Pegylated Liposomal Doxorubicin Combined with Ifosfamide for Treating Advanced or Metastatic Soft-tissue Sarcoma: A Prospective, Single-arm Phase II Study.

PURPOSE: This prospective single-arm phase II clinical trial aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) combined with ifosfamide (IFO) as the first-line treatment for patients with advanced or metastatic soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients received PLD (30 mg/m2; day 1) in combination with IFO (1.8 g/m2; days 1-5) every 21 days until disease progression, unacceptable toxicities, patient death, or for up to six cycles. The primary endpoint was progression-free survival (PFS; NCT03268772). RESULTS: Overall, 69 patients with chemotherapy-naïve advanced or metastatic STS were enrolled between May 2015 and November 2019. At a median follow-up of 47.2 months, the median PFS and overall survival (OS) were found to be 7.3 [95% confidence interval (CI): 5.7-8.9] and 20.6 (95% CI: 16.3-25.0) months, respectively. The response and disease control rates were 26.1% and 81.2%, respectively. Adverse events were manageable, and no grade 3-4 cardiotoxicities were observed. There was no significant change in left ventricular ejection fraction values between baseline and after treatment (P = 0.669). Exploratory biomarker analysis suggested NF1 single-nucleotide variant was associated with poor OS (P < 0.0001) and PFS (P = 0.044). In addition, 2 patients with BRCA2 loss progressed in the initial 2 months and died within 10 months. Improved OS was observed in homologous recombination deficiency (HRD)-negative patients compared with their HRD-positive counterparts (P = 0.0056). CONCLUSIONS: Combination therapy comprising PLD and IFO is an effective and well-tolerated first-line treatment for patients with advanced or metastatic STS.

Arctiin Antagonizes Triptolide-Induced Hepatotoxicity via Activation of Nrf2 Pathway.

Triptolide (TP) is the most effective ingredient found in the traditional Chinese herbal Tripterygium wilfordii Hook F, and it is widely used in therapies of autoimmune and inflammatory disorders. However, the hepatotoxicity induced by TP has restricted its use in clinical trials. Arctiin is known as a protective agent against oxidative stress, and it exerts liver-protecting effect. This study was aimed at investigating the protective role of arctiin against TP-induced hepatotoxicity using in vitro and in vivo models. The results indicated that TP not only obviously induced liver injury in mice but also significantly inhibited the growth of HepG2 cells and increased the level of intracellular reactive oxygen. Furthermore, TP obviously decreased the expressions of proteins of Nrf2 pathway including HO-1, NQO1, and Nrf2 associated with oxidative stress pathway. However, the above experimental indexes were reversed by the treatment of arctiin. Our results suggested that arctiin could alleviate TP-induced hepatotoxicity, and the molecular mechanism is likely related to its capacity against oxidative stress.

[Arctiin antagonizes triptolide-induced renal toxicity in rats via anti-inflammatory pathway].

OBJECTIVE: To investigate the protective effect of arctiin with anti-inflammatory bioactivity against triptolide-induced nephrotoxicity in rats and explore the underlying mechanism. METHODS: Forty SD rats were divided into 4 groups for gastric lavage of normal saline, arctiin (500 mg/kg), triptolide (500 µg/kg), or both arctiin (500 mg/kg) and triptolide (500 µg/kg). Blood samples were collected for analysis of biochemical renal parameters, and the renal tissues were harvested for determining the kidney index and for pathological evaluation with HE staining. In the in vitro experiment, HK-2 cells were treated with arctiin and triptolide either alone or in combination, and the cell viability was determined with MTT assay; the cell morphological changes was observed using laser confocal microscopy, cell apoptosis was detected using flow cytometry, and the expressions of inflammation-related protein expression were detected by Western blotting. RESULTS: In SD rats, arctiin significantly antagonized triptolide-induced elevation of BUN, Scr and kidney index (P < 0.05) and obviously improved renal tissue damages induced by triptolide including cell swelling, vacuolization and spotty necrosis. Arctiin significantly inhibited triptolide-induced cytotoxicity in HK-2 cells and increased the cell viability at 24 h (P < 0.05). Arctiin also attenuated triptolide-induced cell morphological changes, decreased cell apoptosis rate (P < 0.05) and reversed the expressions of IκBα and nuclear p65 (P < 0.05). CONCLUSIONS: Arctiin can protect the kidney from triptolide-induced damages in rats possibly through the anti-inflammatory pathway.

Single institution experience of split course radiotherapy in patients with desmoid tumors.

