Magnesium supplementation therapy to prevent cisplatin-induced acute nephrotoxicity in pediatric cancer: a randomized phase-2 trial.

BACKGROUND: The present study aimed to examine the effect of magnesium (Mg) supplementation on cisplatin-induced nephrotoxicity (CIN) in pediatric cancer patients. METHODS: The present phase-2, open-label, multicenter, randomized controlled trial enrolled patients aged less than 20 years who were scheduled to receive cisplatin-containing chemotherapy and randomly allocated them at a ratio of 1:1 to a Mg supplementation arm with even-numbered chemotherapy courses (arm AB) or another arm with odd-numbered courses (arm BA). Analysis objects were reconstructed into two groups depending on whether the chemotherapy course had Mg supplementation (group B) or not (group A). The primary outcome was the proportion of chemotherapy courses resulting in elevated serum creatinine per chemotherapy course. The secondary outcomes included efficacies evaluated using other biomarkers and the safety of the Mg supplementation. RESULTS: Twenty-eight patients were randomly allocated to either group (16 to arm AB and 12 to arm BA). The baseline characteristics of the groups were similar. There was no significant difference in the proportion of courses with increased serum creatinine between the groups (group A: 10% vs. group B: 6%; P = 0.465) nor was any significant difference observed in other biomarkers during any chemotherapy course. The Mg value during chemotherapy was significantly higher in group B than that in group A. No adverse events related to magnesium administration were observed. CONCLUSIONS: The study design, which treated a single chemotherapy course as a study object, failed to detect a statistically significant benefit of Mg supplementation for preventing CIN in pediatric cancer patients. TRIAL REGISTRATION: JRCT ( https://jrct.niph.go.jp/ ) Identifier UMIN000029215 jRCTs031180251. UMIN-CTR ( http://www.umin.ac.jp/icdr/index.html ) Identifier UMIN000029215.

Time dependent cisplatin dosing differences on hypoalgesia focusing on oxidative stress.

Although cisplatin is a key drug in cancer chemotherapy, it often causes sensory peripheral neuropathy, presenting as allodynia in the early stage and hypoalgesia in the serious stage. Chronotherapy has previously been shown to ameliorate cisplatin-induced peripheral neuropathy that was severe enough to cause hypoalgesia in rats. It also has adverse effects such as renal dysfunction and ototoxicity, which are induced by oxidative stress. Here, we show that oxidative stress causes severe cisplatin-induced peripheral neuropathy, and that differences in oxidative stress occur depending on the dosing time of cisplatin. Cisplatin was administered to rats at 5:00 or 17:00 every seven days for four weeks. The antioxidant agent, 1,3-Dimethylthiourea (DMTU), was administered before and after the administration of cisplatin. The hot plate test was used to assess hypoalgesia. Oxidative stress in the sciatic nerve was assessed from thiobarbituric acid reactive substances (TBARs) and superoxide dismutase (SOD) activity. Nerve apoptosis was analysed with qRT-PCR. We observed an increase in TBARs and a decrease in SOD activity with the development of cisplatin-induced hypoalgesia, which was ameliorated by DMTU treatment. Furthermore, differences in the dosing time of cisplatin caused differences in oxidative stress which were correlated with cisplatin-induced hypoalgesia. Severe oxidative stress caused cisplatin-induced hypoalgesia, and chronotherapy with cisplatin ameliorated hypoalgesia by reducing oxidative stress. In the future, chronotherapy with cisplatin may contribute to the treatment of cancer in humans.

Benefits of immunonutrition in patients with head and neck cancer receiving chemoradiation: A phase II randomized, double-blind study.

