Vectorized gene therapy of liver tumors: proof-of-concept of TG4023 (MVA-FCU1) in combination with flucytosine

BackgroundTG4023 is a modified vaccinia virus Ankara (MVA) containing the yeast-originated transgene FCU1, expressing cytosine deaminase and uracil phosphoribosyltransferase enzymes that transform the prodrug flucytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) and 5-fluorouridine-5′-monophosphate, respectively. This first-in-human study aimed to assess the maximum tolerated dose (MTD) of intratumoral (IT) TG4023 and the safety, feasibility, and proof-of-concept (PoC) of TG4023/5-FC combination to deliver high 5-FU concentrations in tumors.Patients and methodsCancer patients without further therapeutic option and with at least one injectable primary or metastatic liver tumor underwent on day 1 a percutaneous IT injection of TG4023 at doses of 10⁷, 10⁸, or 4.10⁸ plaque forming units (p.f.u.) using ultrasound imaging guidance, after a dose-limiting toxicities (DLTs)-driven 3 + 3 dose-escalating design. On day 2, patients were given intravenous and/or oral 5-FC at a dose of 200 mg/kg/day for 14 days and were followed for safety through day 43. Tumor response was assessed at week 6, according to RECIST. Plasma and tumor 5-FU concentrations were measured to establish the PoC.ResultsIn total, 16 patients completed treatment with TG4023 and 5-FC. One DLT/7 patients (ALT/aspartate aminotransferase transient increase) was observed at 4 × 10⁸ p.f.u.; MTD was therefore not reached. The most frequent adverse events were pyrexia, asthenia, vomiting, and decreased appetite. Eight of 16 patients had stable disease. Mean 5-FU concentrations in plasma were 1.9 ± 2.6 ng/ml and 56 ± 30 ng/g in tumors. Seroconversion for anti-FCU1 antibodies was found for one patient from each cohort (16%, overall).ConclusionsThis phase I study demonstrated that IT injections of TG4023 were feasible and well tolerated; MTD was defined as 4 × 10⁸ p.f.u. Therapeutic 5-FU concentrations in tumors established the virus-directed enzyme-prodrug therapy PoC.ClinicalTrials.gov NumberNCT00978107.     

Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group

AimPatients with metastatic osteosarcoma (OS) have a poor outcome with conventional therapies. Zoledronic acid (ZA) is a third-generation bisphosphonate that reduces skeletal-related events in many adult cancers, and pre-clinical data suggest a possible benefit in OS. This study assessed the maximum tolerated dose (MTD) and the feasibility of ZA when combined with chemotherapy in patients with metastatic OS.Patients and MethodsPatients with a histological diagnosis of OS were eligible if they were <40 years of age, had initially metastatic disease and met organ function requirements. Treatment combined surgery and a conventional chemotherapy regimen. ZA was given concurrent with chemotherapy for a total of eight doses over 36 weeks. Three dose levels of ZA were tested: 1.2 mg/m² [max 2 mg], 2.3 mg/m² [max 4 mg] and 3.5 mg/m² [max 6 mg]. The MTD was determined during induction. Six patients were to be treated at each dose level, with an additional six patients treated with the MTD to help assess post-induction feasibility.ResultsTwenty-four patients (median age 13.5 years [range, 7–22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5 mg/m². DLTs included hypophosphatemia, hypokalemia, hyponatremia, mucositis, limb pain and limb oedema. There were no reports of excessive renal toxicity or osteonecrosis of the jaw. The MTD was defined as 2.3 mg/m² (max 4 mg).ConclusionsZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m² (max 4 mg) for patients with metastatic osteosarcoma.     

