Pacritinib Combined with Sirolimus and Low-Dose Tacrolimus for GVHD Prevention after Allogeneic Hematopoietic Cell Transplantation: Preclinical and Phase I Trial Results.

PURPOSE: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation. PATIENTS AND METHODS: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells. RESULTS: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4+ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias. CONCLUSIONS: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.

Body Composition, Adherence to Anthracycline and Taxane-Based Chemotherapy, and Survival After Nonmetastatic Breast Cancer.

Importance: Although most chemotherapies are dosed on body surface area or weight, body composition (ie, the amount and distribution of muscle and adipose tissues) is thought to be associated with chemotherapy tolerance and adherence. Objectives: To evaluate whether body composition is associated with relative dose intensity (RDI) on anthracycline and taxane-based chemotherapy or hematologic toxic effects and whether lower RDI mediates the association of adiposity with mortality. Design, Setting, and Participants: An observational cohort study with prospectively collected electronic medical record data was conducted at Kaiser Permanente Northern California, a multicenter, community oncology setting within an integrated health care delivery system. Participants included 1395 patients with nonmetastatic breast cancer diagnosed between January 1, 2005, and December 31, 2013, and treated with anthracycline and taxane-based chemotherapy. Data analysis was performed between February 25 and September 4, 2019. Exposures: Intramuscular, visceral, and subcutaneous adiposity as well as skeletal muscle were evaluated from clinically acquired computed tomographic scans at diagnosis. Main Outcomes and Measures: The primary outcome was low RDI (<0.85), which is the ratio of delivered to planned chemotherapy dose, derived from infusion records; in addition, hematologic toxic effects were defined based on laboratory test values. To evaluate associations with overall and breast cancer-specific mortality, logistic regression models adjusted for age and body surface area were fit as well as Cox proportional hazards models adjusted for age, race/ethnicity, adiposity, Charlson comorbidity index score, and tumor stage and subtype. The mediation proportion was computed using the difference method. Results: The mean (SD) age at diagnosis of the 1395 women included in the study was 52.8 (10.2) years. Greater visceral (odds ratio [OR], 1.19; 95% CI, 1.02-1.39 per SD) and intramuscular (OR, 1.16; 95% CI, 1.01-1.34 per SD) adiposity were associated with increased odds of RDI less than 0.85. Greater muscle mass was associated with a decreased odds of hematologic toxic effects (OR, 0.84; 95% CI, 0.71-0.98 per SD). Relative dose intensity less than 0.85 was associated with a 30% increased risk of death (hazard ratio, 1.30; 95% CI, 1.02-1.65). Lower RDI partially explained the association of adiposity with breast cancer-specific mortality (mediation proportion, 0.20; 95% CI, 0.05-0.55). Conclusions and Relevance: Excess adiposity, presenting as larger visceral or intramuscular adiposity, was associated with lower RDI. Lower RDI partially mediated the association of adiposity with worse breast cancer-specific survival. Body composition may help to identify patients likely to experience toxic effects and subsequent dose delays or reductions, which could compromise chemotherapeutic efficacy.

Pacritinib to treat myelofibrosis patients with thrombocytopenia.

INTRODUCTION: Treatment with ruxolitinib, a selective JAK1/2 inhibitor, has significantly improved the lives of patients with myelofibrosis. Unfortunately, this treatment is frequently limited by cytopenias, precluding a high-risk group characterized by baseline thrombocytopenia. Additionally, there are no approved treatments for patients who have progressed while receiving ruxolitinib. Pacritinib is a novel JAK2/FLT3 inhibitor associated with less treatment-related myelosuppression that has the potential to fill these unmet treatment needs. Areas covered: This review will describe the preclinical rationale for JAK2/FLT3 inhibition, review the pharmacology of pacritinib, and detail available clinical data for pacritinib treatment of myelofibrosis. The circumstances surrounding the full clinical hold temporarily placed on pacritinib will also be explored. Expert commentary: Pacritinib has demonstrated promising results in patients with myelofibrosis and thrombocytopenia. Improvements in splenomegaly and symptom burden were observed with the 200 mg twice-daily dose in PERSIST-2, including those with platelet counts <50,000 mm. Safety concerns pertaining to cardiovascular events and bleeding that arose in an early analysis of PERSIST-2 were likely related to the advanced disease state enrolled rather than clear attribution to pacritinib. The results of an ongoing dose-finding, phase II study are eagerly awaited in order to move this promising myelofibrosis therapy forward.