BACKGROUND & AIMS: The benefits of immunonutrition in patients with head and neck cancer (HNC), especially for those undergoing definitive concurrent chemoradiation (CCRT), remain unclear. We evaluated the benefits of immunonutrition regarding the prevention of severe oral mucositis. Secondary objectives included assessments of other treatment-related toxicities, changes of nutritional and inflammatory marker levels, treatment tolerance, and survival. METHODS: In total, 110 patients with HNC undergoing definitive CCRT including 3-week cycles of cisplatin were enrolled in our double-blind phase II study. Patients were randomly assigned to receive an immunonutrient formula containing omega-3-fatty acids, arginine, dietary nucleotides, and soluble fiber (n = 55) or an isocaloric isonitrogenous control (n = 55). All patients received the assigned product 5 consecutive days before each chemotherapy session. The proportion of patients with severe oral mucositis was compared between the immunonutrients and control groups. RESULTS: The rates of nasopharyngeal cancer (NPC) were 67% and 51% in the immunonutrients and control groups, respectively. All patients had 100% compliance to the assigned product. There was no difference of the proportion of patients with grade 3-4 oral mucositis between the two groups (62% vs. 67%, p = 0.690). At the time of analyses, survival tended to be better in the immunonutrients group. The 3-year progression-free survival rates were 69% (95% confidence interval [CI] = 55%-80%) and 44% (95% CI = 30%-57%) in the immunonutrients and control groups, respectively (p = 0.056), whereas the 3-year overall survival rates in these groups were 69% (95% CI = 54%-80%) and 50% (95% CI = 36%-66%; p = 0.065), respectively. In subgroup analyses according to the primary tumor location, the survival benefits were apparently maintained in patients with NPC. CONCLUSIONS: Although our study did not demonstrate a reduced risk of severe oral mucositis, we found that immunonutrition might improve survival. Larger studies are needed to determine the optimal dose and schedule of immunonutrition to prevent oral mucositis. In addition, randomized phase III trials evaluating the survival benefits of immunonutrition in patients with cancer are required, and NPC might be a primary malignancy of interest. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05101889.

Renoprotective activity of Ribes diacanthum pall (RDP) against inflammation in cisplatin-stimulated mice model and human renal tubular epithelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Ribes diacanthum Pall (RDP) is mostly distributed in Mongolia. As a Mongolian folk medicinal plant, it is traditionally used to treat kidney diseases by the native inhabitants of Mongolia due to its effect of increasing urine output and eliminating edema. However, its renal protection mechanism remains to be elucidated. AIM OF THE STUDY: To assess the pharmacological mechanism of RDP from an anti-inflammatory point of view using cisplatin (CDDP)-induced kidney injury models in vivo and in vitro. The influence of RDP on the chemotherapy efficacy of CDDP was also evaluated in vitro. MATERIALS AND METHODS: We established a CDDP-induced nephrotoxicity mouse model and a Human Renal Tubular Epithelial (HK-2) damage cellular model, respectively. In vivo, kidney function, the content of urine albumin, and renal histopathology examination were performed to observe the kidney injury. Moreover, the expression and secretion of inflammatory cytokines and adhesive molecules were examined by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and real-time PCR. The key protein levels of mitogen-activated protein kinase/nuclear factor kappa B (MAPK/NF-κB) signaling pathway were measured by western blotting analysis. Electrophoretic mobility shift assay (EMSA) was carried out to detect the activation of NF-κB. In vitro, inflammatory mediators and the proteins related to the NF-κB signaling pathway in HK-2 cells were measured by western blotting analysis. Besides, A549 cell lines were treated with CDDP and RDP to explore RDP's impact on CDDP chemotherapy. RESULTS: Gavage RDP decreased the elevated levels of serum creatinine (Scr), urea nitrogen (BUN), as well as the ratio of urine albumin and creatinine, ameliorated pathological changes of kidney tissue. Correspondingly, the RDP administration group showed a higher survival rate than that of the CDDP exposed group. The expression levels of a plethora of inflammatory mediators were inhibited by RDP treatment compared with the CDDP-exposed group. Furthermore, protein expression levels of MAPK/NF-κB signaling pathway significantly decreased after RDP intervention. For in vitro studies, we confirmed the inhibitory effect of RDP on relative protein expressions involving in the NF-κB pathway. The results also showed that RDP had no impairment on the inhibitory effect of CDDP on A549 cells. CONCLUSION: These findings demonstrated RDP's anti-inflammatory effect against CDDP nephrotoxicity through in vivo and in vitro experiments, and suggested that RDP may have a potential application as an adjuvant medication for CDDP chemotherapy and other inflammatory kidney diseases.

Period circadian regulator 2 suppresses drug resistance to cisplatin by PI3K/AKT pathway and improves chronochemotherapeutic efficacy in cervical cancer.