The use of health services among elderly patients with stage IV prostate cancer in the initial period following diagnosis

ObjectiveInformation regarding variability in the type and extent of health services used by elderly patients with advanced prostate cancer (PCa) in the initial period following diagnosis is limited. We evaluated health services utilization among elderly men with stage IV PCa with (M1) and without (M0) distant metastasis during the year following diagnosis.MethodsWe evaluated patients aged 66 and older with incident stage IV PCa during 2005–2007 using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Measures included skilled nursing facility (SNF) stay, hospice stay, and hospitalization. Multivariable logistic regression models were estimated to determine the association between M1 PCa and each health service. Poisson regression was used to assess hospital length of stay.ResultsThe final sample included 3379 patients (20% M0; 80% M1). In the year following diagnosis, M1 patients had greater use of SNF (M0: 8%; M1: 22%), hospice (M0: 5%; M1: 20%), and hospitalization (M0: 43%; M1: 61%). Compared to M0 patients, M1 patients had statistically significantly higher adjusted odds of SNF use (OR = 1.89; 95% CI = 1.38–2.59), hospice use (OR = 3.22; 95% CI = 2.19–4.72), and hospitalization (OR = 1.45; 95% CI = 1.20–1.75). Among those hospitalized, M1 patients had 24% longer length of stay (p < 0.01).ConclusionsThere is 2- to 3-fold greater use of SNF and hospice, and higher hospitalization among M1 compared to M0 patients. Elderly patients with advanced PCa face significant clinical burden within the first year after their diagnosis. Greater understanding of the relationship between clinical disease burden and health services utilization can improve healthcare delivery in this population.     

A phase I/II study of lenalidomide in combination with sunitinib in patients with advanced or metastatic renal cell carcinoma

BackgroundThis phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide plus sunitinib in metastatic renal cell carcinoma (RCC) patients.Patients and methodsPatients with histologically confirmed, metastatic RCC were treated with 10 mg/day lenalidomide plus 37.5 mg/day sunitinib, orally in 21-day cycles. Doses were escalated to determine the MTD in phase I, with additional patients planned at this dose in phase II. Primary end points were MTD and response rate.ResultsSixteen patients received a median of 2, 3, and 5 cycles in cohort 1 [lenalidomide 10 mg (days 1–21) and sunitinib 37.5 mg (days 1–21)], cohort 2 [lenalidomide 10 mg (days 1–21) and sunitinib 37.5 mg (days 1–14)], and cohort 3 [lenalidomide 15 mg (days 1–21) and sunitinib 37.5 mg (days 1–14)], respectively. Median treatment durations were 41, 63, and 97 days for lenalidomide; and 41, 57, and 97.5 days for sunitinib. The MTD was found to be continuous dosing of lenalidomide 10 mg/day plus sunitinib 37.5 mg/day for 14 of 21 days. Dose-limiting toxicities included neutropenia, leukopenia, thrombocytopenia, asthenia, atrial fibrillation, and increased transaminases. The most frequent grade 3–4 treatment-emergent adverse events were hematologic, including neutropenia and leukopenia. One patient achieved partial response, and seven had stable disease of which three were confirmed at subsequent tumor assessments. B cells and several T-cell subsets were modulated versus baseline.ConclusionThe dose schedules of lenalidomide and sunitinib evaluated in this study were not well tolerated; cumulative toxicity precluded enrollment at the MTD.     

Comparison of risk and predictors for early radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with radiotherapy with or without surgery

ObjectivesTo investigate risk and predictors for radiation pneumonitis (RP) and tolerance of lung to radiation in patients treated with thoracic radiotherapy (RT) with or without surgery.Methods and materialsA total of 433 consecutive patients with locally advanced non-small cell lung cancer were followed after three-dimensional conformal radiotherapy. Among them 284 received RT without surgical intervention and 149 received postoperative radiotherapy (PORT). RP was graded according to Common Terminology Criteria for Adverse Events version 4.0.ResultsThe rate of grade ≥2 and grade ≥3 RP was 50 and 16% in the PORT group compared with 38 and 9% in the non-surgical group (p < 0.05 for each comparison). The lung volume was significantly smaller in PORT group than in no-surgical group (3181 ± 915 cm³ vs. 4010 ± 1120 cm³, p < 0.05). Age, chemotherapy, mean lung dose (MLD) and planning target volume (PTV) were predictors of RP for both non-surgical group and PORT group. Mean heart dose (MHD) predicted RP in PORT group only (OR = 1.28, p = 0.003). Among patients who developed RP, V20, MLD, and MHD were significantly lower in PORT group than in no-surgical group (p < 0.05 for each comparison).ConclusionsExcept MHD predicting RP in PORT group only, most of predictors for RP were consistent in patients treated with RT with or without surgery. Patients receiving PORT had a higher risk of RP than patients receiving RT without surgery did, possibly due to decreased lung volume and lower tolerance of lung to chemoradiotherapy.     