Simultaneous determination of paeonilactone A and paeonilactone B in rat plasma after oral administration of albiflorin by UPLC/TOF/MS following picolinoyl derivatization.

A new highly sensitive analytical method was developed to investigate the in vivo metabolism of albiflorin, one of the most principal components in traditional Chinese medicine. After hydrolyzation with sulfatase, the main metabolites paeonilactone A and paeonilactone B of paeoniflorin in rat plasma were successfully detected for the first time by liquid chromatography mass spectrometry following picolinoyl derivatization. Borneol was used as the internal standard compound to quantify paeonilactone A and paeonilactone B in rat plasma. Paeonilactone A and paeonilactone B show different pharmacokinetic behaviors. The maximum plasma concentration of paeonilactone A reached 36.4±5.6ng/mL at about 8h after oral administration of albiflorin at a dose of 5mg/kg, while the maximum plasma concentration of paeonilactone B reached 12.4±3.4ng/mL at about 2h. The total metabolic pathway of albiflorin in rats was proposed. Albiflorin was found to be metabolized to the sulfate of paeonilactone A and paeonilactone B which may be responsible for the biological effect of albiflorin. The new analytical method may help to elucidate the clinical efficacy of traditional Chinese formula containing albiflorin.

De-escalating and escalating systemic therapy in triple negative breast cancer.

Triple negative breast cancer has the highest relapse risk of all the clinical subsets, although the escalation of chemotherapy has benefited this subset substantially over recent years. Systemic options are limited to chemotherapy, which makes meaningful de-escalation or escalation of therapy more challenging but possible. Observational cohorts suggest a less than 10% risk of relapse and minimal if any benefit of chemotherapy in very small (<1 cm), node-negative triple negative disease. In higher risk, particularly node-positive disease, anthracycline/taxane-based regimens remain standard. Neoadjuvant chemotherapy clearly de-escalates surgery, although there are insufficient data to give less than standard chemotherapy on the basis of response to neoadjuvant therapy. Efforts to meaningfully escalate therapy in high-risk disease have included incorporating platinums into Neoadjuvant therapy, with clear benefit in pCR but uncertain impact on relapse and survival at this time. Residual disease after neoadjuvant chemotherapy carries a particularly poor prognosis; a recent randomized trial of 6 months' capecitabine in this setting suggested a survival advantage to this approach in higher risk residual disease. While not validated at this time, future directions are likely to include biologic prognostication with tumor and immune variables, as well as targeted non-cytotoxic approaches leveraging the molecular heterogeneity of triple negative disease.