OBJECTIVE: Chronotherapy, a promising therapy, may build up the chemotherapy efficacy through thinking about timing of therapy. Here, we observed the roles of period circadian regulator 2 (PER2) on cervical cancer progression and the therapeutic efficacy of cisplatin (DDP) based on the circadian rhythm of PER2. METHODS: When Hela/DDP and SiHa/DDP transfected with pcDNA3.1-PER2 and/or treated with human epidermal growth factor (hEGF), viability, apoptosis, migration, and nuclear translocation of NF-κB p65 were detected by CCK-8, flow cytometry, transwell, immunofluorescence and western blot. Furthermore, the expression of circadian rhythm regulators, multidrug resistance, and epithelial-mesenchymal transition (EMT) proteins was detected by western blot. Hela/DDP cells-induced tumor formation in nude mice was constructed. The expression of PER2 was measured at different time point by RT-qPCR. Cisplatin was separately injected into mice with cervical cancer at the highest and lowest expression of PER2. After 5 weeks, tumor volume was measured and tumor proliferation was assessed by immunohistochemistry. RESULTS: Overexpression of PER2 significantly reduced proliferative and migrated capacities and nuclear translocation of NF-κB p65 as well as enhanced apoptosis in Hela/DDP and SiHa/DDP cells. Meanwhile, its overexpression elevated the expression of circadian rhythm regulators as well as lowered the expression of multidrug resistance proteins and EMT pathway activation by suppressing PI3K/AKT pathway. PER2 was rhythmically expressed in cervical cancer tissues. Compared to cisplatin treatment at the lowest expression of PER2, tumor growth and proliferation of tumor cells were distinctly suppressed in mice treated with cisplatin at the highest expression of PER2. CONCLUSION: Our findings confirmed the circadian rhythm of PER2 in cervical cancer and its overexpression restrained the resistance to cisplatin in cervical cancer by PI3K/AKT pathway. It may improve cisplatin efficacy through considering the circadian rhythm of PER2.

Combination of Compound Kushen Injection and cisplatin shows synergistic antitumor activity in p53-R273H/P309S mutant colorectal cancer cells through inducing apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Colorectal cancer (CRC) is one type of worldwide popular and refractory tumors. Compound Kushen Injection (CKI) is a frequently applied traditional Chinese medicine formula as an adjuvant drug for the chemotherapy of CRC. P53 is the most commonly mutated gene in CRC, accounting for the development, malignant and prognosis progression of CRC. However, effect of CKI on the therapeutic efficacy of p53-mutant CRC remains understood. Besides, the combined efficacy of different chemotherapeutics drugs in combination with CKI for CRC treatment is rarely concerned. AIM OF STUDY: To investigate the combined efficacy of the CKI-derived combination strategies in the p53-mutant CRC. MATERIALS AND METHODS: Two CRC cell lines HCT116 and SW480 cells, which respectively harbor wild-type p53 and p53-R273H/P309S mutant, were applied. Cisplatin (Cis) and 5-fluorouracil (5FU) were combined chemotherapeutics drugs of CKI-derived combination strategies in this article. In vitro antitumor activity was detected by sulforhodamine B (SRB) assay and colony formation assay. Combenefit soft was applied to evaluate the synergetic/antagonistic effect of drug combination. Lentivirus-mediated overexpression method was used to generate a set of p53-mutant and wild-type CRC cell lines harboring identical genomes. Transcriptomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were applied to predicate the underlying mechanism of synergetic interaction between drug combination. Western blot was performed to verify predicated pathways contributing to the synergy of drug combination. RESULTS: CKI preferentially combined with Cis but not 5FU, to produce a synergistical antitumor efficiency for p53-R273H/P309S mutant, rather than wild-type p53 harboring CRC cells. The combination of CKI and Cis strongly reprogrammed the transcriptional profiles of SW480 cells. Cytokine-cytokine receptor interaction pathway was a key pathway involved in cooperativity between CKI and Cis in SW480 cells. Mechanistically, compared to that Cis individually triggered necroptosis, the co-treatment of CKI and Cis reinforced the cell death of SW480 cells in a possible synergistic manner by inducing extrinsic apoptosis pathway. CONCLUSION: This article provides a novel perspective into the precision clinical application of CKI-derived combination therapy programs of CRC based on genetic variation and the classes of chemotherapeutics drugs.

ypN0 in Patients With Definitive cN-positive Status After Preoperative Treatment Is a Prognostic Factor in Esophageal Cancer.

BACKGROUND: Histopathological tumor regression grade is applied not to lymph nodes but primary tumors modified by preoperative treatments. This study focused on patients whose pathological examination at the time of surgery showed no residual tumor after chemo(radio)therapy in the primary lesion (ypT0) or lymph nodes (ypN0). PATIENTS AND METHODS: A total of 87 patients with clinical stage II/III thoracic esophageal cancer underwent esophagectomy following preoperative treatments to evaluate significances between pathological response and clinical outcomes; 51 patients with clinically definitive lymph node metastasis (cN+) were analyzed as a subgroup. RESULTS: ypT0 rates were 20.7% and 23.5%, and ypN0 rates were 47.1% and 27.5% in the whole cohort and in the cN+ subgroup, respectively. Disease-free survival, from surgery to relapse or death, was significantly influenced by ypN status (p=0.035) but not by ypT status in the 51 patients with definitive cN+ disease. Preoperative chemoradiation was an independent favorable factor for achievement of ypN0 in the 51 patients (odds ratio=0.09; p=0.007). CONCLUSION: ypN status was a predictive factor for DFS in patients treated with docetaxel plus low-dose 5-fluorouracil and cisplatin combined chemotherapy, superior to ypT status, especially in patients with definitive cN+ disease.