Parcours de soins en fin de vie des patients suivis en soins palliatifs à Strasbourg : étude rétrospective

ObjectivesThe goal of palliative care is to relieve suffering and provide the best possible quality of life for patients and their families. We looked for individual factors related to a poor-quality end-of-life pathway in patients followed in palliative care.MethodsWe included all the patients followed in palliative care in Strasbourg deceased from October to December of 2020. We retrospectively collected data about these patients, their first contact with palliative care, their care pathway, and their death. Multivariate analysis was undertaken.ResultsIn total, 116 patients were included. Seventy-nine of them had cancer. At the end of life, people living in an institution were less likely to be admitted to the emergency department (OR = 0.06), as were non-communicative patients (OR = 0.08). Patients expressing a wish to die at home were less likely to be admitted to and die in an intensive care unit (OR = 0.1). Isolated patients and non-communicative patients appeared protected from aggressive treatment (chemotherapy/immunotherapy, dialysis, orotracheal intubation, cardiopulmonary resuscitation) during the last month of life (OR = 0.1, OR = 0.05).DiscussionOur study suggests a profile of patients less exposed to invasive or unreasonable care at the end of life. It leads us to pay particular attention to young subjects, with family, living at home. In our population followed in palliative care, exposure to aggressive care at the end of life appeared to be very low compared to that observed in similar studies with other populations.     

Active and passive cigarette smoking and the risk of endometrial cancer in Poland

BackgroundEpidemiological studies have consistently reported that active cigarette smoking is inversely associated with endometrial cancer risk. However, dose-response relationships with quantitative measures of active smoking or passive smoking remain less clear.MethodsData on lifetime active and passive smoking were collected for 551 endometrial cancer cases and 1925 controls in a population-based case-control study conducted during 2001–2003 in Poland (Warsaw and ?ódz).ResultsCompared with never active smokers, active current (Odds Ratio (OR) = 0.51, 95% Confidence Interval (CI): 0.39, 0.68) and former smokers (OR = 0.60, 95% CI: 0.45, 0.80) were at a statistically significantly decreased risk. We did not observe statistically significant inverse dose-response relationships with increasing exposure with duration and cumulative measures. However, there was some indication that the highest category of number of years (OR = 0.35, 95% CI: 0.23–0.55), intensity (OR = 0.41, 95% CI: 0.24–0.69), and dose (OR = 0.38, 95% CI: 0.24–0.60) of smoking among current smokers had the greatest inverse association compared to never smokers. Our data did not support the presence of an inverse association with passive smoking among never active smokers (OR = 0.92; 95% CI: 0.65, 1.29).ConclusionOur results support that long-term and heavy smoking among current smokers strongly influence endometrial cancer risk.     

I125 irradiation stent for treatment of hepatocellular carcinoma with portal vein thrombosis: A meta-analysis

