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This study included data from 81 consecutively enrolled patients with hematological diseases who had been treated with unrelated umbilical cord blood transplantation (UCBT) between September 2014 and April 2019. All patients received intense conditioning regimens with combined fludarabine and high-dose cyclophosphamide (FC) before undergoing UCBT. Sixty-seven patients received a single UCBT, and 14 patients received a double UCBT. Fifty patients were pretreated with the fludarabine, busulfan, and cyclophosphamide (FBC) protocol, while 31 patients were treated with FC before transplantation. Graft-versus-host disease (GVHD) was prevented with cyclosporine A and mycophenolate mofetil administration. According to low-resolution, human leukocyte antigen (HLA) donor-recipient matching at six sites, 53 patients had 5-6 matches, while 28 patients had 4 matches. Seventy-eight patients (96.3%) achieved complete engraftment in this study. Thirty-six patients developed acute GVHD (aGVHD). The cumulative incidence of grade I-II aGVHD at day 100 posthematopoietic stem cell transplantation was 29.6%, and the cumulative incidence of grade III-IV aGVHD was 14.8%. At the end of the follow-up, 12 patients died due to treatment-related complications, and 4 died of disease relapse after transplantation. The transplant-related deaths were due to transplant-related infection (8 of 81), GVHD (2 of 81), and organ toxicity (2 of 81). The probability of overall survival (OS) was 80.2%. A higher dose of cyclophosphamide combined with fludarabine conditioning in UCBT was an effective curative method for treatment of hematologic disorders and could enhance the engraftment of umbilical cord blood stem cells, promote post-transplant immune reconstitution, and improve OS.

The aim of this study is to determine whether the modified BuCy (semustine, cytarabine, busulfan, and cyclophosphamide, mBuCy) conditioning regimen can be safely used as an alternative to the SEAM (semustine, etoposide, cytarabine, and melphalan) regimen by comparing the efficacy and toxicity of the mBuCy and SEAM regimens. We matched 34 pairs of patients with regard to disease status at the time of autologous stem cell transplantation (auto-SCT). We found no significant difference in the time of platelet engraftment between the two groups. Furthermore, neutrophil engraftment was somewhat faster in the mBuCy group than in the SEAM group (median: 9 days vs 10 days, p = 0.015). With regard to toxicity, the incidence of nausea/vomiting, hepatic impairment, renal impairment, pulmonary infection, and treatment-related mortality (TRM) was similar between the two groups. In addition, compared to patients conditioned with SEAM, patients conditioned with mBuCy were less likely to develop mucositis and diarrhea (p = 0.027; p = 0.050). The 2-year progression-free survival (PFS) rates in the mBuCy and SEAM groups were 79% and 70% (p = 0.378), respectively, and the 2-year overall survival (OS) rates were 81% and 78.0%, respectively (p = 0.789). These analyses showed that the mBuCy conditioning regimen was well tolerated and can be used as an alternative to the SEAM regimen for lymphoma.

Chloroethylating nitrosoureas (CNU), such as lomustine, nimustine, semustine, carmustine and fotemustine are used for the treatment of malignant gliomas, brain metastases of different origin, melanomas and Hodgkin disease. They alkylate the DNA bases and give rise to the formation of monoadducts and subsequently interstrand crosslinks (ICL). ICL are critical cytotoxic DNA lesions that link the DNA strands covalently and block DNA replication and transcription. As a result, S phase progression is inhibited and cells are triggered to undergo apoptosis and necrosis, which both contribute to the effectiveness of CNU-based cancer therapy. However, tumor cells resist chemotherapy through the repair of CNU-induced DNA damage. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes the precursor DNA lesion O6-chloroethylguanine prior to its conversion into ICL. In cells lacking MGMT, the formed ICL evoke complex enzymatic networks to accomplish their removal. Here we discuss the mechanism of ICL repair as a survival strategy of healthy and cancer cells and DNA damage signaling as a mechanism contributing to CNU-induced cell death. We also discuss therapeutic implications and strategies based on sequential and simultaneous treatment with CNU and the methylating drug temozolomide.

