cisplatin resistance is common in patients with bladder cancer. Previous studies showed that loss of homeodomain-interacting protein kinase-2 (HIPK2) contributes to cell proliferation and tumorigenesis. However, the role of HIPK2 in regulating chemoresistance of cancer cell is not fully understood. In the present study, we found that HIPK2 mRNA and protein levels are significantly decreased in cisplatin-resistant bladder cancer cell in vivo and in vitro. Downregulation of HIPK2 increases the cell viability in a dose- and time-dependent manner during cisplatin treatment, whereas overexpression of HIPK2 reduces the cell viability. HIPK2 overexpression partially overcomes cisplatin resistance in RT4-CisR cell. Furthermore, we showed that Wip1 (wild-type p53-induced phosphatase 1) expression is upregulated in RT4-CisR cell compared with RT4 cell, and HIPK2 negatively regulates Wip1 expression in bladder cancer cell. HIPK2 and Wip1 expression is also negatively correlated after cisplatin-based combination chemotherapy in vivo. Finally, we demonstrated that overexpression of HIPK2 sensitizes chemoresistant bladder cancer cell to cisplatin by regulating Wip1 expression.

Conclusions

These data suggest that HIPK2/Wip1 signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of bladder cancer.     

Microarray-Assisted Pathway Analysis Identifies MT1X & NFκB as Mediators of TCRP1-Associated Resistance to Cisplatin in Oral Squamous Cell Carcinoma

We recently reported that TCRP1, a novel multidrug-resistance associated human gene, can mediate cisplatin resistance in OSCC cells. However, the molecular mechanism underlying this role of TCRP1 remained to be elucidated. In this study, by using Human Toxicology and Drug Resistance Microarray, we identified 30 genes with significantly different expression levels between Tca/PYM and TCRP1 knockdown cell lines. Co-immunoprecipitation experiments and GST-pull down assays showed that metallothionein1X (MT1X) and Akt interact with TCRP1. siRNA-mediated knockdown of TCRP1 and MT1X was found to sensitize cells to cisplatin, leading to increased apoptosis and inhibition of cell proliferation. These functions of TCRP1 may be caused at least in part via activation of the PI3K/Akt/NF-κB signaling pathway. Taken together, our findings indicate that TCRP1 may be an important drug target for improvement of the treatment and survival of patients with oral squamous cell carcinoma.     

Distinct Antiretroviral Mechanisms Elicited by a Viral Mutagen

5-aza-cytidine (5-aza-C) has been shown to be a potent human immunodeficiency virus type 1 (HIV-1) mutagen that induces G-to-C hypermutagenesis by incorporation of the reduced form (i.e., 5-aza-dC, 5-aza-dCTP). Evidence to date suggests that this lethal mutagenesis is the primary antiretroviral mechanism for 5-aza-C. To investigate the breadth of application of 5-aza-C as an antiretroviral mutagen, we have conducted a comparative, parallel analysis of the antiviral mechanism of 5-aza-C between HIV-1 and gammaretroviruses – i.e., murine leukemia virus (MuLV) and feline leukemia virus (FeLV). Intriguingly, in contrast to the hallmark G-to-C hypermutagenesis observed with HIV-1, MuLV and FeLV did not reveal the presence of a significant increase in mutational burden, particularly that of G-to-C transversion mutations. The effect of 5-aza-dCTP on DNA synthesis revealed that while HIV-1 RT was not inhibited by 5-aza-dCTP even at 100 µM, 5-aza-dCTP was incorporated and significantly inhibited MuLV RT, generating pause sites and reducing the fully extended product. 5-aza-dCTP was found to be incorporated into DNA by MuLV RT or HIV-1 RT, but only acted as a non-obligate chain terminator for MuLV RT. This biochemical data provides an independent line of experimental evidence in support of the conclusion that HIV-1 and MuLV have distinct primary mechanisms of antiretroviral action with 5-aza-C. Taken together, our data provides striking evidence that an antiretroviral mutagen can have strong potency via distinct mechanisms of action among closely related viruses, unlinking antiviral activity from antiviral mechanism of action.     