Adjuvant chemotherapy after radiotherapy or concurrent chemoradiotherapy for pelvic lymph node-positive patients with locally advanced cervical cancer: a propensity score matching analysis.

OBJECTIVE: The benefit of adjuvant chemotherapy after definitive chemoradiotherapy in patients with pelvic lymph node-positive cervical cancer has been poorly studied. This study aimed to test the hypothesis that the addition of adjuvant chemotherapy to definitive radiotherapy or concurrent chemoradiotherapy improves survival in patients with pelvic lymph node-positive cervical squamous cell carcinoma. METHODS: This retrospective study enrolled patients with stage IB-IVA pelvic lymph node-positive cervical squamous cell carcinoma, without para-aortic lymph node metastases and initially treated with definitive radiotherapy or concurrent chemoradiotherapy between March 2007 and February 2018. Patients were classified into the adjuvant chemotherapy (5-fluorouracil or paclitaxel, plus cisplatin) and no-adjuvant chemotherapy groups. Treatment outcomes were compared between the two groups before and after 1:1 ratio propensity score matching. RESULTS: Medical records of 951 patients were reviewed and 792 patients were excluded. Finally, 159 patients were enrolled for analysis. Of these, 42 patients received a median of two cycles (range, 1-6) of adjuvant chemotherapy and 117 patients under observation after primary treatment. The median follow-up period was 33.8 months (range, 2.9-113.0). Before propensity score matching, no significant difference was observed in survivals between the two groups (P>0.05). After propensity score matching, 37 pairs of patients were selected. The 3-year rates of progression-free survival, overall survival, local control, and distant metastasis-free survival in the adjuvant chemotherapy and no-adjuvant chemotherapy groups were 80.2% and 60.4% (P=0.07), 83.0% and 63.7% (P=0.17), 94.0% and 81.9% (P=0.12), and 85.9% and 60.1% (P=0.04), respectively. The incidences of grade 3-4 acute and late toxicities were comparable between the two groups (P>0.05). DISCUSSION: Adjuvant chemotherapy significantly improved 3-year distant metastasis-free survival in patients with pelvic lymph node-positive cervical squamous cell carcinoma. Further prospective studies are needed to provide supportive evidence for the therapeutic efficacy of adjuvant chemotherapy.

Evaluation of an EZH2 inhibitor in patient-derived orthotopic xenograft models of pediatric brain tumors alone and in combination with chemo- and radiation therapies.

Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mg/kg, gavaged, twice daily) alone and in combination with cisplatin (5 mg/kg, i.p., twice) and/or radiation (2 Gy/day × 5 days). Compared with the untreated controls, tazemetostat significantly (Pcorrected < 0.05) prolonged survival times in IC-L1115ATRT (101% at 400 mg/kg) and IC-2305GBM (32% at 250 mg/kg, 45% at 400 mg/kg) in a dose-dependent manner. The addition of tazemetostat with radiation was evaluated in 3 models, with only one [IC-1078MB (group 4)] showing a substantial, though not statistically significant, prolongation in survival compared to radiation treatment alone. Combining tazemetostat (250 mg/kg) with cisplatin was not superior to cisplatin alone in any model. Analysis of in vivo drug resistance detected predominance of EZH2-negative cells in the remnant PDOX tumors accompanied by decreased H3K27me2 and H3K27me3 expressions. These data supported the use of tazemetostat in a subset of pediatric brain tumors and suggests that EZH2-negative tumor cells may have caused therapy resistance and should be prioritized for the search of new therapeutic targets.

Alteration of Oxidative stress and apoptotic markers alterations in the rat prefrontal cortex influence behavioral response induced by cisplatin and N-acetylcysteine in the tail suspension test.