Treatment Patterns and Overall Survival Associated with First-Line Systemic Therapy for Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: A variety of regimens are used as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC), which may include combination regimens and single agents, depending on histology, molecular profile, and performance status. OBJECTIVE: To describe the types of first-line therapies and compare overall survival between therapies used for patients with advanced NSCLC in an integrated health care system. METHODS: This retrospective cohort study included patients aged 18 years or older from Kaiser Permanente California with a diagnosis of stage IIIB/IV NSCLC. First systemic treatment date occurred from January 1, 2008, through September 30, 2013. Overall survival was measured as the number of months from initial treatment until death, end of enrollment, or September 30, 2014. Treatment regimens were categorized into 6 mutually exclusive groups: platinum doublets; pemetrexed-based, bevacizumab-based, and pemetrexed + bevacizumab-based combinations; singlets; and tyrosine-kinase inhibitors (TKIs). Survival was compared using Kaplan-Meier curves and adjusted Cox proportional hazard models. Subgroup analyses were performed by age group and by nonsquamous histology. RESULTS: Of 2,081 patients, approximately half (52.3%) received platinum doublets, followed by TKIs (19.0%), pemetrexed-based regimens (13.4%), bevacizumab-regimens (8.0%), singlets (5.5%), and pemetrexed + bevacizumab-based combinations (1.8%). Median survival was longest for pemetrexed + bevacizumab-based combinations (18.5 months), followed by bevacizumab-based regimens (14.5), TKIs (12.7), pemetrexed-based regimens (10.4), doublets (9.2), and singlets (5.3). There was a significantly reduced risk of mortality for pemetrexed + bevacizumab-based combinations (HR = 0.64; 95% CI = 0.42-0.94) and TKIs (HR = 0.83; 95% CI = 0.73-0.94) compared with doublets. Singlets were associated with an increased risk of mortality (HR = 1.50; 95% CI = 1.22-1.84). Subgroup analysis among patients aged 65 years and over found no significant differences among treatment groups, with the exception of singlets, which were associated with an increased risk of mortality compared with doublets (HR = 1.51; 95% CI = 1.20-1.90). Among patients under aged 65 years, pemetrexed + bevacizumab-based combinations (HR = 0.36; 95% CI = 0.21-0.64) and TKIs (HR = 0.76; 95% CI = 0.59-0.97) were associated with a reduced risk of mortality, and singlets were associated with an increased risk (HR = 1.85; 95% CI = 1.17-2.92). CONCLUSIONS: In this cohort of patients with advanced NSCLC, patients received a platinum agent with or without bevacizumab or pemetrexed, a TKI, or a single agent. Younger patients (aged < 65 years) receiving bevacizumab + pemetrexed-based combinations had a survival advantage over those receiving platinum doublets, and this finding merits further investigation. Younger patients receiving TKIs also had longer survival. Compared with platinum doublets, we found no survival advantage for older patients receiving bevacizumab or pemetrexed, which suggests that combination therapy of a platinum agent and taxane, such as carboplatin and paclitaxel, could be a reasonable option for older patients who are not candidates for targeted therapy. DISCLOSURES: No outside funding supported this study. Rashid has received past funding from Bristol-Myers Squibb, Astellas, Novartis, and Pfizer. No other authors report any potential financial conflicts of interest. Study concept and design were primarily contributed by Spence and Hui, with input from the other authors. Hui, Spence, and Rashid took the lead in data collection, and data interpretation was performed by Schottinger, Millares, and Spence, assisted by the other authors. The manuscript was written primarily by Spence, along with Chang, and revised by Spence, with input from the other authors.

Anti-PTSD-like effects of albiflorin extracted from Radix paeoniae Alba.

ETHNOPHARMACOLOGY RELEVANCE: Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder that is characterized by symptoms of re-experiencing, avoidance and hyperarousal, as well as social and professional dysfunction at least one month after the exposure to a traumatic event. Biosynthesis of allopregnanolone has been suggested as one of the important contributors to PTSD. Albiflorin (AF) extracted from Radix paeoniae Alba had been shown to be effective in the therapy of depression. However, few studies were concerned about the anti-PTSD-like effects of AF. AIM OF THE STUDY: The current study aimed to evaluate the anti-PTSD-like effects of AF in an animal model and its possible mechanism. MATERIALS AND METHODS: To evaluate this, the single prolonged stress (SPS) model was used in the present study. The SPS rats were administered by AF (at doses of 3.5, 7 and 14.0mg/kg, i.g.) after induction of SPS from days 2-13. After the exposure to SPS, behavioral assessments were conducted, including contextual fear paradigm (CFP), elevated plus-maze test (EPMT), open-field test (OFT). The rats were decapitated at the end of the behavioral tests and levels of allopregnanolone in prefrontal cortex, hippocampus and amygdala were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: It had been shown that behavioral deficits of SPS rats were reversed by AF (7.0 and 14.0mg/kg, i.g.), which attenuated the PTSD-like associated contextual freezing behavior in CFP and improved PTSD-like associated anxiogenic behavior in EPMT without affecting locomotor activity in OFT. Moreover, decreased levels of allopregnanolone in prefrontal cortex, hippocampus, and amygdala were reversed by AF (7.0 and 14.0mg/kg, i.g.), respectively. CONCLUSION: In summary, the present study indicated that AF exerted the anti-PTSD-like effects, which maybe associated with allopregnanolone biosynthesis in the brain.

Protective effects of paeoniflorin and albiflorin on chemotherapy-induced myelosuppression in mice.