Concurrent Chemoradiotherapy With or Without Induction Chemotherapy for Patients with Stage II Nasopharyngeal Carcinoma: An Update

PURPOSE: In contrast to other studies, our previous study showed that adding induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) significantly worsened the prognosis of patients with stage II nasopharyngeal carcinoma (NPC). However, the population used was small; therefore, there is an urgent need to confirm the result in a larger population because IC is still widely used in certain sections of china for stage II NPC. METHODS AND MATERIALS: We retrospectively analyzed an additional 272 patients. Therefore, in total, we report the results for 445 patients with stage II NPC treated with IC + CCRT or CCRT between June 2003 to June 2016 at the Zhejiang Cancer Hospital and Sun Yat-Sen University Cancer Center. RESULTS: This study included 445 patients treated with IC + CCRT (n = 195) or CCRT (n = 250). By last analysis, 22 (11.3%) patients in the IC + CCRT group developed local-regional recurrence and 23 (11.8%) patients developed distant metastases. Twenty-four (9.6%) patients in the CCRT group developed local-regional recurrence and 12 (4.8%) patients developed distant metastases. Univariate analyses showed that adding IC to CCRT significantly decreased the 5-year disease-free survival (DFS) (80.6% vs. 88.5%, P = .043); however, there was no statistically significant difference in 5-year overall survival (OS) (90.5% vs. 95.0%, P = .375). CONCLUSION: Using a larger population, the present study showed that adding IC to CCRT had a negative effect on patients with stage II NPC, which warrants further investigation.     

Thermal plasticity in the invasive south American tomato pinworm Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae)

South American tomato pinworm, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) is a devastating invasive global insect pest of tomato, Solanum lycopersicum (Solanaceae). In nature, pests face multiple overlapping environmental stressors, which may significantly influence survival. To cope with rapidly changing environments, insects often employ a suite of mechanisms at both acute and chronic time-scales, thereby improving fitness at sub-optimal thermal environments. For T. absoluta, physiological responses to transient thermal variability remain under explored. Moreso, environmental effects and physiological responses may differ across insect life stages and this can have implications for population dynamics. Against this background, we investigated short and long term plastic responses to temperature of T. absoluta larvae (4th instar) and adults (24–48 h old) from field populations. We measured traits of temperature tolerance vis critical thermal limits [critical thermal minima (CT_min) and maxima (CT_max)], heat knockdown time (HKDT), chill coma recovery time (CCRT) and supercooling points (SCP). Our results showed that at the larval stage, Rapid Cold Hardening (RCH) significantly improved CT_min and HKDT but impaired SCP and CCRT. Heat hardening in larvae impaired CT_min, CCRT, SCP, CT_max but not HKDT. In adults, both heat and cold hardening generally impaired CT_min and CT_max, but had no effects on HKDT, SCP and CCRT. Low temperature acclimation significantly improved CT_min and HKDT while marginally compromising CCRT and CT_max, whereas high temperature acclimation had no significant effects on any traits except for HKDT in larvae. Similarly, low and high temperature acclimation had no effects on CT_min, SCPs and CT_max, while high temperature acclimation significantly compromised adult CCRT. Our results show that larvae are more thermally plastic than adults and can shift their thermal tolerance in short and long timescales. The larval plasticity reported here could be advantageous in new envirnments, suggesting an asymmetrical ecological role of larva relative to adults in facilitating T. absoluta invasion.     

