Narrative review of the utility of magnetic resonance imaging in radiotherapy for cervical cancer.

BACKGROUND AND OBJECTIVE: In radiotherapy (RT) for locally advanced cervical cancer, high soft tissue contrast on magnetic resonance imaging (MRI) can ensure accurate delineation of target volumes (TVs) and optimal dose distribution to the RT target and organs at risk (OAR). MRI-guided adaptive RT (MRIgART) is a novel technology that revises RT plans according to anatomical changes occurring throughout the treatment to improve target coverage and minimise OAR toxicity. This review aims to assess the evidence and gaps of MRI use in RT planning and MRIgART in the treatment of cervical cancer, as well as challenges in its clinical implementation. METHODS: Ovid Medline and PubMed were searched using keywords for MRI in RT for cervical cancer. After applying the inclusion and exclusion criteria, the initial search was deduced to 32 studies. A total of 37 final studies were reviewed, including eight additional articles from references. KEY CONTENT AND FINDINGS: In the primary studies, TVs and organ motion were assessed before, during, and after treatment. MRI was used to investigate dose distribution and therapeutic response to the treatment in association with its outcome. Lastly, rationales for MRIgART were evaluated. CONCLUSIONS: It was concluded that MRI enables accurate target delineation, assessment of organ motion and interfraction changes, and monitoring of treatment response through dynamic parameters. Enhanced target coverage and reduced OAR irradiation through MRIgART can improve local control and the overall outcome, although its rationales against the logistical challenges need to be evaluated on further research.

Paediatric foreign body aspiration and endobronchial granuloma.

Paediatric foreign body aspiration can result in pulmonary complications including the formation of endobronchial granuloma, which can be managed conservatively or via surgical or bronchoscopic intervention. This case highlights the importance of having a high index of suspicion for foreign body aspiration in patients with persistent symptoms or abnormal imaging.

Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.

Gynecological intrauterine brachytherapy training for radiation therapists: The development and implementation of a training program.

PURPOSE: Gynecological brachytherapy (GynBT) is an important part of gynecological cancer management. At Olivia Newton-John Cancer Wellness & Research Centre (ONJCWRC), Melbourne, Australia, radiation therapists (RTs) are integral to the MRI adaptive GynBT program workflow. However, there is limited GynBT training available for RTs in Australia. A GynBT training program has been developed at ONJCWRC to meet this need and support RTs in becoming competent, proficient and confident in the various roles in GynBT. This is a preliminary report on the development and implementation of a credentialing program, providing a structured approach to GynBT training of RTs. METHODS AND MATERIALS: A credentialing program was designed with modules and competency assessments to ensure efficiency and proficiency of RTs in the GynBT workflow. The program includes theoretical modules in anatomy, international GynBT guidelines, radiation safety and local protocols; and practical modules in equipment, ultrasound for GynBT, operating theatre procedures, MRI, contouring, applicator reconstruction, planning, quality assurance and treatment delivery. Learning strategies include self-directed learning, tutorials, practical sessions, and third-party courses. The program concludes with an exit examination assessing major competencies. RESULTS: The program was implemented in April 2018 with three RTs completing the program and passing the exit examination on first attempt. On post-program survey, the RTs felt the program was comprehensive, helping to build their confidence, and proficiency in GynBT. CONCLUSIONS: A GynBT RT credentialing program was successfully developed and implemented to improve the quality of training at ONJCWRC. This program is mandatory for RTs joining the GynBT team. This program can provide a framework for implementation of GynBT training in other centers.