Paeonia lactiflora root (baishao in Chinese) is a commonly used herb in traditional Chinese medicines (TCM). Two isomers, paeoniflorin (PF) and albiflorin (AF), are isolated from P. lactiflora. The present study aimed to investigate the protective effects of PF and AF on myelosuppression induced by chemotherapy in mice and to explore the underlying mechanisms. The mouse myelosuppression model was established by intraperitoneal (i.p.) injection of cyclophosphamide (CP, 200 mg·kg(-1)). The blood cell counts were performed. The thymus index and spleen index were also determined and bone morrow histological examination was performed. The levels of tumor necrosis factor-α (TNF-α) in serum and colony-stimulating factor (G-CSF) in plasma were measured by Enzyme-Linked Immunosorbent Assays (ELISA) and the serum levels of interleukin-3 (IL-3), granulocyte-macrophagecolony-stimulatingfactor (GM-CSF), and interleukin-6 (IL-6) were measured by radioimmunoassay (RIA). The levels of mRNA expression protein of IL-3, GM-CSF and G-CSF in spleen and bone marrow cells were determined respectively. PF and AF significantly increased the white blood cell (WBC) counts and reversed the atrophy of thymus. They also increased the serum levels of GM-CSF and IL-3 and the plasma level of G-CSF and reduced the level of TNF-α in serum. PF enhanced the mRNA level of IL-3 and AF enhanced the mRNA levels of GM-CSF and G-CSF in the spleen. PF and AF both increased the protein levels of GM-CSF and G-CSF in bone marrow cells. In conclusion, our results demonstrated that PF and AF promoted the recovery of bone marrow hemopoietic function in the mouse myelosuppression model.

Enhancement of Exposure and Reduction of Elimination for Paeoniflorin or Albiflorin via Co-Administration with Total Peony Glucosides and Hypoxic Pharmacokinetics Comparison.

There is evidence suggesting that herbal extracts demonstrate greater bioactivities than their isolated constituents at an equivalent dose. This phenomenon could be attributed to the absence of interacting substances present in the extracts. By measuring the pharmacokinetic parameters of paeoniflorin (PF) and albiflorin (AF) after being orally administered to rats in isolated form, in combination with each other and within total peony glucosides (TPG), respectively, the current study aimed to identify positive pharmacokinetic interactions between components of peony radix extracts. Moreover, the pharmacokinetic profiles of PF and AF under normoxia and hypoxia were also investigated and compared. In order to achieve these goals, a highly sensitive and reproducible ultra-peformance liquid chromatography-mass spectrometry (UPLC-MS) method was developed and validated for simultaneously quantitation of PF and AF in rat plasma. This study found that compared with that of single component (PF/AF), the exposure of PF in rat plasma after combination administration or TPG administration was significantly increased, meanwhile the elimination of PF/AF was remarkably reduced. It was also noticed that AUC and Cmax of PF in hypoxia rats were significantly decreased compared with that of normaxia rats, suggesting that there was a decreased exposure of PF in rats under hypoxia. The current study, for the first time, revealed the pharmacokinetic interactions between PF/AF and other constitutes in TGP and the pharmacokinetic profiles of PF and AF under hypoxia. In view of the current findings, it could be supposed that the clinical performance of total peony glucosides would be better than that of single constitute (PF/AF). The outcomes of this animal study are expected to serve as a basis for development of clinical guidelines on total peony glucosides usage.

A Combination of Cisplatin and 5-Fluorouracil With a Taxane in Patients Who Underwent Lymph Node Dissection for Nodal Metastases From Squamous Cell Carcinoma of the Penis: Treatment Outcome and Survival Analyses in Neoadjuvant and Adjuvant Settings.