Cisplatin therapy is often accompanied by neurotoxicity manifestation, and since the prefrontal cortex is strongly involved in emotion regulation, the aim of this study was to analyze the alterations in the oxidative and apoptotic status of this brain region, with its behavioral impact in rats, following cisplatin administration, with or without N-acetylcysteine supplementation. Thirty-two male Wistar albino rats were randomly divided into four equal experimental groups: control, cisplatin group (single dose of 7.5 mg/kg, intraperitoneally (i.p.), on the fifth day), N-acetylcysteine group (500 mg/kg i.p., on the first and the fifth day), cisplatin + N-acetylcysteine group. Behavioral testing was performed in the tail suspension test. Oxidative stress and apoptotic markers were determined in the prefrontal cortex tissue samples. Cisplatin administration increased lipid peroxidation and decreased the activity of antioxidant enzymes in the prefrontal cortex. Also, cisplatin induced increase in Bax and decrease in Bcl-2 relative gene expression. Simultaneous application of N-acetylcysteine diminished cisplatin-induced alterations in oxidative stress and apoptotic markers. The results obtained in the tail suspension test that nominally resembles antidepressant action of cisplatin (attenuated by N-acetylcysteine), should be attributed to strong motor expression of anxiogenic response to cisplatin (also reversed by N-acetylcysteine). The antioxidant supplementation with NAC diminished cisplatin-induced oxidative damage and pro-apoptotic action in the prefrontal cortex, and significantly influenced specific behavioral alterations.

Combinations of indole based alkaloids from Mitragyna speciosa (Kratom) and cisplatin inhibit cell proliferation and migration of nasopharyngeal carcinoma cell lines.

ETHNOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa (Korth.) or kratom is a medicinal plant indigenous to Southeast Asia. The leaf of M. speciosa is used as a remedy in pain management including cancer related pain, in a similar way as opioids and cannabis. Despite its well-known analgesic effect, there is a scarce of information on the cancer-suppressing potential of M. speciosa and its active constituents. AIM OF THE STUDY: To assess the potential applicability of M. speciosa alkaloids (mitragynine, speciociliatine or paynantheine) as chemosensitizers for cisplatin in Nasopharyngeal carcinoma (NPC) cell lines. MATERIALS AND METHODS: The cytotoxic effects of the extracts, fractions and compounds were determined by conducting in vitro cytotoxicity assays. Based on the cytotoxic screening, the alkaloid extract of M. speciosa exhibited potent inhibitory effect on the NPC cell line NPC/HK1, and therefore, was chosen for further fractionation and purification. NPC cell lines NPC/HK1 and C666-1 were treated with combinations of cisplatin and M. speciosa alkaloids combinations in 2D monolayer culture. The effect of cisplatin and mitragynine as a combination on cell migration was tested using in vitro wound healing and spheroid invasion assays. RESULTS: In our bioassay guided isolation, both methanolic and alkaloid extracts showed mild to moderate cytotoxic effect against the NPC/HK1 cell line. Both NPC cell lines (NPC/HK1 and C666-1) were insensitive to single agent and combination treatments of the M. speciosa alkaloids. However, mitragynine and speciociliatine sensitized the NPC/HK1 and C666-1 cells to cisplatin at ~4- and >5-fold, respectively in 2D monolayer culture. The combination of mitragynine and cisplatin also significantly inhibited cell migration of the NPC cell lines. Similarly, the combination also of mitragynine and cisplatin inhibited growth and invasion of NPC/HK1 spheroids in a dose-dependent manner. In addition, the spheroids did not rapidly develop resistance to the drug combinations at higher concentrations over 10 days. CONCLUSION: Our data indicate that both mitragynine and speciociliatine could be potential chemosensitizers for cisplatin. Further elucidation focusing on the drug mechanistic studies and in vivo studies are necessary to support delineate the therapeutic applicability of M. speciosa alkaloids for NPC treatment.

Association of tumor downstaging after neoadjuvant chemotherapy with survival in patients with locally advanced nasopharyngeal carcinoma: a retrospective cohort study.

PURPOSE: Assessing the downstaging effects of neoadjuvant chemotherapy (NACT) in patients with locally advanced nasopharyngeal carcinoma (LANPC) and predicting response to treatment remain challenging. The present study aimed to evaluate the long-term prognosis of downstaging after NACT in patients with LANPC and to investigate the prognostic value of post-NACT tumor downstaging on treatment outcomes in the era of concurrent chemoradiotherapy (CCRT). METHODS: This retrospective study included 226 patients with stage III (n = 188) and IVA (n = 38) NPC admitted to Haikou People's Hospital between 1 October 2009 and 1 October 2012. The patients were grouped as downstaging or no after NACT. Overall survival (OS), locoregional failure-free survival (LFFS), and distant failure-free survival (DFFS) were analyzed. RESULTS: Among 226 patients, 196 (86.7%) were in the downstaging group and 30 (13.3%) were in the non-downstaging group. The longest follow-up was 76 months, and the median was 45 months. The 3-year OS rates of the downstaging group and non-downstaging group were 91.0% (95% CI 0.89-0.93) and 69.5% (95% CI 0.66-0.72) (P = 0.005). The 5-year OS rates were 81.6% (95% CI 0.78-0.86) and 53.3% (95% CI 0.49-0.61) (P = 0.001). N downstaging (3-year OS, HR 0.491, 95% CI 0.221-0.881, P = 0.022; 5-year OS, HR = 0.597, 95% CI 0.378-0.878, P = 0.021) was independently associated with OS. CONCLUSION: In the treatment of LANPC, the patients with downstaging after NACT have a better prognosis than those without downstaging. This study suggests that NACT can improve the prognosis for patients with LANPC if there is downstaging.