PurposeA meta-analysis aimed to systematically evaluate the safety and efficiency of I¹²⁵ irradiation stent placement for patients with hepatocellular carcinoma (HCC) combined with portal vein tumor thrombosis (PVTT).Materials and methodsThe Cochrane library, PubMed/Medline, EMBASE, CNKI, Wanfang Data and CQVIP were systematically screened out from the earliest to December 2019. The qualities of all included studies were assessed. The primary endpoints were the 6-month, 12-month stent cumulative patency rate and 6-month, 12-month, 24-month overall survival rate while the secondary endpoints were the objective response rate of PVTT, main portal venous pressure changes and treatment-related adverse events. Our meta-analysis was conducted using Stata 12.0 software.ResultsTotally seven studies with 1018 patients were included in the final analysis, in which 602 patients received TACE and I¹²⁵ irradiation stent placement, and 416 patients in control group underwent TACE and stent placement without endovascular brachytherapy (EVBT). Meta-analysis showed that the I¹²⁵ irradiation stent improved the cumulative stent patency rates in 6 months [OR = 1.65, 95% CI (1.32–2.05), P < 0.001] and 12 months [OR = 2.55, 95% CI (1.90–3.42), P < 0.001] and the survival rates in 6 months [OR = 1.77, 95% CI (1.41–2.22), P < 0.001], 12 months [OR = 3.14, 95% CI (2.24–4.40), P < 0.001] and 24 months [OR = 7.39, 95% CI (3.55–15.41), P < 0.001]. However, there was no difference in the objective response rate of PVTT [OR = 1.13, 95% CI (0.87–1.48), P = 0.365], main portal venous pressure and the occurrence adverse event [OR = 0.88, CI = 0.72–1.08, P = 0.212] between two groups.ConclusionI¹²⁵ irradiation stent seems to be more effective in treating hepatocellular carcinoma with portal vein tumor thrombosis. The usage of portal vein stent combined endovascular brachytherapy has the potential to act as an alternative therapy for HCC with PVTT. On account of the limitation of studies included, more studies with high-level evidence, such as RCTs, are requisite to support the above promising results.     

Analyses on clinical characteristic and prognoses of 41 patients with chronic myelomonocytic leukemia in China

PurposeTo investigate clinical characteristic and prognostic factors for chronic myelomonocytic leukemia (CMML).MethodsA retrospective cohort study was used in the research. We investigated clinical and laboratory characteristics of CMML patients and survival status. Patients were followed up regularly through out the course of the research.ResultsForty-one cases were diagnosed as CMML, including 27 male and 14 female patients. Median WBC was 13.7 × 10⁹/L. Five patients had leukocytopenia (1.92–3.46 × 10⁹/L). Median monocyte count in the peripheral blood was 2.13 × 10⁹/L. All patients presented with bone marrow dysplasia, and most showed hyperplasia, except 3 cases. Abnormal chromosome was detected in 34% cases. Median survival time for CMML-1 and CMML-2 was 20 and 12 months, respectively, but there were no statistical significance of survival duration between them. Univariable analysis showed that age (>60 years), neutrophil count (<2.0 × 10⁹/L), lymphocyte count (<1.0 × 10⁹/L), mature monocyte count (≥5 × 10⁹/L) and anemia (Hb < 60 g/L) were associated with poor prognosis for CMML. There was no statistical significance in LDH, gender, and abnormal chromosome for survival time. Only lymphocyte count and neutrophil count in peripheral blood were independent prognostic factors for CMML after multivariate analysis.ConclusionCMML mainly occurs in elderly patients. Although most patients have leukocytosis and monocytosis at diagnosis, few cases show leucopenia and monocytopenia. Age, neutrophil, lymphopenia, monocytosis, and severe anemia are associated with inferior prognosis of CMML. Lymphocyte < 1.0 × 10⁹/L and neutrophil count < 2.0 × 10⁹/L are adversely independent prognostic factors for CMML.     

Does every woman require a post-lumpectomy mammogram and ultrasound before radiotherapy when negative margins?

PurposeMost studies regarding the value of post lumpectomy imaging (PLI) studies rely on mammography alone and are often focused on patients that present with suspicious microcalcifications or in situ disease. This way, its true benefit remains controversial, which explained the heterogeneity between centers. This is the first study to evaluate the role of mammography with breast and axillary ultrasound undertaken before radiotherapy in patients with conservatively managed invasive and/or in situ carcinoma with negative margins.Materials and MethodsIn this retrospective study, medical records for patients referred to our External Radiotherapy Unit between January 2018 and December 2019 were reviewed.ResultsA total of 1251 patients (1262 breasts) were analyzed. A total of 3.4% had suspicious findings for local residual breast disease, with 1.0% having a re-excision positive for residual malignancy. Presentation with microcalcifications alone (OR = 4.854), extension of microcalcifications > 3 cm (OR = 13.500), histologic subtype pure ductal carcinoma in situ (OR = 12.348), presence of invasive carcinoma ≤ 1 mm of the pathological margins (OR = 4.630), stage pTis (5.630), and absence of invasive component (OR = 4.629), were associated with an increased risk for residual malignancy. Only one patient (0.1%) had nodal residual involvement.ConclusionPLI detected residual local cancer in 1.0% of the patients. PLI plays an important role in the evaluation of patients undergoing breast-conserving therapy with negative margins. The major question that remains is whether it changes survival outcomes.     