A growing body of evidence has indicated that behaviors of cancers are defined by not only intrinsic activities of tumor cells but also tumor-infiltrating immune cells (TIICs) in the tumor microenvironment. However, it still lacks a well-structured and comprehensive analysis of TIICs and its therapeutic value in esophageal cancer (EC). The proportions of 22 TIICs were evaluated between 150 normal tissues and 141 tumor tissues of EC by the CIBERSORT algorithm. Besides, correlation analyses between proportions of TIICs and clinicopathological characters, including age, gender, histologic grade, tumor location, histologic type, LRP1B mutation, TP53 mutation, tumor stage, lymph node stage, and TNM stage, were conducted. We constructed a risk score model to improve prognostic capacity with 5 TIICs by least absolute shrinkage and selection operator (lasso) regression analysis. The risk score=−1.86∗plasma+2.56∗T cell follicular helper−1.37∗monocytes−3.64∗activated dendritic cells−2.24∗resting mast cells (immune cells in the risk model mean the proportions of immune cell infiltration in EC). Patients in the high-risk group had significantly worse overall survival than these in the low-risk group (HR: 2.146, 95% CI: 1.243-3.705, p=0.0061). Finally, we identified Semustine and Sirolimus as two candidate compounds for the treatment of EC based on CMap analysis. In conclusion, the proportions of TIICs may be important to the progression, prognosis, and treatment of EC.

A new method to evaluate the anticancer activity at the molecular level has been developed. In our assay, the interaction between alkylating anticancer drugs-Fe3O4/CA with DNA has been investigated for the Resonance Light Scattering (RLS) signal enhancement. Water-based nano-Fe3O4, as a probe, has the ability of good solubility, biodegradability and low bulk resistivity etc. The experimental results show that, the activity order of three kinds of drugs is Nimustine (ACNU)>Semustine (Me-CCNU)>Chlormethine (HN2), which is satisfied with the results of the cell apoptosis experiment and the IC50 by MTT method. This assay is simple, sensitive and high efficient. And the theoretical basics for the development of new anticancer drugs as well as the assessments of their efficacy to cure breast and hepatic cancer have been provided.

Osteosarcoma (OS) is the third most frequent type of cancer in adolescents and represents >56% of all bone tumors. In addition, metastatic OS frequently demonstrates resistance to conventional chemotherapy; thus, the development of novel therapeutic agents for the treatment of patients with metastatic OS is warranted. In the present study, the metabolic mechanisms underlying OS metastasis were investigated using a subpathway analysis method and lead to the identification of candidate drugs for the treatment of metastatic OS. Using the GSE14827 microarray dataset from the Gene Expression Omnibus database, 546 differentially expressed genes were identified between samples from patients with OS who did or did not develop metastatic OS. Furthermore, nine significantly enriched metabolic subpathways were identified, which may be involved in OS metastasis. Finally, using an integrated analysis of metastatic OS-associated subpathways and drug-affected subpathways, 98 small molecule drug candidates capable of targeting the metastatic OS-associated subpathways were identified. This method identified existing anti-cancer drugs, including semustine, in addition to predicting potential drugs, such as lansoprazole, for the treatment of metastatic OS. Transwell and wound healing assays demonstrated that lansoprazole reduced the invasiveness and migration of U2OS cells. These small molecule drug candidates identified through a bioinformatics approach may provide insights into novel therapy options for the treatment of patients with metastatic OS.

Chloroethyl nitrosoureas constitute an important family of cancer chemotherapeutic agents, used in the treatment of various types of cancer. They exert antitumor activity by inducing DNA interstrand cross-links. Semustine, a chloroethyl nitrosourea, is a 4-methyl derivative of lomustine. There exist some interesting reports dealing with DNA-binding properties of chloroethyl nitrosoureas; however, underlying mechanism of cytotoxicity caused by semustine has not been precisely and completely delineated. The present work focuses on understanding semustine-DNA interaction to comprehend its anti-proliferative action at molecular level using various spectroscopic techniques. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy is used to determine the binding site of semustine on DNA. Conformational transition in DNA after semustine complexation is investigated using circular dichroism (CD) spectroscopy. Stability of semustine-DNA complexes is determined using absorption spectroscopy. Results of the present study demonstrate that semustine performs major-groove-directed DNA alkylation at guanine residues in an incubation-time-drug-concentration-dependent manner. CD spectral outcomes suggest partial transition of DNA from native B-conformation to C-form. Calculated binding constants (Ka) for semustine and lomustine interactions with DNA are 1.53 × 10(3) M(-1) and 8.12 × 10(3) M(-1), respectively. Moreover, molecular modeling simulation is performed to predict preferential binding orientation of semustine with DNA that corroborates well with spectral outcomes. Results based on comparative study of DNA-binding properties of semustine and lomustine, presented here, may establish a correlation between molecular structure and cytotoxicity of chloroethyl nitrosoureas that may be instrumental in the designing and synthesis of new nitrosourea therapeutics possessing better efficacy and fewer side effects.