Significance of liver resection for intermediate stage hepatocellular carcinoma according to subclassification.

BACKGROUND: Patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) intermediate stage hepatocellular carcinoma (HCC) encompass a broad clinical population. Kinki criteria subclassifications have been proposed to better predict prognoses and determine appropriate treatment strategies for these patients. This study validated the prognostic significance within the Kinki criteria substages and analyzed the role of liver resection in patients with intermediate stage HCC. METHODS: Patients with intermediate stage HCC (n = 378) were retrospectively subclassified according to the Kinki criteria (B1, n = 123; B2, n = 225; and B3, n = 30). We analyzed the overall survival (OS) and treatment methods. RESULTS: The OS was significantly different between adjacent substages. Patients in substage B1 who underwent liver resection had a significantly better prognosis than those who did not, even after propensity score matching (PSM). Patients in substage B2 who underwent liver resection had a significantly better prognosis than those who did not; however, there was no difference after PSM. There was no difference in prognosis based on treatments among patients in substage B3. CONCLUSIONS: The Kinki criteria clearly stratify patients with intermediate stage HCC by prognosis. For substage B1 HCC patients, liver resection provides a better prognosis than other treatment modalities. In patients with substage B2 and B3, an alternative approach is required.

Efficacy and safety of two different adjuvant chemotherapy regimens in combination with concurrent chemoradiotherapy in treating patients with advanced nasopharyngeal carcinoma: A protocol for randomized controlled trial.

BACKGROUND: Concurrent chemoradiotherapy is widely utilised as a standardized primary method of treatment for patients with advanced nasopharyngeal carcinoma (NPC). However, the combination of concurrent chemoradiotherapy and adjuvant chemotherapy for treating NPC patients remain unclear. Therefore, this study attempts to elucidate the efficiency and safety of concurrent chemoradiotherapy combined with adjuvant chemotherapy (gemcitabine plus cisplatin versus 5-fluorouracil plus cisplatin) for treating patients with NPC. MATERIALS AND METHODS: This study is a randomized, multicentral, open-labelled trial to assess the clinical efficiency and safety of using concurrent chemoradiotherapy combined with adjuvant chemotherapy as a therapeutic measure for advanced NPC patients. A total of 50 patients will be randomly assigned into 2 groups, namely treatment-group-one and treatment-group-two. Eligible patients will be administered with concurrent chemoradiotherapy and subsequentially with adjuvant chemotherapy (gemcitabine plus cisplatin or 5-fluorouracil plus cisplatin). Moreover, the primary endpoint is a comparison of progression-free survival between concurrent chemoradiotherapy and subsequentially adjuvant gemcitabine and cisplatin and chemoradiotherapy, which is proceeded by adjuvant 5-fluorouracil and cisplatin in advanced NPC patients. Overall survival, overall response rate, incidence of acute and late toxicity, and adverse events are the minor endpoints. Statistical analyses will be performed with SPSS 25.0 software. DISCUSSION: The current research evaluates the clinical efficiency and safety of utilising concurrent chemoradiotherapy combined with adjuvant chemotherapy as a therapeutic strategy to treat advanced NPC patients. The work done in this study will provide a clinical basis for concurrent chemoradiotherapy in combination with adjuvant chemotherapy for treating advanced NPC. TRIAL REGISTRATION: DOI 10.17605/OSF.IO/5UPVM.

Treatment efficacy by hepatic arterial infusion chemotherapy vs. sorafenib after liver-directed concurrent chemoradiotherapy for advanced hepatocellular carcinoma.