7-Hydroxycoumarin protects against cisplatin-induced acute kidney injury by inhibiting necroptosis and promoting Sox9-mediated tubular epithelial cell proliferation

Background7-Hydroxycoumarin (7-HC), also known as umbelliferon, is commonly found in Chinese herbs (e.g. Eucommiae Cortex, Prunellae Spica, Radix Angelicae Biseratae). Previous laboratory studies have indicated that 7-HC has anti-inflammatory, anti-oxidative, and anti-tumor effects. Cisplatin is a widely used chemotherapeutic agent for cancer. Nephrotoxicity is one of the limiting side effects of cisplatin use.PurposeThis study aimed to evaluate the renoprotective effect of 7-HC in a cisplatin-induced acute kidney injury (AKI) mouse model.MethodsAKI was induced in male C57BL/6 mice (aged 6–8 weeks) by a single intraperitoneal injection of cisplatin at 20 mg/kg. The mice received 7-HC at 30, 60, and 90 mg/kg intraperitoneally before or after cisplatin administration. Renal function, necroptosis, and cell proliferation were measured. Mechanisms underlying the reno-protective effect of 7-HC were explored in renal tubular epithelial cells treated with or without cisplatin.ResultsIn-vivo experiments showed that 7-HC significantly improved the loss in kidney function induced by cisplatin, as indicated by lower levels of serum creatinine and blood urea nitrogen, in AKI mice. Consistent herewith, cisplatin-induced tubular damage was alleviated by 7-HC as shown by morphological (periodic acid–Schiff staining) and kidney injury marker (KIM-1) analyses. We found that 7-HC suppressed renal necroptosis via the RIPK1/RIPK3/MLKL pathway and accelerated renal repair as evidenced by the upregulation of cyclin D1 in cisplatin-induced nephropathy. In-vitro experiments showed that knockdown of Sox9 attenuated the suppressive effect of 7-HC on KIM-1 and reversed the stimulatory effect of 7-HC on cyclin D1 expression in cisplatin-treated HK-2 cells, indicating that 7-HC may protect against AKI via a Sox9-dependent mechanism.Conclusion7-HC inhibits cisplatin-induced AKI by suppressing RIPK1/RIPK3/MLKL-mediated necroptosis and promoting Sox9-mediated tubular epithelial cell proliferation. 7-HC may serve as a preventive and therapeutic agent for AKI.     

The effect of adding concurrent chemotherapy to radiotherapy for stage II nasopharyngeal carcinoma with undetectable pretreatment Epstein-Barr virus DNA: Retrospective analysis with a large institutional-based cohort

Little is known about the value of adding concurrent chemotherapy (CC) to radiotherapy for stage II nasopharyngeal carcinoma (NPC) with undetectable (0 copies/mL) pretreatment Epstein-Barr Virus (EBV) DNA in the intensity-modulated radiotherapy (IMRT) era. To address this question, the present study retrospectively reviewed 514 patients with newly diagnosed stage II NPC and undetectable pretreatment EBV DNA from Sun Yat-sen University Cancer Center between March 2008 and October 2016. Clinical characteristics and survival outcomes between concurrent chemoradiotherapy (CCRT) and IMRT alone groups were compared. Propensity score matching analysis was conducted to control for confounding factors. Although CCRT group had significantly higher proportions of stage N1 disease than IMRT alone group before matching (85% vs. 61%, p < 0.001), no statistically significant differences were noted for OS (97.8% vs. 98.1%, p = 0.700), DFS (93.4% vs. 94.5%, p = 0.846), DMFS (96.0% vs. 96.9%, p = 0.762), and LRFS (97.3% vs. 98.1%, p = 0.701). After 1:1 propensity-score matching, 177 pairs were identified. Patients in each group were found to be well balanced in baseline characteristics and risk factors (all P > 0.05). The five-year OS (96.9% vs. 98.2%, p = 0.302), DFS (92.0% vs. 95.2%, p = 0.777), DMFS (95.2% vs. 97.6%, p = 0.896), and LRFS (97.3% vs. 97.6%, p = 0.328) rates remain comparable for both CCRT and RT alone groups. Additionally, subgroup analysis still failed to observe any significant survival benefit for the addition of CC to IMRT for N1 disease (P>0.05 for all). Our results indicated that IMRT alone appeared to achieve comparable survival to CCRT for stage II NPC with undetectable pretreatment EBV DNA.Keyword: Nasopharyngeal carcinoma, Epstein–Barr virus DNA, Survival, Intensity-modulated radiotherapy, Concurrent chemotherapy, Effect     

Improving the antibacterial activity and selectivity of an ultra short peptide by hydrophobic and hydrophilic amino acid stretches