The modified busulfan-cyclophosphamide (mBuCy) regimen, combined with hydroxyurea, cytarabine and semustine, is the most frequently used myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation in our unit. It is unknown, however, whether fludarabine can be substituted for cyclophosphamide in the mBuCy regimen. We carried out a prospective study to compare modified busulfan-fludarabine (mBuF) with mBuCy, aiming to reduce the treatment-related mortality, with non-inferiority of other outcomes. The mBuCy regimen consisted of hydroxyurea 80 mg/kg on day −10; cytarabine 2 g/m2 on day −9; busulfan 9.6 mg/kg, intravenously on day −8 through –6; and cyclophosphamide 3.6 g/m2 on day −5 and −4 and semustine 250 mg/m2 on day −3. In the mBuF regimen, cyclophosphamide was substituted with fludarabine 30 mg/m2 through day −5 to −1. Mobilized blood and marrow stem cells were collected from HLA-matched siblings. The trial was suspended due to a tendency of higher incidence of severe pneumonia in the mBuF arm, in which 105 patients were enrolled. After follow-up for another 22 months, a significantly increased incidence of severe pneumonia (31.1 %) was observed in the mBuF arm (11.6 % in mBuCy). This finding suggests that it is uncertain whether it is appropriate to substitute fludarabine for cyclophosphamide under any drug combination. This study was registered at www.chictr.org/cn under identifier ChiCTR-TRC-09000470.

Aim: To investigated the mechanism of Chloroethylnitrosoureas (CENUs) leading to secondary tumors after therapy, three kinds of CENUs, namely, Nimustine (ACNU), Carmustine (BCNU) and Semustine (MeCCNU) were used to investigated drug-induced DNA interstrand crosslinks(ICLs). Method: The alkaline comet assay was adopted to compare DNA damages induced by CENUs under different concentrations. Results: With the increase of drug’s concentration, DNA migration exhibited a positive concentration-dependent relationship in all three drugs. ACNU was shown to cause significant crosslinking. The other two drugs also induced crosslinking, but this could not be analyzed at high concentrations due to the high cytotoxicity of the drugs which caused cells death.

// Minyong Kang 1 , Chang Wook Jeong 1 , Cheol Kwak 1 , Hyeon Hoe Kim 1 , Ja Hyeon Ku 1 1 Department of Urology, Seoul National University Hospital, Seoul, Republic of Korea Correspondence to: Ja Hyeon Ku, email: kuuro70@snu.ac.kr Keywords: urinary bladder neoplasm, chemotherapy, drug therapy, single instillation, systematic review Received: March 18, 2016 Accepted: May 29, 2016 Published: June 14, 2016 ABSTRACT We performed a network meta-analysis of randomized controlled trials (RCTs) to compare the efficacy of several intravesical chemotherapeutic (IVC) agents after transurethral resection of bladder tumor (TURB) in non-muscle invasive bladder cancer patients. The literature search was conducted using the Embase, Scopus and PubMed databases for RCTs, including patients with single or multiple, primary or recurrent stage Ta or T1 urothelial carcinoma of the bladder managed with a single, immediate instillation of IVC after TURB. Thirteen RCTs met the eligibility criteria. Pair-wise meta-analysis (direct comparison) showed that pirarubicin [hazard ratio (HR): 0.31], epirubicin (HR: 0.62), and MMC (HR: 0.40) were the most effective drugs for reducing tumor recurrence. Bayesian network meta-analysis (indirect comparison) revealed that treatment with pirarubicin (HR: 0.31), MMC (HR: 0.44), or epirubicin (HR: 0.60) was associated with prolonged recurrence-free survival. Among the drugs examined, only pirarubicin reduced disease progression compared to controls. These results suggest that a single, immediate administration of IVC with pirarubicin, MMC, or epirubicin is associated with prolonged recurrence-free survival following TURB in non-muscle invasive bladder cancer patients, though only pirarubicin also reduced disease progression.