BACKGROUND: We compared the clinical efficacies of hepatic arterial infusion chemotherapy (HAIC) vs. sorafenib as sequential maintenance therapy following liver-directed concurrent chemoradiotherapy (LD-CCRT) for locally advanced-stage hepatocellular carcinoma (HCC). METHODS: Patients undergoing HAIC with 5-fluorouracil and cisplatin (HAIC-maintain group, n = 151) or sorafenib (Sorafenib-maintain group, n = 37) after LD-CCRT were consecutively enrolled. The study endpoints were overall survival (OS), progression-free survival (PFS), and treatment response rates. RESULTS: The median OS among HAIC-maintain and Sorafenib-maintain groups were 15.9 and 24.3 months (p = 0.287), whereas the median PFS were 8.1 and 9.1 months (p = 0.651), respectively. During the planned treatments, the radiological objective response rate (54.3% vs. 64.9%; p = 0.246), and conversion rate to surgical resection or liver transplantation after successful down-staging (15.9% vs. 18.9%; p = 0.657) were comparable between the HAIC-maintain and Sorafenib-maintain groups. Similar results were found after the inverse probability of treatment weighting and propensity score-matching analyses. Regarding treatment-related adverse events, the HAIC-maintain group showed worse profiles in terms of leukopenia (all grades [p = 0.001] and grades 3 or 4 [p = 0.041]) and hypoalbuminemia (p = 0.001) than the Sorafenib-maintain group. CONCLUSIONS: The overall clinical efficacies between the sequential treatment of HAIC vs. sorafenib after LD-CCRT were comparable for locally advanced HCC.

Why Concurrent CDDP and Radiotherapy Has Synergistic Antitumor Effects: A Review of In Vitro Experimental and Clinical-Based Studies.

Chemo-radiotherapy, which combines chemotherapy with radiotherapy, has been clinically practiced since the 1970s, and various anticancer drugs have been shown to have a synergistic effect when used in combination with radiotherapy. In particular, cisplatin (CDDP), which is often the cornerstone of multi-drug combination cancer therapies, is highly versatile and frequently used in combination with radiotherapy for the treatment of many cancers. Therefore, the mechanisms underlying the synergistic effect of CDDP and radiotherapy have been widely investigated, although no definitive conclusions have been reached. We present a review of the combined use of CDDP and radiotherapy, including the latest findings, and propose a mechanism that could explain their synergistic effects. Our hypothesis involves the concepts of overlap and complementation. "Overlap" refers to the overlapping reactions of CDDP and radiation-induced excessive oxidative loading, which lead to accumulating damage to cell components, mostly within the cytoplasm. "Complementation" refers to the complementary functions of CDDP and radiation that lead to DNA damage, primarily in the nucleus. In fact, the two concepts are inseparable, but conceptualizing them separately will help us understand the mechanism underlying the synergism between radiation therapy and other anticancer drugs, and help us to design future radiosensitizers.

Randomized placebo-controlled phase II trial of high-dose melatonin mucoadhesive oral gel for the prevention and treatment of oral mucositis in patients with head and neck cancer undergoing radiation therapy concurrent with systemic treatment.

PURPOSE: The objective of this trial was to evaluate the safety and efficacy of melatonin oral gel mouthwashes in the prevention and treatment of oral mucositis (OM) in patients treated with concurrent radiation and systemic treatment for head and neck cancer. METHODS: Randomized, phase II, double-blind, placebo-controlled trial (1:1 ratio) of 3% melatonin oral gel mouthwashes vs. placebo, during IMRT (total dose ≥ 66 Gy) plus concurrent Q3W cisplatin or cetuximab. Primary endpoint: grade 3-4 OM or Severe Oral Mucositis (SOM) incidence by RTOG, NCI, and a composite RTOG-NCI scales. Secondary endpoints: SOM duration and grade 2-4 OM or Ulcerative Oral Mucositis (UOM) incidence and duration. RESULTS: Eighty-four patients were included in the study. Concurrent systemic treatments were cisplatin (n = 54; 64%) or cetuximab (n = 30; 36%). Compared with the placebo arm, RTOG-defined SOM incidence was numerically lower in the 3% melatonin oral gel arm (53 vs. 64%, P = 0.36). In patients treated with cisplatin, assessed by the RTOG-NCI composite scale, both SOM incidence (44 vs. 78%; P = 0.02) and median SOM duration (0 vs. 22 days; P = 0.022) were significantly reduced in the melatonin arm. Median UOM duration assessed by the RTOG-NCI scale was also significantly shorter in the melatonin arm (49 vs. 73 days; P = 0.014). Rate of adverse events and overall response rate were similar between the two arms. CONCLUSIONS: Treatment with melatonin oral gel showed a consistent trend to lower incidence and shorter SOM duration and shorter duration of UOM. These results warrant further investigation in phase III clinical trial.