A new approach to understanding racial disparities in prostate cancer treatment

Objective:Previous studies addressing racial disparities in treatment for early-stage prostate cancer have focused on the etiology of undertreatment of black men. Our objective was to determine whether racial disparities are attributable to undertreatment, overtreatment, or both.Methods:Using the SEER-Medicare dataset, we identified men 67–84 years-old diagnosed with localized prostate cancer from 1998 to 2007. We stratified men into clinical benefit groups using tumor aggressiveness and life expectancy. Low-benefit was defined as low-risk tumors and life expectancy < 10 years; high-benefit as moderate-risk tumors and life expectancy ≥ 10 years; all others were intermediate-benefit. Logistic regression modeled the association between race and treatment (radical prostatectomy or radiotherapy) across benefit groups.Results:Of 68,817 men (9.8% black and 90.2% white), 56.2% of black and 66.3% of white men received treatment (adjusted odds ratio (OR) = 0.65; 95% CI, 0.62–0.69). The percent of low-, intermediate-, and high-benefit men who received treatment was 56.7%, 68.4%, and 79.6%, respectively (P = < 0.001). In the low-benefit group, 51.9% of black vs. 57.2% of white patients received treatment (OR = 0.74; 95% CI, 0.67–0.81) compared to 57.2% vs. 69.6% in the intermediate-benefit group (OR = 0.64; 95% CI, 0.59–0.70). Racial disparity was largest in the high-benefit group (64.2% of black vs. 81.4% of white patients received treatment; OR = 0.57; 95% CI, 0.48–0.68). The interaction between race and clinical benefit was significant (P < 0.001).Conclusion:Racial disparities were largest among men most likely to benefit from treatment. However, a substantial proportion of both black and white men with a low clinical benefit received treatment, indicating a high level of overtreatment.     

Predictors of outcome and methodological issues in children with acute lymphoblastic leukaemia in El Salvador

BackgroundMost children with cancer live in low-income countries (LICs) where risk factors in paediatric acute lymphoblastic leukaemia (ALL) developed in high-income countries may not apply.MethodsWe describe predictors of survival for children in El Salvador with ALL. We included patients <16 years diagnosed with ALL between January 2001 and July 2007 treated with the El Salvador–Guatemala–Honduras II protocol. Demographic, disease-related, socioeconomic and nutritional variables were examined as potential predictors of event-free survival (EFS) and overall survival (OS).Results260/443 patients (58.7%) were classified as standard risk. Standard- and high-risk 5-year EFS were 56.3 ± 4.5% and 48.6 ± 5.5%; 5-year OS were 77.7 ± 3.8% and 61.9 ± 5.8%, respectively. Among standard-risk children, socioeconomic variables such as higher monthly income (hazard ratio [HR] per $100 = 0.84 [95% confidence interval (CI) 0.70–0.99; P = 0.04]) and parental secondary education (HR = 0.49, 95% CI 0.29–0.84; P = 0.01) were associated with better EFS. Among high-risk children, higher initial white blood cell (HR per 10 × 10⁹/L = 1.03, 95% CI 1.02–1.05; P < 0.001) predicted worse EFS; socioeconomic variables were not predictive. The difference in EFS and OS appeared related to overestimating OS secondary to poor follow-up after abandonment/relapse.ConclusionSocioeconomic variables predicted worse EFS in standard-risk children while disease-related variables were predictive in high-risk patients. Further studies should delineate pathways through which socioeconomic status affects EFS in order to design effective interventions. EFS should be the primary outcome in LIC studies.     