The "gain of function" of mutant TP53 is an important determinant in human tumor development and progression. This study aimed to investigate the possible mechanism of mutant TP53 inducing temozolomide resistance in glioblastoma cells. Three established human glioma cell lines, T98G, U87, and U138, were chemoresistant cells. The mRNA of cells was sequenced to confirm the status of TP53. Synthetic small interfering RNA (siRNA) was used to knock down TP53 in cells. TP53 mRNA was detected "silenced" by reverse transcriptase-polymerase chain reaction (RT-PCR) in five consecutive days. Viable cell survival was measured when these cells were exposed to temozolomide or semustine in step-up concentrations. The expression of O(6)-methylguanine DNA-methyltransferase (MGMT) at mRNA level was also determined. T98G, U87, and U138 cells were resistant to temozolomide. T98G and U138 cells expressed mutant-type TP53 with positive MGMT, while U87 cell expressed wild-type TP53 with negative MGMT. TP53-siRNA knocked down TP53 effectively (P = 0.021) in five consecutive days. Knockdown of mutant TP53 in T98G and U138 cells led to a fivefold increase in chemosensitivity to temozolomide, but not semustine. Knockdown of wild TP53 in U87 cell did not affect the chemoresistance. In addition, mutant TP53 knockdown induced a dramatic decrease of MGMT expression (P = 0.0000034). TP53 mutation decreases the chemosensitivity of malignant gliomas to temozolomide. This "gain of function" in drug resistance may be obtained by increasing MGMT expression.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of aggressive T-cell lymphomas with no treatment consensus and poor prognosis. We herein described an extraordinary refractory case of PTCL-NOS with widely involvement of subcutaneous tissue, which showed an excellent response to Semustine personalized chemotherapy based on the detection finding of positive O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. This is the first english report to indicate that single nitrosourea agent such as Semustine may have good efficacy and safety for widespread subcutaneous involvement of PTCL-NOS with positive MGMT promoter methylation.

Within the United States, primary brain tumors account for 20 to 25 percent of all pediatric cancers. Chemotherapy utilizing a nitrosourea, notably semustine (MeCCNU) and carmustine (BCNU), has shown significant success in the treatment of tumors found in the central nervous system. In silico optimization of molecular properties by substituent substitution that is followed by pattern recognition analysis is utilized in this study to develop 14 novel anti-cancer drugs for the treatment of malignant cancers of the central nervous system. These 14 agents exhibit molecular properties that are suitable for penetration through the blood-brain barrier (BBB). All 14 agents are nitrosoureas having values of Log P ranging from 2.188 to 2.942, and having a constant total of 5 oxygens and nitrogens with zero violations of the Rule of 5 which indicates favorable bioavailability. Value of Log BB (Log [Cbrain/Cblood]) for these agents does not vary from - 0.441 (BB value of 0.362). The formula weight of the agents is highly correlated to molecular volume (r= 0.9848) and total number of atoms (r= 0.9948), but not correlated to number of rotatable bonds (r= 0.1814). Analysis of similarity (ANOSIM) indicated that all 14 new constructs are similar to the parent compound semustine. The Log P value for all 14 agents predicts favorable attributes for penetrating the BBB. Multiple regression analysis established that number of atoms, number of rotatable bonds, and molecular volume are strong prognosticators for molecular weight of this assemblage of pharmaceuticals. This study attests to the efficacy of in silico optimization of molecular substituents followed by pattern recognition analysis to develop new drug designs based on a successful nitrosourea framework for the treatment of malignant tumors of the brain.

Ninety patients with advanced breast cancer received a polychemotherapeutic program composed of 5-fluorouracil, cyclophosphamide, and prednisone with or without vincristine as a control group in a series of four consecutive Phase II clinical trials of new drug programs. Objective regression rates were 59% without vincristine and 46% with vincristine. Projected mean length of regressions exceeds 1 year. Site of dominant disease, disease-free interval, or performance scale score (if score was 0, 1, or 2, ECOG scale) failed to influence response rates; decreasing response rates were noted as the length of time increased after menopause. No advantage existed in patients experiencing severe myelosuppression (nadir leukocyte count of less than 1,500/mm), and appreciable response rates occurred without significant myelosuppression. The addition of vincristine to the regimen failed to increase the response rates, and only increased toxicity. The program as outlined is reasonably tolerable and effective for this group of patients with advanced breast cancer.