An Outpatient Management Strategy Using a Coronataxi Digital Early Warning System Reduces Coronavirus Disease 2019 Mortality.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused sudden, severe strain to healthcare systems. Better outpatient management is required to save lives, manage resources effectively, and prepare for future pandemics. Methods: The Coronataxi digital early warning (CDEW) system deployed in Rhein-Neckar County and Heidelberg, Germany is an outpatient care system consisting of remote digital monitoring via a mobile application, a medical doctor dashboard, and medical care delivery to COVID-19 patients in home quarantine when indicated. Patients reported their symptoms, temperature, breathing rate, oxygen saturation, and pulse via the app. This single-center cohort study compared outcomes of the population with and without using the CDEW system. The primary outcome was mortality; the secondary outcomes were hospitalization, duration of hospitalization, intensive care therapy, and mechanical ventilation. Results: Mortality rate was 3- to 4-fold lower and hospitalization rate was higher in the CDEW cohort (459 patients) compared with the cohort without CDEW in the same test area and other regions (Mannheim, Karlsruhe town, Karlsruhe district, and Germany), (mortality rate: 0.65% [95% confidence interval {CI}, .13%-1.90%] versus 2.16%, 2.32%, 2.48%, 2.82% and 2.76%, respectively, P < .05 for all; hospitalization rate: 14.81% [95% CI, 11.69%-18.40%] versus 6.89%, 6.93%, 6.59%, 6.15%, and 7.22%, respectively, P < .001 for all). The median duration of hospitalization in the CDEW cohort was significantly lower compared with a national sentinel cohort (6 days [interquartile range {IQR}, 4-9.75 days] versus 10 days [IQR, 5-19 days]; Z = -3.156; P = .002). A total of 1.96% patients needed intensive care and 1.09% were mechanically ventilated. Conclusions: The CDEW system significantly reduced COVID-19 mortality and duration of hospitalization and can be applied to the management of future pandemics.

To biopsy or not to biopsy? Outcomes following stereotactic body radiotherapy (SBRT) for biopsy-confirmed versus radiologically-diagnosed primary lung cancer in a single Australian institution.

INTRODUCTION: Obtaining tissue diagnosis for lung cancer can sometimes be difficult and unsafe. We evaluated outcomes of biopsy-confirmed versus radiologically-diagnosed lung cancer treated with stereotactic body radiotherapy (SBRT). METHODS: A single-institutional retrospective cohort of lung cancer patients treated with SBRT between February 2014 and October 2018. Outcomes of interest were: local failure (LF), distant failure (DF), and overall survival (OS). Probability of LF, DF, and OS were estimated using the Kaplan-Meier method. Differences in outcomes between biopsy-confirmed versus radiologically-diagnosed lung cancer were evaluated using the log-rank test. RESULTS: Sixty-five lung lesions in 61 patients were treated with SBRT. Mean age was 75.6 years. Twenty-seven patients (44.3%) were ECOG 2-3. Thirty-nine patients (64%) were radiologically-diagnosed. There were five cases of LF observed at median of 12.8 months post-SBRT and 12-month LF-free survival was 96% (95% CI, 86-99%), with no differences between groups (p = 0.1). Sixteen patients developed DF, with 12-month DF-free survival of 84% (95% CI, 71-91%), and no difference between groups (p = 0.06). Sixteen deaths were reported at a median of 12.5 months post-SBRT, with 12-month OS of 85% (95% CI, 73-92%), and no differences between study groups (p = 0.5). No grade 3 toxicities were reported. CONCLUSION: The oncological outcomes were similar in patients with early lung cancer treated with SBRT with or without biopsy-confirmation. In situations where tissue diagnosis is not feasible or unsafe, it is not unreasonable to offer SBRT based on clinical and radiological suspicion following multidisciplinary discussions.

Persistent Symptoms in Adult Patients 1 Year After Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study.