PURPOSE: This study aimed to assess the feasibility of split course radiotherapy (SCRT) and reports long-term outcomes in patients with desmoid tumors (DT). PATIENTS AND METHODS: Between 2001 and 2004, 31 patients with recurrent (n=19) or primary large desmoid fibromatosis (≥10 cm) (n=12) who were treated with SCRT were retrospectively analyzed. All patients were treated with two phases of radiotherapy with a median interval time of 99 days (range: 81-122 days) and a median total dose of 6,399 cGy (range: 5,013-7,039 cGy). The median dose for the first phase was 3,969 cGy/22 Fx (range: 2,999-4,305 cGy), and 2,495 cGy/14 Fx (range: 1,982-3,039 cGy) for the second phase. Progression-free survival (PFS) in response to radiotherapy was evaluated using the Kaplan-Meier method and compared using the log-rank test. The prognostic factors associated with survival were evaluated by univariate and multivariate analyses. RESULTS: The median age of all patients was 30 years (range, 7-58 years). With a median follow-up of 60.4 months (range, 2-187 months), eight patients experienced disease progression after treatment. The PFS rate at 3 and 5 years for the whole population was 90% and 71.3%, respectively. PFS for patients with split course of <100 days or ≥100 days interval was 100% vs 78.6% at 3 years, and 80.4% vs 62.9% at 5 years, respectively (P=0.189). In multivariate analysis, the radiotherapy (RT) interval time was an independent prognostic factor for PFS (≥100 days vs <100 days, HR 11.544, 95% CI 1.034-128.878, P=0.047). PFS was not significantly influenced by age, gender, surgery, tumor location, RT technology, or RT dose. Radiation-related acute complications occurred in nine (29%) patients after RT, and RT-related long-term complications occurred in three (9.7%) patients. CONCLUSION: SCRT with an appropriate treatment interval (<100 days) is well tolerated by DT patients with favorable long-term outcomes.

RAD51 is a potential marker for prognosis and regulates cell proliferation in pancreatic cancer.

BACKGROUND: The DNA damage and repair pathway is considered a promising target for developing strategies against cancer. RAD51, also known as RECA, is a recombinase that performs the critical step in homologous recombination. RAD51 has recently received considerable attention due to its function in tumor progression and its decisive role in tumor resistance to chemotherapy. However, its role in pancreatic cancer has seldom been investigated. In this report, we provide evidence that RAD51, regulated by KRAS, promotes pancreatic cancer cell proliferation. Furthermore, RAD51 regulated aerobic glycolysis by targeting hypoxia inducible factor 1α (HIF1α). METHODS: TCGA (The Cancer Genome Atlas) dataset analysis was used to examine the impact of RAD51 expression on overall survival of pancreatic cancer patients. Lentivirus-mediated transduction was used to silence RAD51 and KRAS expression. Quantitative real-time PCR and western blot analysis validated the efficacy of the knockdown effect. Analysis of the glycolysis process in pancreatic cancer cells was also performed. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay. RESULTS: Pancreatic cancer patients with higher levels of RAD51 exhibited worse survival. In pancreatic cancer cells, RAD51 positively regulated cell proliferation, decreased intracellular reactive oxygen species (ROS) production and increased the HIF1α protein level. KRAS/MEK/ERK activation increased RAD51 expression. In addition, RAD51 was a positive regulator of aerobic glycolysis. CONCLUSION: The present study reveals novel roles for RAD51 in pancreatic cancer that are associated with overall survival prediction, possibly through a mechanism involving regulation of aerobic glycolysis. These findings may provide new predictive and treatment targets for pancreatic cancer.

Prognostic role of elevated preoperative systemic inflammatory markers in localized soft tissue sarcoma.

BACKGROUND: Systemic inflammation has been implicated in cancer development and progression. The aim of the present study was to evaluate whether pre-operative systemic inflammatory markers can predict outcomes in bone and soft tissue sarcomas. METHODS: Relevant literature was mainly identified using Pubmed, EMBASE and CNKI. Patients' clinical characteristics, overall survival (OS), disease/relapse free survival (DFS/RFS) with high-level CRP or neutrophils to lymphocytes ratio (NLR) were extracted. The statistics extracted from Kaplan-Meier survival curves with log-rank p value were calculated with methods developed by Parmar, Williamson, and Tierney; multivariate Cox hazard regression analysis data were used directly in STATA 10.0. Pooled hazard ratio (HR) and 95% CI were calculated to evaluate the prognostic role of these systemic inflammatory markers (CRP/NLR). RESULTS: After full text review, 11 articles containing 1809 patients were identified as eligible articles. The meta-analysis for survival outcome showed significant prognostic value of systemic inflammatory markers including CRP and NLR in pre-operative blood. The combined HRs (95% CI) for five year overall survival (OS) and disease/recurrence free survival (DFS/RFS) were 2.54 [2.04, 3.16] and 2.28 [1.72, 3.04]. Specifically, higher NLR was associated with decreased 5-year OS (HR 3.75, 95% CI 1.24 to 11.37) and 3 year RFS/DFS (HR 2.43, 95% CI 0.84 to 7.05). Besides, the pooled HR showed a higher risk of 5-year disease progression (HR 2.55, 95% CI 1.60 to 4.08, I2 = 52%) and lower 5-year OS (HR 2.50, 95% CI 2.00 to 3.12, I2 = 0%) in sarcoma patients with high CRP level. We then grouped the meta-analysis by patient source (Asian and non-Asian), tumor stage (I/II or III/IV) and grade (high or low), respectively. All the subgroup analysis showed significant prognostic role in survival condition. The CRP/NLR levels are also found closely related with patient age, tumor stage and size. CONCLUSION: Higher level of pre-operative CRP and NLR demonstrated a significantly higher risk of recurrence and overall decreased survival rates in sarcomas.