Aim: To analyze the results of idarubicin (IDA)- versus etoposide (VP16)-intensified myeloablative conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-SCT) for high-risk acute leukemia. Methods: From January 2005 to June 2008, 48 consecutive patients (male: n=29; median age: 30 years, range 14–51 years) with high-risk acute leukemia underwent allo-SCT following an IDA- or VP16-intensified conditioning regimen. The conditioning regimens were modified BUCY2 (busulfan+cyclophosphamide) consisting of IDA (15 mg/m2 per day, days -12 to -10) or VP16 (25 mg/kg per day, days -3 to -2) and CY/TBI (cyclophosphamide/total body irradiation) intensified with IDA (15 mg/m2 per day, days -6 to -5) or VP16 (25 mg/kg per day, days -3 to -2) for acute myeloid leukemia and acute lymphoblastic leukemia, respectively. Results: Between the two groups, no significant differences in terms of baseline characteristics, incidence of acute or chronic graft-versus-host disease (GVHD) or transplant-related mortality (TRM) (P=0.50) were observed. However, the IDA group demonstrated higher incidences of mucositis and Aspergillus pneumonia (P

UNLABELLED Subclinical acute rejection (SCR) has been increasingly recognized in adult renal transplant recipients with the advent of surveillance biopsies. However, in children, surveillance biopsies are not routinely performed at most centers. Therefore, the incidence, predisposing factors, treatment, and clinical outcomes of SCR remain unclear in children. From August 2004 to December 2005, we performed 36 protocol biopsies at three months post-transplantation. All patients had received induction therapy with basiliximab and were maintained on prednisone, MMF, and tacrolimus. Sixteen cases of SCR were detected by biopsy (44%). Age, gender, race, donor source, or serum creatinine did not discriminate between children with SCR and those with normal biopsies. All cases of SCR were treated with high doses of methylprednisolone. At one yr post-transplant, renal function was similar in children with SCR to those with normal surveillance biopsies (p = 0.62). Because of the high incidence of SCR, the maintenance dose of MMF was increased by 50% in 20 children transplanted after December 2005. This resulted in a significant decline in the incidence of SCR from 44 to 15% (p < 0.05). However, the incidence of polyomavirus (BK) viremia also increased significantly in these children (p < 0.005). CONCLUSION A high incidence of SCR was found on surveillance biopsies at three months post-transplant and could not be predicted by age, gender, race, donor source, or serum creatinine. The occurrence of SCR declined significantly by increasing the dose of MMF, but resulted in an increase in BK viremia. We conclude that surveillance biopsies provide valuable information in the management of pediatric renal transplant recipients. Increasing immunosuppression to avoid SCR should be weighed against the risk for infection.

Background The diagnosis of extraneural metastasis from glioblastoma is usually based on the histopathology and immunohistochemical staining of a tumor specimen. Information regarding the molecular features of glioblastoma and optimal treatment strategies for extraneural metastasis is limited. Case Description A 58-year-old woman with a glioblastoma located in the left temporal lobe underwent resection followed by radiotherapy plus concomitant and adjuvant temozolomide. Ipsilateral cervical lymph node tumors were treated 29 months later with supraomohyoid neck dissection and temozolomide. The diagnosis of lymph node metastases from glioblastoma was confirmed with an OncoScan assay and pathologic analysis. The brain and lymph node tumors had identical genotypes: C228T-mutated TERT promoter, wild-type IDH1 , wild-type IDH2 , wild-type TP53 , EGFR amplification, and unmethylated MGMT promoter. Subsequently, multiple bone metastases were detected and treated with CyberKnife radiosurgery. Widespread extraneural metastases were detected 49 months after the initial diagnosis, and the patient underwent chemotherapy with cisplatin and semustine. There was no evidence of intracranial relapse until death, which occurred 5 months after chemotherapy. Conclusions Similar to carcinomas, glioblastomas can spread via the lymphatic route. Extensive therapies for extraneural metastases from glioblastoma can alleviate discomfort and prolong survival, especially in patients without intracranial relapse.

A new method to evaluate the anticancer activity at the molecular level has been developed. In our assay, the interaction between alkylating anticancer drugs-Fe

Bioassay-guided fractionation led to the discovery of a novel neo-clerodane diterpenoid, scutebarbalactone VN (BalA: 8,13-epoxy-3-en-7-hydroxy-6,11- O-dibenzoyl-15,16-clerodanolide), from the methanol extract of the whole-plant of Vietnamese Scutellaria barbata D. Don. A microarray technique combined with bioinformatic analyses showed that BalA could inhibit cell cycle pathways by downregulating genes such as CDC25A and AURKA. BalA also showed the potential to reactivate downregulated genes in hepatocellular carcinoma cells and genes in antioxidant pathways such as HMOX1 and HSPA1A. Querying Connectivity map 2.0 resulted in a match of the BalA-modulated gene signature with that of 10 known compounds, most of which are currently marketed chemotherapy drugs. The highest matching scores belonged to lomustine, semustine, and withaferin A. Lomustine and semustine were found to alkylate DNA and RNA, while withaferin A inhibits nuclear factor kappa B (NF-κB) activity. A luciferase reporter assay was also conducted on 293/NF-κB human embryonic kidney cells that had been transfected with the NF-κB-luciferase plasmid to verify the anticancer activity of BalA. The assay showed that Ba1A effectively blocked NF-κB with an IC50 of 38.6 ± 0.05 μM.