BACKGROUND: Long COVID is defined as the persistence of symptoms beyond 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To better understand the long-term course and etiology of symptoms we analyzed a cohort of patients with COVID-19 prospectively. METHODS: Patients were included at 5 months after acute COVID-19 in this prospective, noninterventional, follow-up study. Patients followed until 12 months after COVID-19 symptom onset (n = 96; 32.3% hospitalized, 55.2% females) were included in this analysis of symptoms, quality of life (based on an SF-12 survey), laboratory parameters including antinuclear antibodies (ANAs), and SARS-CoV-2 antibody levels. RESULTS: At month 12, only 22.9% of patients were completely free of symptoms and the most frequent symptoms were reduced exercise capacity (56.3%), fatigue (53.1%), dyspnea (37.5%), and problems with concentration (39.6%), finding words (32.3%), and sleeping (26.0%). Females showed significantly more neurocognitive symptoms than males. ANA titers were ≥1:160 in 43.6% of patients at 12 months post-COVID-19 symptom onset, and neurocognitive symptom frequency was significantly higher in the group with an ANA titer ≥1:160 versus <1:160. Compared with patients without symptoms, patients with ≥1 long-COVID symptom at 12 months did not differ significantly with respect to their SARS-CoV-2 antibody levels but had a significantly reduced physical and mental life quality compared with patients without symptoms. CONCLUSIONS: Neurocognitive long-COVID symptoms can persist ≥1 year after COVID-19 symptom onset and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titer elevations. This may indicate autoimmunity as a cofactor in etiology of long COVID.

Management of Submassive Bilateral Pulmonary Embolism in an Adolescent Female.

Pulmonary embolism (PE) is a rare presentation in the pediatric population. We report a case of submassive PE in an adolescent female following commencement of a combined oral contraceptive pill (COCP). In the setting of cardiac dysfunction, she received systemic thrombolysis with significant reduction of clot burden and clinical improvement objectively demonstrated shortly thereafter. This case highlights challenges in clinical decision-making regarding surgical or catheter-based interventions versus medical management approaches when addressing life-threatening PE in children. Our case demonstrates that submassive PE in pediatrics can be managed successfully with systemic thrombolysis and therapeutic anticoagulation.

Pleural effusion secondary to chronic pancreatitis in childhood.

Pleural effusion secondary to a pancreatico-pleural fistula is a very rare presentation in children, with limited reports in the literature. We describe two differing presentations of pleural effusions resulting from chronic pancreatitis (CP) with successful resolution of the pleural effusion. These cases highlight the need for consideration of this rare paediatric diagnosis, and the variety of investigations, management strategies, and complications that can occur in the setting of CP in children.

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COVID-19 disease severity and indicator of the need for mechanical ventilation, ARDS and mortality.

BACKGROUND: COVID-19 pneumonia and subsequent respiratory failure is causing an immense strain on intensive care units globally. Early prediction of severe disease enables clinicians to avoid acute respiratory distress syndrome (ARDS) development and improve management of critically ill patients. The soluble receptor of advanced glycation endproducts (sRAGE) is a biomarker shown to predict ARDS. Although sRAGE level varies depending on the type of disease, there is limited information available on changes in sRAGE levels in COVID-19. Therefore, sRAGE was measured in COVID-19 patients to determine sRAGE level variation in COVID-19 severity and to examine its ability to predict the need for mechanical ventilation (MV) and mortality in COVID-19. METHODS: In this single-centre observational cohort study in Germany, serum sRAGE during acute COVID-19, 20 weeks after the start of COVID-19 symptoms, as well as in control groups of non-COVID-19 pneumonia patients and healthy controls were measured using ELISA. The primary endpoint was severe disease (high-flow nasal oxygen therapy (HFNO)/MV and need of organ support). The secondary endpoints were respiratory failure with need of MV and 30-day mortality. The area under the curve (AUC), cut-off based on Youden's index and odds ratio with 95% CI for sRAGE were calculated with regard to prediction of MV need and mortality. RESULTS: Serum sRAGE in 164 COVID-19 patients, 101 matched COVID-19 convalescent patients, 23 non-COVID-19 pneumonia patients and 15 healthy volunteers were measured. sRAGE level increased with COVID-19 severity, need for oxygen therapy, HFNO/MV, ARDS severity, need of dialysis and catecholamine support, 30-day mortality, sequential organ failure assessment (SOFA) and quick SOFA (qSOFA) score. sRAGE was found to be a good predictor of MV need in COVID-19 inpatients and mortality with an AUC of 0.871 (0.770-0.973) and 0.903 (0.817-0.990), respectively. When adjusted for male gender, age, comorbidity and SOFA score ≥ 3, sRAGE was independently associated with risk of need for HFNO/MV. When adjusted for SOFA score ≥ 3, sRAGE was independently associated with risk of need for MV. CONCLUSIONS: Serum sRAGE concentrations are elevated in COVID-19 patients as disease severity increases. sRAGE should be considered as a biomarker for predicting the need for MV and mortality in COVID-19.