Basal cell carcinoma of the prostate: clinicopathologic analysis of three cases and a review of the literature.

BACKGROUND: Although conventional adenocarcinoma accounts for the majority of prostatic carcinomas, it is important to recognize rare variants, like basal cell carcinoma (BCC), which has distinctive histopathological and biological features. CASE REPORT: We analyzed three cases of prostatic BCC and all of them complained of acute urinary retention and digital rectal examination disclosed a stony hard prostate. However, all of them presented with low prostate-specific antigen. The diagnosis relied on transrectal ultrasound-guided needle biopsies or transurethral resection of the prostate (TURP). The microscopic findings suggested basaloid cells with large pleomorphic nuclei and scant cytoplasm, showing peripheral palisading and forming solid nests, and immunohistochemical markers like 34ßE12, p63 and Ki67 staining, were positive. After active treatment, two of the patients are alive with tumor and one died five months after discharge from our hospital.

Long-term outcome of irradiation with or without chemotherapy for esophageal squamous cell carcinoma: a final report on a prospective trial.

PURPOSE: To investigate the long-term outcome of esophageal squamous cell carcinoma (SCC) treated by irradiation with or without concurrent chemotherapy. METHODS AND MATERIALS: A prospective clinical trial was carried out from 1998 to 2000. One hundred and eleven patients were randomly enrolled to receive either late course accelerated hyperfractionated irradiation (LCAF) or LCAF with concurrent chemotherapy (LCAF + CT). For LCAF, 41.4 Gy in 23 fractions was first delivered at five fractions per week, followed by 27 Gy in 18 fractions at two 1.5 Gy fractions a day. Concurrent chemotherapy of cis-platinum and 5-fluorouracil was administered for four cycles. Overall survival (OS), locoregional recurrence and distant metastasis were observed. Late toxicity was scored by RTOG criteria, and quality of life (QOL) was also evaluated. RESULTS: The median follow-up time was 24 months for all patients and 138 months for 17 living patients. Median survival time was 25 months and 32 months in LCAF and LCAF + CT (p = 0.653), respectively. For an entire group of patients, overall survivals were 34%, 27% and 22%; locoregional recurrence rates were 30%, 36% and 41%; and distant metastasis rates were 26%, 28% and 29% at 5-yr, 8-yr and 10-yr, respectively. Incidences of ≥ Grade 3 late toxicity were 29% at 10-yr. There were no statistically significant differences between LCAF and LCAF + CT with respect to the parameters mentioned above. Cumulative incidence of late toxicities of ≥ Grade 3 increased sharply after the attained age of 70 years. Eighty-eight percent of patients lived with good KPS (≥ 90) and 94% could eat regular or soft diet. CONCLUSION: The long-term outcome of esophageal SCC patients who received LCAF or LCAF + CT was good. The locoregional and distant failures occurred more often in the first three years after treatment, but could continuously occur up to 10 years. The late toxicity was acceptable. Late toxicities ≥ Grade 3 were more likely to occur in elderly patients. QOL was good in living patients.

Late course accelerated hyperfractionated radiotherapy plus concurrent chemotherapy for squamous cell carcinoma of the esophagus: a phase III randomized study.