The aim of this retrospective analysis was to evaluate feasibility and effectiveness of definitive chemoradiotherapy without split-course technique in anal cancer patients. From 1993 to 2003, 81 patients were treated; 13 were excluded due to various chemotherapeutic regimes, thus 68 patients were analysed. In case of acute grade 3 toxicities, treatment was halted until improvement or resolution independent of dose. Short interruption was defined as completing treatment without exceeding eight cumulative treatment days beyond scheduled plan, other patients were considered to have had prolonged interruption. Median follow-up was 46 months. Median overall treatment time was 53 days corresponding to an interruption of eight cumulative treatment days. Thirty-five patients (51%) had treatment interruption of

The FAS receptor–ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis. We have recently demonstrated (Sun, T., X. Miao, X. Zhang, W. Tan, P. Xiong, and D. Lin. 2004. J. Natl. Cancer Inst. 96:1030–1036; Zhang, X., X. Miao, T. Sun, W. Tan, S. Qu, P. Xiong, Y. Zhou, and D. Lin. 2005. J. Med. Genet. 42:479–484) that functional polymorphisms in FAS and FAS ligand (FASL) are associated with susceptibility to lung cancer and esophageal cancer; however, the mechanisms underlying this association have not been elucidated. We show that the FAS –1377G, FAS –670A, and FASL –844T variants are expressed more highly on ex vivo–stimulated T cells than the FAS –1377A, FAS –670G, and FASL –844C variants. Moreover, activation-induced cell death (AICD) of T cells carrying the FASL –844C allele was increased. We also found a threefold increased risk of cervical cancer among subjects with the FASL –844CC genotype compared with those with the –844TT genotype in a case-control study in Chinese women. Together, these observations suggest that genetic polymorphisms in the FAS–FASL pathway confer host susceptibility to cervical cancers, which might be caused by immune escape of tumor cells because of enhanced AICD of tumor-specific T cells.

Evidence indicating that hybrid steroid compounds of anti-cancer agents produce reduced toxicity, significantly lower than the cytotoxic components alone, and increased anti-cancer activity has prompted the design and development of such steroids, mostly alkylating esters. We investigated the in-vitro and in-vivo activity of a homo-aza-steroidal alkylating ester (HASE), in comparison with dacarbazine (DTIC), cisplatin (CPDD), carmustine (BCNU) and semustine (MeCCNU), in the treatment of malignant melanoma. Cytotoxicity was assessed in vitro by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using a panel of six human malignant melanoma cell lines, with or without the presence of rat liver microsome assay. B16 melanoma-bearing mice were used to evaluate in vivo the anti-tumour activity of the tested compounds. In all cases of in-vitro screening, HASE displayed a significantly higher (P

Nowadays, leiomyosarcoma is still difficult to early diagnosis, has no standard treatment to follow, and the therapeutic value of surgery, chemotherapy and radiotherapy haven’t been evaluated effectively. Here was a case, which was misdiagnosed as uterine myoma, and was found already to occur lung metastasis after surgery. Complete remission (CR) was achieved after four cycles of albupax-containing chemotherapy. But six months later brain metastases was found. Then the patient received semustine, local radiotherapy and surgery, once again, achieved CR.