Prevention of central venous catheter-associated bloodstream infections in paediatric oncology patients using 70% ethanol locks: A randomised controlled multi-centre trial

BackgroundThe prevention of central venous catheter (CVC) associated bloodstream infections (CABSIs) in paediatric oncology patients is essential. Ethanol locks can eliminate pathogens colonising CVCs and microbial resistance is rare. Aim of this study was to determine whether two hour 70% ethanol locks can reduce CABSI in paediatric oncology patients.MethodsWe conducted a randomised, double blind, multi-centre trial in paediatric oncology patients (1–18 years) with newly inserted CVCs. Patients were randomly assigned to receive two hour ethanol locks (1.5 or 3 ml 70%) or heparin locks (1.5 or 3 ml 100 IU/ml), whenever it was needed to use the CVC, maximum frequency once weekly. Primary outcomes were time to CABSI or death due to CABSI.ResultsWe recruited 307 patients (ethanol, n = 153; heparin, n = 154). In the ethanol group, 16/153 (10%) patients developed a CABSI versus 29/154 (19%) in the heparin group. The incidence of CABSI was 0.77/1000 and 1.46/1000 catheter days respectively (p = 0.039). The number-needed-to-treat was 13. No patients died of CABSI. In particular, Gram-positive CABSIs were reduced (ethanol, n = 8; heparin, n = 21; p = 0.012). Fewer CVCs were removed because of CABSI in the ethanol group (p = 0.077). The ethanol lock patients experienced significantly more transient symptoms compared to the heparin lock patients (maximum grade 2) (nausea, p = 0.030; taste alteration, p < 0.001; dizziness, p = 0.001; blushing, p < 0.001), no suspected unexpected serious adverse reactions (SUSAR) occurred.ConclusionsThis is the first randomised controlled trial to show that ethanol locks can prevent CABSI in paediatric oncology patients, in particular CABSI caused by Gram-positive bacteria. Implementation of ethanol locks in clinical practice should be considered.     

Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy

BackgroundNeratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer.Patients and methodsPhase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m²; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR).ResultsIn phase I (n = 12), neratinib (240 mg) plus vinorelbine (25 mg/m²) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine.ConclusionNeratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients.Trial registrationClinicalTrials.gov #NCT00706030.     

Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study

BackgroundTrastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1 + docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1 + docetaxel ± pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC).Patients and methodsPhase Ib (part 1) explored dose escalation, with T-DM1 + docetaxel administered for greater than or equal to six cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered less than or equal to six cycles of T-DM1 + docetaxel or T-DM1 + docetaxel + pertuzumab. Phase IIa explored the MTDs identified in phase Ib.ResultsAdministered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m² in MBC. In LABC, the MTD was 100 mg/m² docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony-stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg) + pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m² with G-CSF support. Neutropenia was the most common grade 3–4 adverse event (AE; MBC, 72% and LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced AEs requiring dose modification. In MBC (median prior systemic agents = 5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3–93.2) and the median progression-free survival was 13.8 months (range, 1.6–33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1–71.5). Pharmacokinetic analyses indicated a low risk of drug–drug interaction between T-DM1 and docetaxel.ConclusionsT-DM1 combined with docetaxel ± pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced AEs requiring dose reductions with these T-DM1 combinations.ClinicalTrials.gov identifierNCT00934856.     