BACKGROUND: The role of chemotherapy in nodal metastases from penile squamous cell carcinoma is not defined. We evaluated the efficacy of a combination of T-PF (a taxane, cisplatin, and 5-fluorouracil) in neoadjuvant and adjuvant settings. PATIENTS AND METHODS: Since June of 2004, T-PF was administered to stage N2 to 3 patients. With time, neoadjuvant chemotherapy administration prevailed with respect to use in the adjuvant setting. Primary end points were progression-free (PFS) and overall (OS) survival. Secondary objectives were tolerability and activity in the neoadjuvant setting. Nonparametric tests, Kaplan-Meier, and regression analyses were performed. RESULTS: As of October of 2012, 47 consecutive N2 to 3 M0 patients had undergone neoadjuvant (n = 28) or adjuvant (n = 19) T-PF: 18 patients (38.3%) remain disease-free after a median follow-up of 22 months (interquartile range, 17-42 months). The 2-year disease-free survivals were 36.8% (95% confidence interval [CI], 15.2-58.5) versus 7.1% (95% CI, 0-16.7) after adjuvant and neoadjuvant therapy, respectively. N3 metastases were associated with a poorer PFS, and bilateral metastases and mutated p53 were associated with a poorer OS. After neoadjuvant treatment, 43% clinical responses and 14% complete pathologic remissions were recorded, but responses were not associated with survival. Neutropenia (25.5%) was the most frequent Grade ≥ 2 toxicity. CONCLUSION: The T-PF regimen is well tolerated and compares with other regimens in terms of activity and efficacy in the neoadjuvant setting, and very long survivals have been recorded after adjuvant administration. The role of perioperative treatment in these patients remains controversial. Some caution in administering preemptive treatment in patients with resectable disease is needed.

Effectiveness of an Adjuvant Chemotherapy Regimen for Early-Stage Breast Cancer: A Systematic Review and Network Meta-analysis.

IMPORTANCE: Different adjuvant chemotherapy regimens are available for early-stage breast cancer. Because conventional meta-analysis does not allow comparing all regimens, we performed a network meta-analysis to identify the most effective adjuvant chemotherapy regimen. OBJECTIVE: To find the most effective adjuvant therapy regimen for early-stage breast cancer. DATA SOURCES: We searched MEDLINE, Embase, and the Cochrane Library for articles published before June 2015; the American Society of Clinical Oncology annual meeting abstracts from January 1983 through December 2014; and the American Association for Cancer Research annual meeting abstracts from January 1916 through December 2014. Additionally, we manually searched bibliographies for related references. STUDY SELECTION: We included randomized clinical trials of adjuvant treatments for early-stage breast cancer that compared 2 or more of the following: no adjuvant chemotherapy; sequential anthracycline-cyclophosphamide and taxane (AC-T); concurrent anthracycline-cyclophosphamide and taxane (ACT); anthracycline-cyclophosphamide without taxane (AC); docetaxel and cyclophosphamide (TC); cyclophosphamide, methotrexate, and fluorouracil (CMF); and platinum-containing regimens. DATA EXTRACTION AND SYNTHESIS: We followed the PRISMA guidelines. Two investigators independently selected the articles and extracted information. Disagreements were resolved by discussion with another author. Quality was assessed by Cochrane risk-of-bias method. Data were pooled using random-effects models. MAIN OUTCOMES AND MEASURES: We used network meta-analysis to test the most effective adjuvant therapy regimen in terms of overall survival (OS) by comparing regimens listed in the National Comprehensive Cancer Network guidelines and platinum-containing regimens. RESULTS: We identified 24 trials. The TC and platinum-containing regimens had OS benefit similar to that of sequential AC-T (TC hazard ratio [HR], 0.93; 95% CI, 0.62-1.40; and platinum HR, 0.93; 95% CI, 0.66-1.31). Patients treated with CMF or AC had significantly worse OS than those treated with sequential AC-T (CMF HR, 1.56; 95% CI, 1.32-1.85; and AC HR, 1.22; 95% CI, 1.10-1.37). Platinum-containing regimens tended to be more toxic than sequential AC-T. The toxicity of TC was similar to or less than that of sequential AC-T. Meta-regression analysis showed that hormone receptor status did not impact the HRs for OS for any regimen. CONCLUSIONS AND RELEVANCE: Sequential AC-T is likely to be the most effective adjuvant therapy regimen for early-stage breast cancer regardless of hormone receptor status.

Defining optimal duration and predicting benefit from chemotherapy in patients with luminal-like subtypes.