The principle of amino acid stretches tagged at the C terminal of Luecrocin I, which is an ultra-short antibacterial peptide, by tryptophan and arginine or lysine has been reported. The choice of amino acid type at each stretch position depends on the hydrophobic and hydrophilic regions visualized in the helical wheel pattern of Luecrocin I. Oligopeptide tagging should also consider the properties such as positive charge, hydrophobicity, the content of hydrophobic amino acids, polar angle, the properly hydrophilic and hydrophobic facets. Amidation at C terminal and lysine substitute for arginine can increase selectivity between mammalian cells (hemolytic and MTT assay) and bacterial cells tested. KT2 and RT2 which have 53% hydrophobic residues, 7 positive charges, 160° polar angle, ?0.02 (KT2) and ?0.04 (RT2) hydrophobicity were effective against S. typhi DMST 22842, S. epidermidis ATCC 12228, E. coli ATCC 25922 and V. cholerae non-O1, non-O139. The SEM images implied that the antibacterial mechanism of RT2 and KT2 may depend on concentration rather than time. Finally, RT2 and KT2 can be new antibacterial agents or may be further developed for alternative antibiotics.     

Induction Chemotherapy Has No Prognostic Value in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma and Chronic Hepatitis B Infection in the IMRT Era

BACKGROUND: The effectiveness of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) over CCRT alone in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and chronic hepatitis B infection in the intensity-modulated radiotherapy (IMRT) era is unknown. PATIENTS AND METHODS: A total of 249 patients with stage T1-2 N2-3 or T3-4 N1-3 NPC and chronic hepatitis B infection treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) was employed to balance covariates; 140 patients were propensity-matched (1:1 basis). Survival outcomes in the IC + CCRT and CCRT groups were compared using the Kaplan–Meier method, log-rank test and Cox proportional hazards model. RESULTS: No significant survival differences were observed between IC + CCRT and CCRT (5-year overall survival, 88.3% vs. 82.2%; P = .484; disease-free survival, 73.9% vs. 75.2%; P = .643; distant metastasis-free survival, 84.1% vs. 85.1%; P = .781; and locoregional failure-free survival, 87.9% vs. 85.1%; P = .834). After adjusting for known prognostic factors in multivariate analysis, IC was not an independent prognostic factor for any outcome (all P > .05); subgroup analysis based on T category (T1-2/T3-4), N category (N0-1/N2-3), and overall stage (III/IV) confirmed these results. The incidence of hepatic function damage in the IC + CCRT and CCRT groups was not significantly different. CONCLUSION: IC + CCRT leads to comparable survival outcomes and hepatic function damage compared to CCRT alone in patients with locoregionally advanced NPC with chronic hepatitis B infection in the IMRT era. Further investigations are warranted.     

Comparison of a Concurrent Fluorouracil-Based Regimen and a Taxane-Based Regimen Combined with Radiotherapy in Elderly Patients with Esophageal Squamous Cell Carcinoma

Elderly patients with esophageal carcinoma may benefit from concurrent chemoradiotherapy (CCRT). However, the optimal concurrent chemotherapy regimen has not been determined. The aim of our study was to assess the efficiency and tolerance of treatment with a concurrent 5-fluorouracil (5-Fu)–based regimen and a taxane-based regimen combined with radiotherapy in elderly patients with esophageal squamous cell carcinoma (ESCC). A total of 46 patients with ESCC aged older than 65 years were included in this study. The patient population was divided into two treatment groups: 24 patients who received CCRT with a 5-Fu–based regimen were allocated to the PF group, and 22 patients who received CCRT with a taxane-based regimen were allocated to the DP group. The median overall survival (OS), median progression-free survival (PFS), overall response rate, and treatment-related toxicity were assessed. For patients in the PF group, the median OS time was 27.8 ± 9.1 months, and the median PFS time was 12.5 ± 2.7 months. Patients in the DP group had comparable survival outcomes, with a median OS time of 34.4 ± 6.4 months and a median PFS time of 21.1 ± 6.4 months (P = .296 and P = .115, respectively). Grade ≥3 leukocytopenia and grade ≥2 anemia occurred in 63.6% and 59.1% of patients in the DP group, respectively, and in 25.0% and 16.7% of patients in the PF group, respectively. Our results suggest that CCRT with a taxane-based regimen results in a higher incidence of treatment-related toxicity than CCRT with a 5-Fu–based regimen but comparable survival outcomes.     