Purpose To determine survival and relapse rates by T and N stage and treatment method in five randomized phase III North American rectal adjuvant studies. Patients and Methods Data were pooled from 3,791 eligible patients enrolled onto North Central Cancer Treatment Group (NCCTG) 79-47-51, NCCTG 86-47-51, US Gastrointestinal Intergroup 0114, National Surgical Adjuvant Breast and Bowel Project (NSABP) R01, and NSABP R02. Surgery alone (S) was the treatment arm in 179 patients. The remaining patients received adjuvant treatment as follows: irradiation (RT) alone (n = 281), RT + fluorouracil (FU) ± semustine bolus chemotherapy (CT; n = 779), RT + protracted venous infusion CT (n = 325), RT + FU ± leucovorin or levamisole bolus CT (n = 1,695), or CT alone (n = 532). Five-year follow-up was available in 94% of surviving patients, and 8-year follow-up, in 62%. Results Overall (OS) and disease-free survival were dependent on TN stage, NT stage, and treatment method. Even among N2 patients, T substage influenced 5-year OS (T1-2, 67%; T3, 44%; T4, 37%; P < .001). Three risk groups of patients were defined: (1) intermediate (T1-2/N1, T3/N0), (2) moderately high (T1-2/N2, T3/N1, T4/N0), and (3) high (T3/N2, T4/N1, T4/N2). For intermediate-risk patients, those receiving S plus CT had 5-year OS rates of 85% (T1-2/N1) and 84% (T3/N0), which was similar to results with S plus RT plus CT (T1-2/N1, 78% to 83%; T3/N0, 74% to 80%). For moderately high-risk lesions, 5-year OS ranged from 43% to 70% with S plus CT, and 44% to 80% with S plus RT plus CT. For high-risk lesions, 5-year OS ranged from 25% to 45% with S plus CT, and 29% to 57% with S plus RT plus CT. Conclusion Different treatment strategies may be indicated for intermediate-risk versus moderately high- or high-risk patients based on differential survival rates and rates of relapse. Use of trimodality treatment for all patients with intermediate-risk lesions may be excessive, since S plus CT resulted in 5-year OS of approximately 85%; however, 5-year disease-free survival rates with S plus CT were 78% (T1-2/N1) and 69%(T3/N0), indicating room for improvement.

To report the 4-year outcomes of a consecutive series of anal cancer patients treated with concurrent chemo-radiation delivered with intensity-modulated radiotherapy (IMRT), employing a simultaneous integrated boost (SIB) approach.A consecutive series of 54 patients was enrolled between 2007 and 2013. Treatment schedule consisted of 50.4 Gy/28 fractions (1.8 Gy daily) to the gross tumor volume, while the elective nodal volumes were prescribed 42 Gy/28 fractions (1.5 Gy/daily) for patients having a cT2N0 disease. Patients with cT3-T4/N0-N3 tumors were prescribed 54 (T3) or 60 (T4) Gy/30 fractions (1.8-2 Gy daily) to the gross tumor volume; gross nodal volumes were prescribed 50.4 Gy/30 fr (1.68 Gy daily) if sized ≤ 3 cm or 54 Gy/30 fr (1.8 Gy daily) if3 cm; elective nodal regions were given 45 Gy/30 fractions (1.5 Gy daily). Chemotherapy was administered concurrently according to the Nigro's regimen. Primary endpoint was colostomy-free survival (CFS). Secondary endpoints were local control (LC), disease-free survival (DFS), cancer-specific survival (CSS), overall survival (OS), and toxicity profile.Median follow up was 32.6 months (range 12-84). The actuarial probability of being alive at 4 years without a colostomy (CFS) was 68.9% (95% CI: 50.3%-84.7%). Actuarial 4-year OS, CSS, DFS, and LC were 77.7% (95% CI: 60.7-88.1%), 81.5% (95% CI: 64%-91%), 65.5% (95% CI: 47.7%-78.5%), and 84.6% (95% CI: 71.6%-92%). Actuarial 4-year metastasis-free survival was 74.4% (95% CI: 55.5%-86.2%). Maximum detected acute toxicities were as follows: dermatologic -G3: 13%; GI-G3: 8%; GU-G3: 2%; anemia-G3: 2%; neutropenia-G3:11%; G4: 2%; thrombocytopenia- G3:2%. Four-year G2 chronic toxicity rates were 2.5% (95% CI: 3.6-16.4) for GU, 14.4% (95% CI: 7.1-28) for GI, 3.9% (95% CI: 1%-14.5%) for skin, and 4.2% (95% CI: 1.1-15.9) for genitalia.Our study shows the feasibility of IMRT in the combined modality treatment of anal cancer, with comparable results to the literature with respect to LC, sphincter preservation and survival. Acute toxicity is lower if compared to series employing standard techniques. Our results support the use of IMRT on a routine basis for the treatment of anal cancer.