The molecular subtypes of breast cancer have individual patterns of behaviour, prognosis and sensitivity to treatment, with subsequent implications for the choice of, or indeed role for adjuvant therapy. The luminal A and B subtypes make up the majority of breast cancers, but despite sharing expression of the oestrogen receptor (ER), they are molecularly distinct. It follows then that they would have different sensitivities to chemotherapy. Clinically, luminal A disease has a better prognosis than luminal B, and may not derive significant benefit from adjuvant chemotherapy. However no prospective trials have specifically investigated the benefit of adjuvant chemotherapy in each subtype, nor do we know if certain agents are more or less effective. This paper will briefly summarise the role of molecular profiles in assessing the need for chemotherapy and predicting its effectiveness, followed by an assessment of the relative value of newer anthracycline- or taxane-containing regimes in the luminal-like subtypes, providing a review of retrospective analyses.

Pharmacokinetic synergy from the taxane extract of Taxus chinensis improves the bioavailability of paclitaxel.

BACKGROUND: Taxus chinensis (Pilger) Rehd is widely distributed in China and the northern hemisphere, and the most popular medicinal component isolated from Taxus chinensis is paclitaxel (PTX), which has now become the first-line chemotherapeutic drug for breast cancer and ovarian cancer. Oral administration of pure PTX as a potential anti-cancer agent is compromised by low bioavailability. HYPOTHESIS/PURPOSE: In the clinical practice of traditional Chinese medicine, drug co-administration in the form of mixtures or formula could achieve pharmacokinetic/pharmacodynamic synergies. In this study, we aimed to investigate whether there exist any 'inherent' phytochemical synergy from Taxus chinensis extract that could improve PTX bioavailability. STUDY DESIGN: Pharmacokinetic study of PTX after oral administration of Taxus chinensis extracts or single PTX was performed. In addition, comparative cytotoxic studies were carried out on the MCF-7 breast cancer cell lines. METHODS: The plasma concentrations of PTX were determined using a validated high performance chromatography tandem mass spectrometry method. The cytotoxicity was compared using the MTT assay. RESULTS: Oral administration of taxane fractions isolated from Taxus chinensis (containing 17.2% PTX) could achieve remarkably higher blood concentration and systemic exposure of PTX in rats, while the retention of PTX was significantly improved. Further tissue distribution analysis revealed that the penetration of PTX into major tissues was drastically increased compared with that of single PTX. In addition, in MCF-7 cells, the co-existing components in taxane mixtures could strengthen the inhibitory effects of PTX on tumor cell proliferation. CONCLUSION: Together, these results support that administration of PTX in the form of taxane mixtures may become a novel approach to improve the poor bioavailability of PTX. Moreover, the inherent synergy from Taxus chinensis taxane extracts promises a novel strategy to strengthen PTX efficacy.

Low FOXA1 expression predicts good response to neo-adjuvant chemotherapy resulting in good outcomes for luminal HER2-negative breast cancer cases.

BACKGROUND: FOXA1 expression is a good prognostic marker for endocrine therapy in hormone-positive breast cancer. We retrospectively examined breast cancer patients with luminal human epidermal growth factor receptor 2 (HER2)-negative tumours, as defined by immunohistochemistry, who received neo-adjuvant chemotherapy (NAC) and investigated the relationship between treatment effects and FOXA1 expression. METHODS: Biopsy specimens from 103 luminal HER2-negative tumours were immunohistochemically examined. FOXA1 effects on chemo-sensitivity were also investigated employing in vitro experiments. RESULTS: FOXA1 and Ki67 expressions independently predicted a pathological complete response (pCR). Knockdown of FOXA1 by siRNA boosted the chemo-effect in oestrogen receptor-positive cells. The Cox hazards model revealed a pCR to be the strongest factor predicting a good patient outcome. CONCLUSIONS: Our present study showed low FOXA1 expression to be associated with a good response to NAC in luminal HER2-negative breast cancer. Improved outcomes of these patients suggest that NAC should be recommended to patients with low FOXA1 tumours.

Comparison of patient reported quality of life and impact of treatment side effects experienced with a taxane-containing regimen and standard anthracycline based chemotherapy for early breast cancer: 6 year results from the UK TACT trial (CRUK/01/001).