Dosimetric challenges of small animal irradiation with a commercial X-ray unit

IntroductionA commercial X-ray unit was recently installed at the Medical University Vienna for partial and whole body irradiation of small experimental animals. For 200 kV X-rays the dose deviations with respect to the reference dose measured in the geometrical center of the potential available field size was investigated for various experimental setup plates used for mouse irradiations. Furthermore, the HVL was measured in mm Al and mm Cu at 200 kV for two types of filtration.Material and MethodsThree different setup constructions for small animal irradiation were dosimetrically characterized, covering field sizes from 9 × 20 mm² to 210 × 200 mm². Different types of detectors were investigated. Additionally LiF:MG,Ti TLD chips were used for mouse in-vivo dosimetry.ResultsThe use of an additional 0.5 mm Cu filter reduced the deviation of the dose between each irradiation position on the setup plates. Multiple animals were irradiated at the same time using an individual setup plate for each experimental purpose. The dose deviations of each irradiation position to the center was measured to be ±4% or better. The depth dose curve measured in a solid water phantom was more pronounced for smaller field sizes. The comparison between estimated dose and measured dose in a PMMA phantom regarding the dose decline yielded in a difference of 3.9% at 20 mm depth. In-vivo measurements in a mouse snouts irradiation model confirmed the reference dosimetry, accomplished in PMMA phantoms, in terms of administered dose and deviation within different points of measurement.Discussion and ConclusionThe outlined experiments dealt with a wide variety of dosimetric challenges during the installation of a new X-ray unit in the laboratory. The depth dose profiles measured for different field sizes were in good agreement with literature data. Different field sizes and spatial arrangement of the animals (depending on each purpose) provide additional challenges for the dosimetric measurements. Thorough dosimetric commissioning has to be performed before a new experimental setup is approved for biological experiments.     

Ca/Mg infusions for the prevention of oxaliplatin-related neurotoxicity in patients with colorectal cancer: a meta-analysis

BackgroundOxaliplatin-related neurotoxicity is the main limitation for its continuation in adjuvant and palliative chemotherapy for patients with colorectal cancer. The purpose of this meta-analysis was to determine the efficacy of calcium and magnesium (Ca/Mg) infusions in oxaliplatin-induced neurotoxicity.MethodsTwo independent authors conducted database searches of the literature to find clinical-controlled trials analyzing Ca/Mg infusions in oxaliplatin-induced neurotoxicity. The keywords used to search were oxaliplatin, neurotoxicity, calcium, magnesium, neuropathy, and peripheral. Clinical studies that included at least one primary or secondary event were eligible for the analysis, where primary events were incidences of acute and cumulative neurotoxicity, and secondary events were the total doses and cycles of oxaliplatin, response rate (RR), overall survival (OS), and progression-free survival (PFS). Odds ratios (ORs) and weighted mean differences (MD) were analyzed using models of fixed and random effects.ResultsThis meta-analysis comprised four prospective randomized clinical trials and three retrospective clinical trials involving 1170 colorectal cancer patients, of which 802 received Ca/Mg infusions (Ca/Mg group) and 368 did not (control group). According to the National Cancer Institute-Common Terminology Criteria for Adverse Events, the incidence of grade 3 acute neurotoxicity in those who received Ca/Mg was significantly lower than that of the control group (OR = 0.26; 95% confidence interval (CI), 0.11 to 0.62; P = 0.0002). The total rate of cumulative neurotoxicity, and that of grade 3 in particular, was significantly lower in the Ca/Mg group than in the control group (OR = 0.42; 95% CI 0.26–0.65; P = 0.0001; OR = 0.60; 95% CI 0.39–0.92; P = 0.02, respectively). The differences in total doses and cycles of oxaliplatin were also significant between the Ca/Mg and control group (MD = 246.73 mg/m²; 95% CI 3.01–490.45; P = 0.05; MD = 1.55; 95% CI 0.46–2.63; P = 0.005, respectively). No significant differences were found in median PFS (MD = 0.71 month; 95% CI -0.59–2.01; P = 0.29), median OS (MD = 0.10 month; 95% CI -0.41–0.61; P = 0.70) or RRs (OR = 0.82; 95% CI 0.61–1.10; P = 0.18).ConclusionCa/Mg infusions tend to decrease the incidence of oxaliplatin-induced acute and cumulative neurotoxicity and thus enhance patients' tolerance to oxaliplatin, without significantly altering the efficacy of chemotherapy.     

A phase I study of daily afatinib,an irreversible ErbB family blocker,in combination with weekly paclitaxel in patients with advanced solid tumours

BackgroundThis phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2.MethodsOral afatinib was combined with intravenous paclitaxel (80 mg/m²; days 1, 8 and 15 every four weeks) starting at 20 mg once daily and escalated to 40 and 50 mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity.ResultsSixteen patients were treated. Dose-limiting toxicities with afatinib 50 mg were fatigue and mucositis. The MTD was determined as afatinib 40 mg with paclitaxel 80 mg/m², which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n = 3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6 months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination.ConclusionsThe MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80 mg/m² (days 1, 8 and 15 every four weeks) was 40 mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity.Trial registrationClinicalTrials.gov, NCT00809133.     