Prognosis of Cervical Cancer in the Era of Concurrent Chemoradiation from National Database in Korea: A Comparison between Squamous Cell Carcinoma and Adenocarcinoma

In 1999, the National Cancer Institute issued a clinical advisory strongly touting the advantage of cisplatin-based chemoradiation (CCRT) for cervical cancer patients requiring radiation for their treatment. This study aimed to compare survival outcomes of cervical squamous cell carcinoma and adenocarcinoma before and after the advent of CCRT. Data were obtained from the Korea National Cancer Incidence Database for patients who were diagnosed with cervical cancers between 1993 and 2012. We compared survival according to histologic subtypes in cervical cancer patients diagnosed before (1993–1997), during (1998–2002), and after (2003–2012) the introduction of CCRT. A total of 80,766 patients were identified, including 64,531 (79.9%) women with squamous cell carcinomas and 7,265 (9.0%) with adenocarcinoma. With the introduction of CCRT, survival trends gradually increased in patients of both histologic subtypes with regional tumors. However, survival was significantly higher in squamous cell carcinoma than in adenocarcinoma patients regardless of treatment modalities (surgery alone, P < 0.001; surgery followed by CCRT, P < 0.001; or primary CCRT, P = 0.003). Multivariate analysis showed that adenocarcinoma was an independent negative prognostic factor for survival regardless of the time period (before CCRT, hazard ratio (HR) = 1.49; 95% confidence interval (CI), 1.37–1.62; after introduction of CCRT, HR = 1.40; 95% CI, 1.30–1.50). Although the survival of adenocarcinoma has improved after the introduction of CCRT, adenocarcinoma is still associated with worse overall survival compared to squamous cell carcinoma in the era of CCRT.     

PRKCD/PKCδ contributes to nephrotoxicity during cisplatin chemotherapy by suppressing autophagy

Nephrotoxicity is a major side effect during chemotherapy with cisplatin and related platinum compounds. Previous work unveiled a role of PRKCD/PKCδ (protein kinase C delta) in cisplatin-induced nephrotoxicity; however, the underlying mechanism was largely unknown. Our recent work showed that PRKCD may suppress macroautophagy/autophagy, a cytoprotective mechanism, to promote kidney tubule cell death during cisplatin treatment. Interestingly, PRKCD may do so by phosphorylating AKT, which further phosphorylates MTOR to repress ULK1.     

Induction ofMRP/GS-X pump and cellular resistance to anticancer prostaglandins

We provide evidence that the expression of the humanMRP/GS-X pump encoded by theMRP (multidrug resistance associated protein) gene is induced by cisplatin in human leukemia HL-60/R-CP (cisplatin-resistant) cells and modulates cell growth inhibition by Δ⁷-prostaglandin A₁ (PGA₁) methyl ester. TheMRP mRNA level in HL-60/R-CP cells increased remarkably after a 24-h incubation with 20 μM cisplatin; interestingly, however, no amplification of theMRP gene was detected. In cisplatin-sensitive HL-60 cells, which express theMRP/GS-X pump at low levels, c-myc expression was substantially supressed by Δ⁷-PGA₁ methyl ester and the cell cycle was arrested in G1 phase. By contrast, in HL-60/R-CP cells overexpressing theMRP/GS-X pump, c-myc expression and cell proliferation were much less affected by Δ⁷-PGA₁ methyl ester. This suggests that induction of theMRP/GS-X pump may confer on cancer cells resistance to anticancer prostaglandins and that the resistance mechanism may involve the increased efflux of PG-glutathione conjugates, as active intermediates, from the cells via theMRP/GS-X pump.