BACKGROUND: The TACT trial (CRUK/01/001) compared adjuvant sequential FEC-docetaxel (FEC-D) chemotherapy with standard anthracycline-based chemotherapy of similar duration in women with early breast cancer. Results at a median of 5 years suggested no improvement in disease-free survival with FEC-D. Given differing toxicity profiles of the regimens, the impact on quality of life (QL) was explored. METHODS: Patients from 44 centres completed standardised QL questionnaires before chemotherapy, after cycles 4 and 8, at 9, 12, 18 and 24 months and at 6 years follow-up. Patient diaries assessed frequency, associated distress and impact on daily activity of 15 treatment related side effects. FINDINGS: 830 patients (415 FEC-D; 415 controls) contributed assessments during 0-24 months; 362 of whom participated again at 6 years. During chemotherapy, FEC-D impaired global health/QL and depression rates and significantly more QL domains than standard regimens. Novel diary card ratings highlighted significantly more distress and interference with daily activities due to FEC-D side effects compared with standard treatment. In both groups, most QL parameters returned to baseline levels by 2 years and were unchanged at 6 years. INTERPRETATION: Within expected negative effects of chemotherapy on wide ranging QL domains FEC-D patients reported greater toxicity, disruption and distress during treatment with no improvement in disease outcome at 5 years than patients receiving standard anthracycline-based chemotherapy. Findings should inform future patients of relative costs and benefits of adjuvant chemotherapy.

[Study on rational daily administration frequency of Fufang Biejia Ruangan tablet based on integrated serum pharmacologic and pharmacokinetic model].

To observe in vitro the effect of rat drug serum on the proliferation of HSC-T6 hepatic stellate cells in the pharmacokinetic model for determining peoniflorin in Fufang Biejia Ruangan tablet, in order to discover the rational daily administration frequency of Fufang Biejia Ruangan tablet. Fufang Biejia Ruangan tablet was orally administered to rats with different daily administration frequency. Their blood was collected from veins behind eye sockets at different time points before the administration and after the first administration, in order to determine the concentration of peoniflorin in blood plasma and the effect of rat drug serums on the proliferation of HSC-T6. A comprehensive analysis was made on the relationship between pharmacodynamics and pharmacokinetics to determine the rational daily administration frequency of Fufang Biejia Ruangan tablet. The results showed a good correlation between the inhibitory effect of Fufang Biejia Ruangan tablet-contained serum on HSC-T6 and the concentration of peoniflorin in blood. The two-time administration group showed higher pharmacologic and pharmacokinetic AUCs than one-time administration and three-time administration groups. In conclusion, Fufang Biejia Ruangan table is recommended to be taken twice a day for treating liver fibrosis in chronic hepatitis.

Survival impact of complete cytoreduction to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis.

OBJECTIVE: To quantify the impact of complete cytoreduction to no gross residual disease on overall survival among patients with advanced-stage ovarian cancer treated during the platinum-taxane era. METHODS: PubMed and Cochrane Library databases were searched for all articles on primary cytoreductive surgery for advanced-stage ovarian cancer published from 1/1996 to 7/2011. A total of 18 relevant studies (13,257 patients) were identified for analysis. Simple and multiple linear regression analyses, with weighted correlation calculations, were used to assess the effect on median survival time of clinical and treatment-related factors. RESULTS: The mean weighted median overall survival time for all cohorts was 44.4 months (range, 27.6-66.9 months). Simple linear regression analysis revealed that residual disease, stage IV disease, and use of intraperitoneal chemotherapy were significantly associated with median survival time. After controlling for other factors on multiple linear regression analysis, each 10% increase in the proportion of patients undergoing complete cytoreduction to no gross residual disease was associated with a significant and independent 2.3-month increase (95%CI = 0.6-4.0, p = 0.011) in cohort median survival compared to a 1.8-month increase (95%CI = 0.6-3.0, p = 0.004) in cohort median survival for optimal cytoreduction (residual disease≤1cm). Each 10% increase in the proportion of patients receiving intraperitoneal chemotherapy was associated with a significant and independent 3.9-month increase (95%CI = 1.1-6.8, p=0.008) in median cohort survival time. CONCLUSIONS: For advanced-stage ovarian cancer treated during the platinum-taxane era, the proportions of patients left with no gross residual disease and receiving intraperitoneal chemotherapy are independently significant factors associated with the most favorable cohort survival time.