Sulforaphane-cisplatin combination inhibits the stemness and metastatic potential of TNBCs via down regulation of sirtuins-mediated EMT signaling axis.

BACKGROUND: Sulforaphane (SFN) is a naturally occurring organosulfur compound found in cruciferous vegetables such as broccoli, brussels sprouts and cabbage. SFN is known for its multiple therapeutic properties, such as HDAC inhibitory, chemo preventive and anti-cancer effects. Cisplatin (CIS) has limited effect against metastatic triple-negative breast cancer (TNBC). Additionally, CIS impose severe side effects to normal cells, and later TNBC cells develops resistance. Studies suggest that the overexpression of sirtuins (SIRTs) promotes CIS resistance and metastasis by activating epithelial-to-mesenchymal transition (EMT) pathway in TNBC. PURPOSE: In view of the above information, we investigated the therapeutic efficacy of SFN, in combination with CIS against TNBC metastasis and CIS resistance. METHODS: The anti-cancerous effect of SFN-CIS combination on human TNBC cell lines was demonstrated by utilizing MTT assay and, apoptosis and cell cycle assay followed by FACS analysis. The synergistic effect of SFN-CIS combination on the experimental metastasis was demonstrated by utilizing migration, invasion, chemotaxis, mammosphere and colony formation assay on human TNBC MDA-MB-231 and MDA-MB-468 cells. The role of SIRTs-mediated EMT signaling axis in the metastasis and chemoresistance was investigated by western blotting technique as well as sirtuin activity tests. This was further validated by using Chromatin immunoprecipitation (ChIP) analysis. RESULTS: We found that SFN-CIS combination synergistically inhibits cellular growth of MDA-MB-231 and MDA-MB-468 cells. More importantly, SFN was found to protect normal kidney cells from CIS-induced toxicity. Further, SFN-CIS combination was found to synergistically inhibit metastatic-events via significantly altering EMT markers which was further associated with the suppression of SIRTs functions in TNBC cells. ChIP analysis validated that SFN-CIS combination suppresses EMT mechanism through altered chromatin modifications at E-cadherin promoter resulting in its re-expression. CONCLUSION: The results of the current study suggests that CIS when supplemented with SFN, inhibits metastasis and stemness potential of TNBC cells by down regulating SIRTs-mediated EMT cascade. Overall this study affirms that, this novel combination could be a promising strategy against SIRT-mediated TNBC metastasis and CIS-resistance.

Reconstruction using a frozen autograft for a skull and humeral lesion of synchronous multicentric osteosarcoma after undergoing successful neoadjuvant chemotherapy: a case report and review of the literature.

BACKGROUND: Synchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously. CASE PRESENTATION: We report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free. CONCLUSIONS: An early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.

Acute kidney injury after cytoreductive surgery and hyperthermic intraoperative cisplatin chemotherapy for malignant pleural mesothelioma.

OBJECTIVES: Cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin has been used successfully to treat malignant pleural mesothelioma, a highly aggressive malignancy that is rapidly fatal in most cases. We hypothesized that the combination of ischemic injury with nephrotoxic injury from cisplatin would result in high rates of acute kidney injury. METHODS: We conducted an observational study in 503 patients to study the risks and outcomes of acute kidney injury after surgical resection of malignant pleural mesothelioma. Eligible subjects underwent extrapleural pneumonectomy or pleurectomy/decortication with or without hyperthermic intraoperative chemotherapy. Acute kidney injury was defined as an increase in creatinine of 26.5 µmol/L or greater within 48 hours of surgery or a 50% or greater increase over 7 days. RESULTS: Acute kidney injury developed in 243 patients (48.3%). Severe acute kidney injury requiring renal replacement therapy developed in 16 patients (3.2%). Major significant predictors for acute kidney injury included male sex (odds ratio, 2.98; P < .001), intraoperative cisplatin administration (odds ratio, 3.12; P < .001), previous cisplatin exposure (odds ratio, 1.96; P = .02), hypertension (odds ratio, 1.57; P = .02), and longer surgical time (odds ratio, 1.15 per hour; P = .02). Compared with patients without acute kidney injury, those with severe acute kidney injury had longer length of stay (26 vs 13 days) and a 2.71-fold increased risk of death in multivariable-adjusted models. CONCLUSIONS: Acute kidney injury is common after cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin and is associated with poor long-term outcomes. Strategies to prevent postoperative acute kidney injury are needed to improve multimodal treatment of malignant pleural mesothelioma.