During the last decade, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has completed six adjuvant chemotherapy trials comparing different adjuvant therapy regimens or adjuvant therapy versus surgery alone. A seventh trial is ongoing. These trials have contributed to defining the role of adjuvant therapy in colon cancer. Patients eligible for inclusion in NSABP trials had been diagnosed as having stage II or III colon cancer with no evidence of gross residual or metastatic disease. The follow-up strategies were similar in the reported trials with follow-up every 3 months for the first 2 years, then every 6 months for the next 3 to 5 years, and annually thereafter. The NSABP C-01 protocol was a three-arm trial comparing an adjuvant semustine/vincristine/5-fluorouracil (5-FU) regimen (MOF) to a Bacille Calmette-Guerin treatment, and to surgery alone. The C-02 protocol investigated whether portal vein infusion of 5-FU improved survival outcome compared with surgery alone. Protocol C-03 compared a semustine/vincristine/5-FU regimen to a 5-FU plus leucovorin (LV) (5-FU/LV) regimen. The NSABP C-04 protocol was a three-arm trial comparing 5-FU/LV, 5-FU plus levamisole, and 5-FU/LV plus levamisole. The NSABP C-05 trial compared 5-FU/LV to 5-FU/LV plus alpha-interferon. Results of NSABP C-01, C-02, C-03, C-04, and C-05 trials are summarized in this report. Patient accrual has completed in the NSABP C-06 trial comparing 5-FU/LV with oral tegafur and plus uracil leucovorin. The NSABP is currently conducting another trial (C-07) comparing 5-FU/LV with 5-FU/LV plus oxaliplatin. The role of adjuvant chemotherapy in stage II colon cancer is also discussed in this report. A recent pooled analysis of studies C-01, C-02, C-03, and C-04 has indicated that the relative treatment benefit in stage II disease is at least equal to the benefit in stage III colon cancers, and concluded that adjuvant chemotherapy also should be considered as the standard of care for stage II colon cancer patients.

Combined modality therapy is the standard adjuvant therapy for selected patients with adenocarcinoma of the rectum. In the postoperative setting, the primary goal is to decrease local recurrence and improve overall survival. In the preoperative setting, adjuvant therapy has the additional potential benefit of enhancing sphincter preservation and less acute toxicity as compared with postoperative adjuvant therapy. Investigational trials are in progress to examine new systemic chemotherapeutic agents and altered radiation fractionation schemes.

Seventy-three eligible, chemotherapy-naive, ambulatory patients with advanced pancreatic carcinoma were allocated to one of two treatment regimens: 35 received PALA (1250 mg/m2 daily x 5 every 4 weeks) and 38 were given SAM (streptozotocin 400 mg/m2 i.v. daily x 5, doxorubicin 45 mg/m2 i.v. on day 1 and 22, and methyl CCNU 60 mg/m2 orally on days 1 and 22 every 6 weeks). Doses were modified for myelo-, gi-, or cardiotoxicity. Adequate organ, bone marrow and cardiac function; a measurable lesion; adequate caloric intake; and a life expectancy of 2 months were required for treatment on this trial. One patient on each regimen had a partial response for response rates of 3% (95% confidence intervals, 0.08 to 17%). Median survival on the PALA arm was 5 months and median time to treatment failure was 2.6 months. SAM patients experienced median overall and progression free survivals of 3.4 and 1.9 months, respectively. The severe toxicity observed was almost exclusively myelosuppression on both regimens. One patient receiving SAM had lethal leukopenic sepsis during the first cycle as the only treatment-related death. Neither PALA nor SAM offer any therapeutic utility to patients with advanced pancreatic cancer.

Methyl-CCNU [1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea] (CAS 13909-09-6) is an investigational drug used in chemotherapy to treat various types of cancers like Hodgkin's disease, malignant gliomas, gastrointestinal tract adenocarcinomas, breast carcinomas, squamous-cell carcinomas, malignant melanoma, and epidermoid carcinoma of the lung. Me-CCNU can be fatal if inhaled. Mouse oral LD 50 is 50 mg kg − 1 . It is an antineoplastic agent that functions as an alkylating agent. It is cytotoxic in all stages of the cell cycle. Me-CCNU is known to be a human carcinogen based on sufficient evidence of carcinogenicity in humans. It causes respiratory tract irritation, toxic to skin when absorbed, and causes skin and eye irritation. Human systemic effects by ingestion may lead to nausea or vomiting, damage to kidney tubules and glomeruli, and hematuria (blood in the urine). Pulmonary fibrosis is a serious side effect of nitrosourea therapy. Me-CCNU is known to cause severe renal impairment in many forms, and is believed to be metabolized by the liver and kidneys. Most recent development in this area has been to design hybrid steroid compounds of anticancer agents, which presumably produce less toxicity, significantly lower than the cytotoxic components alone, and increase anticancer activity. The focus has been to design alkylating esters.