PURPOSE: Late course accelerated hyperfractionated (LCAF) radiotherapy (RT) is as effective as standard chemoradiotherapy for nonsurgical management of locally advanced esophageal squamous cell carcinoma (SCC). We have evaluated further the efficacy of concurrent LCAF RT and chemotherapy. METHODS AND MATERIALS: In all, 111 eligible patients with esophageal SCC were randomized to receive LCAF alone (LCAF) or concurrent LCAF and chemotherapy (LCAT+CT) between March 1998 and July 2000. All patients received conventional fractionation irradiation of 1.8 Gy per day, to a dose of 41.4 Gy/23 fractions in 4-5 weeks, followed by accelerated hyperfractionated irradiation using reduced fields, 1.5 Gy/fractions twice a day, to a dose of 27 Gy in 18 days. Thus, the total dose was 68.4 Gy/41 fractions in 44 days. Fifty-four patients in the LCAF+CT arm had an additional four cycles of chemotherapy using cisplatin 25 mg/m(2) daily and fluorouracil (5-FU) 600 mg/m(2) daily on Days 1-3 every 4 weeks starting on the same day that LCAF was delivered. RESULTS: The median survival was 23.9 months (95% confidence [CI], 20.1-27.7) for the LCAF arm and 30.8 months (95% CI, 17.6-44.1) for the LCAF+CT arm, respectively. Survival rates at 1, 3, and 5 years of the LCAF arm were 77%, 39%, and 28%, respectively, while those of the LCAF+CT arm were 67%, 44%, and 40%, respectively (p = 0.310). Grades 3 and 4 acute toxicities occurred in 46% and 25% of the patients in the LCAF arm and the LCAF+CT arm, respectively; 6% of the patients in the combined arm had Grade 5 acute toxicities, whereas none was noted in the LCAF alone arm. CONCLUSIONS: Late course accelerated hyperfractionation was effective for locally advanced esophageal SCC. There was a trend toward better survival among patients who received intensified treatment with concurrent chemotherapy. Further randomized studies with a larger number of patients should be carried out, but additional measures must be taken to reduce the higher mortality rate due to chemotherapy-related acute toxicities.

Comparison between continuous accelerated hyperfractionated and late-course accelerated hyperfractionated radiotherapy for esophageal carcinoma.

PURPOSE: To compare the treatment results and toxicity of continuous accelerated hyperfractionated (CAHF) and late-course accelerated hyperfractionated (LCAF) radiotherapy (RT) for esophageal carcinoma. METHODS AND MATERIALS: Between August 1996 and March 1999, 101 patients with squamous cell carcinoma of the esophagus were randomized into two groups: 49 to the CAHF group and 52 to the LCAF group. Patients in the CAHF group received RT at 1.5 Gy/fraction b.i.d. (6-h interval), 5 d/wk, to a total dose 66 Gy in 44 fractions during 4.4 weeks. The patients in the LCAF group received conventional fractionation RT, 1.8 Gy/fraction, to a dose of 41.4 Gy in 23 fractions during 4.6 weeks, followed by accelerated fractionation RT using reduced fields, b.i.d., at 1.5 Gy/fraction, with a minimal interval of 6 h between fractions. The total dose was 68.4 Gy in 41 fraction during 6.4 weeks. Patient age, gender, performance score, diet, lesion location, lesion length, stage, and fractionation (CAHF or LCAF) were entered into the univariate and multivariate analyses. RESULTS: All patients finished the treatment course, except for 1 patient in the CAHF group because of severe acute esophagitis. The rate of Grade I, II, and III acute bronchitis was 18.4% (9 of 49), 30.6% (15 of 49), and 8.2% (4 of 49) in the CAHF group and 13.5% (7 of 52), 21.2% (11 of 52), and 3.8% (2 of 52) in the LCAF group, respectively. However, the difference between the two groups was not statistically significant (p = 0.084). The rate of Grade I, II, III, and IV acute esophagitis was 6.1% (3 of 49), 32.7% (16 of 49), 46.9% (23 of 49), and 14.3% (7 of 49) in the CAHF group and 26.9% (14 of 52), 32.7% (17 of 52), 7.7% (4 of 52), and 1.9% (1 of 52) in the LCAF group, respectively. The difference was statistically significant (p < 0.001). The local control rate at 1, 2, and 3 years was 88.7%, 83.9%, and 55.9% in the CAHF group and 80.7%, 71.4%, and 57.1% in the LCAF group, respectively (p = 0.1251). The 1-, 2-, and 3-year survival rate was 79.6%, 51.6%, and 37.6% in the CAHF group and 80.0%, 57.6%, and 41.2% in the LCAF group, respectively (p = 0.5757). Multivariate analysis showed that age and lesion length were independent significant prognostic factors for local control rate, and age was for the overall survival rate. The fractionation schedule had no significant prognostic effect. CONCLUSION: CAHF and LCAF result in similar 1-, 2-, and 3-year local control and survival rates. CAHF resulted in more severe acute esophagitis and may be less well tolerated than LCAF. The treatment results after the CAHF and LCAF regimens were better than those of historical conventional RT.