Serum inflammatory miRNAs predict radiation esophagitis in patients receiving definitive radiochemotherapy for non-small cell lung cancer

Background and purposeMicroRNAs (miRNAs) are small, highly conserved non-coding RNAs that regulate many biological processes. We sought to investigate whether three serum miRNAs related to immunity or inflammation were associated with esophagitis induced by chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC).Material and methodsWe measured serum miR-155, miR-221 and miR-21, before and during week 1–2 of CRT for 101 NSCLC patients by real-time PCR. Associations between miRNA and severe radiation-induced esophageal toxicity (RIET) were analyzed by logistic regression.ResultsWe found that patients with stage IIIB–IV disease, higher mean esophagus dose or esophageal V₅₀ had higher rates of severe RIET. Furthermore, high levels of miR-155 and miR-221 at week 1–2 of CRT were also risk factors for severe RIET (miR-155: OR = 1.53, 95% CI: 1.04–2.25, P = 0.03; miR-221: OR = 2.07, 95% CI: 1.17–3.64, P = 0.012). In addition, the fold change of miR-221 was also predictive of severe RIET (OR = 1.18, 95% CI: 1.02–1.37, P = 0.026). However, pretreatment miRNAs was not predictive of severe RIET.ConclusionsHigh serum miR-155 and miR-221 during the first 2 weeks of CRT were associated with the development of severe RIET, suggesting that these miRNAs may be useful as an early surrogate for this form of toxicity.     

Adolescents and young adults with classical Hodgkin lymphoma in northern Tunisia: insights from an adult single-institutional study

PurposeThe aim of this study was to extensively describe the epidemiological, clinical and therapeutic outcomes of adolescents and young adults (AYA) population with classical Hodgkin Lymphoma (cHL). Then, a comparison between AYAs and adults and between the subgroups of AYAs treated with the same adult protocol was accomplished to further inform on optimal therapy approach of choice for adolescent patients.Material and methodsIn this mono-centric, retrospective study, we reviewed the medical records. We analyzed 112 consecutive North Tunisian patients, including 66 AYAs (15 to 39 years) and 46 adults (≥ 40 years) affected by cHL treated from 2000 to 2015 at Salah Azaiez Institute. Then, we performed a comparative analysis between AYA and 46 adult patients and a subgroup analysis between adolescents and young adults. All patients were treated according to the national protocol for HL, edited by the Tunisian Society of Hematology. The treatment included chemotherapy and involved-field radiotherapy (RT) at a dose of 20 or 30 Grays (Gy) for responders and 36 Gy for non-responders.ResultsAYA patients presented with adverse features with nodular sclerosis subtype (p = 3.88 × 10⁻⁰²) and mediastinal mass involvement (p = 9.40 × 10⁻⁰⁴). At a median follow-up of 51 and 32 months for AYAs and adults, respectively, no statistical difference in terms of 3 and 5-years overall survival (OS) and event-free survival (EFS) was shown. Using the Kaplan-Meier method, in AYAs, the ABVD regimen has an impact on 3-years EFS (p = 4.63 × 10⁻⁰²). The 36 Gy RT was associated with the best 3-years EFS (p = 9.24 × 10⁻⁰³). Besides, AYA patients with advanced-stage had the worst 3-years OS (76%) (p = 2.41 × 10⁻⁰²). Although the adolescents and young adults shared similar clinical presentation, we noted that the adolescent group had the worst 3-years EFS (48%), but the best 3-years OS (91%). We identified 15% of primary refractory patients and a rate of toxicity of 5.3% in AYA.ConclusionThe treatment approach used is well tolerated by adult patients. However, the AYA patients and particularly adolescent subgroup had more advanced disease at diagnosis and should be treated more intensively in dedicated units. RT dose < 36 Gy and ABVD chemotherapy were associated with lower EFS in this population.