Neo-adjuvant chemotherapy in advanced hypopharyngeal carcinoma.

OBJECTIVE: The aim of this retrospective study was to find out the role of neo-adjuvant chemotherapy (NACT) in changing the management and outcome of advanced hypopharyngeal cancer patients. MATERIALS AND METHODS: This is a retrospective analysis of 59 treatment naïve, advanced hypopharyngeal cancer patients presenting to our tertiary care center from April 2010 to October 2011. NACT was given as two (platinum with taxane) or three drug with (platinum, taxane with 5-flurouracil [5 FU]) as 3 weekly regimen with cisplatin and docetaxel as 75 mg/m 2 each, 5-FU as 1000 mg/m 2 . NACT was either given with the intent of achieving: (1) surgical resection (extensive soft tissue disease, oropharyngeal involvement, extensive disease with cartilage erosion) or (2) organ preservation (Bulky disease with inner cartilage erosion, exolaryngeal disease without cartilage erosion, large N3 nodes). RESULTS: The mean age of this population was 55 years. Most (83%) of the patients had pyriform sinus (PFS) involvement. 69% patients had Stage IVa disease, 21% Stage IVb and 10% Stage III. The overall response rate was 66%, including 06% complete responses and 60% partial responses. Following NACT, resectability was achieved in 30% (10/33) and organ preservation protocol was planned after NACT in 73% (19/26) patients. The main toxicities were neutropenia (grade 3, 4, 04%; febrile neutropenia, 4%), mucositis 5%, diarrhea 5%. The median progression free survival was 20 months. CONCLUSIONS: NACT can be useful in patients with oropharyngeal involvement to achieve surgical resection and larynx preservation in patients with bulky T3 disease.

Pharmacokinetic study of multiple active constituents after oral gavage of Guizhi decoction in rats using a LC-MS/MS method.

Guizhi decoction (GZD) is a classic traditional Chinese medicine formula, clinically used for the treatment of influenza, common cold, and other pyretic conditions. A sensitive, specific, and validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed to investigate the pharmacokinetic properties of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid in rat. After single dose oral administration of 7.9 g extract/kg body weight GZD in rats, plasma concentrations of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid were measured by LC-MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration-time data. The values of AUC0-t, half-life (t 1/2), and C max were 7.2 ± 2.3 µg h/mL, 1.2 ± 0.3 h, and 9.2 ± 5.2 µg/mL for cinnamic acid, 53 ± 31 µg h/mL, 2.8 ± 2.0 h, and 17 ± 3 µg/mL for hippuric acid, 1.1 ± 0.5 µg h/mL, 1.9 ± 1.1 h, and 0.6 ± 0.3 µg/mL for paeoniflorin, and 11 ± 6 µg h/mL, 6.6 ± 2.5 h, and 0.9 ± 0.6 µg/mL for glycyrrhetic acid, respectively. The results would offer useful information for effective components of GZD in vivo.

Hypofractionated palliative radiotherapy for advanced head and neck cancer: the IHF2SQ regimen.

BACKGROUND: Standard treatment for unresectable advanced head and neck squamous cell carcinoma is chemoradiotherapy, which can be toxic, particularly among patients with coexisting medical conditions. We report our experience with the hypofractionated radiotherapy regimen Irradiation HypoFractionnée 2 Séances Quotidiennes (IHF2SQ). METHODS: We retrospectively reviewed 78 patients treated with the IHF2SQ regimen. Radiotherapy was administrated as 2 fractions of 3 Gy per day (days 1 and 3), during the first, third, fifth, and seventh week of treatment with concurrent platinum-based chemotherapy. RESULTS: Tolerance was excellent. Forty-one patients had complete or partial response. Median overall survival (OS) was 12.9 months and median progression-free survival (PFS) was 10.3 months. One-year OS, specific survival (SS), and PFS were 58%, 71%, 51.5%, respectively. Independent predictive factors increasing the PFS were response to chemoradiotherapy, male sex, and laryngeal tumor location. CONCLUSIONS: This regimen is an alternative to conventional chemoradiotherapy with good response rates and acceptable toxicity for selected patients.