Adjuvant radiotherapy for endometrial cancer with cervical stromal involvement: A patterns of practice survey in Australia and New Zealand.

INTRODUCTION: The purpose of this study is to describe the patterns of practice in Australia and New Zealand for post-operative radiotherapy in endometrial cancer with cervical stromal involvement. METHODS: A ten-item survey including five clinical case scenarios in endometrial cancer with cervical stromal invasion was emailed to Royal Australian and New Zealand College of Radiologists (RANZCR) radiation oncologists in 2018. Responses were analysed to determine relative frequency distributions and preferred adjuvant treatment modalities for the clinical case scenarios. RESULTS: A total of 65 respondents initiated the survey with 27 respondents treating more than 11 endometrial cancer cases annually. Only 31 respondents answered all five clinical case scenarios. Preferred adjuvant radiotherapy modalities varied for the Stage II cases between vault brachytherapy (VB), pelvic external beam radiotherapy (EBRT) or a combination. For the stage IIIA and IIIC1 cases, the majority recommended pelvic EBRT with or without VB boost (79% and 77%), and of these, most combined with chemotherapy (61% and 88%). For 4 of the 5 case scenarios, when pelvic EBRT was offered, most recommended a VB boost. CONCLUSION: This patterns of practice survey suggests variability in adjuvant radiotherapy recommendations in endometrial cancer with cervical involvement, particularly in cases where there is lack of randomised data and discrepancies in consensus guidelines.

Synthesis, Characterization, Adsorption Isotherm, and Kinetic Study of Oil Palm Trunk-Derived Activated Carbon for Tannin Removal from Aqueous Solution.

Oil palm trunk (OPT) represents one of the five main oil palm biomass wastes with high carbon content that can be economically converted to a large surface area, porous activated carbon (AC) adsorbent to treat palm oil mill effluent wastewater in Indonesia and Malaysia. In the first portion of this work, the design of the experiment was used to determine the optimum set of synthesis parameters required to maximize the iodine number of AC [i.e., Brunauer-Emmett-Teller (BET) specific surface area indicator] prepared from OPT via chemical activation route using H3PO4. The iodine numbers of AC and AC yield were probed as the impregnation ratio, the activation time, and the activation temperature were varied in the range of 0.28-3.47, 5.68-69.32 min, and 379-521 °C, respectively. An impregnation ratio of 2.29, an activation time of 6 min, and an activation temperature of 450 °C were identified as the optimum set of synthesis parameters. In the second portion of the work, the AC synthesized using the optimum parameters were then characterized and tested as an adsorbent for tannin. N2 sorption results revealed that the AC exhibits type IV isotherm, that is, contains micropores and mesopores and displays a relatively high BET specific surface area of 1657 m2 g-1. Adsorption equilibria isotherms for tannin adsorption onto the AC were collected at three different pH of 2, 4, and 6 and were nonlinearly fitted using Langmuir and Freundlich isotherm models, where the Langmuir isotherm gave better fitting than Freundlich. The higher adsorption capacity at lower pH can be explained in terms of the absence of electrostatic repulsion interaction between the AC surface and the tannic acid species as suggested by the point of zero charges (pHpzc) of 4.8 and an increasing ionization of tannic acid with pH rise between 4 and 7. Adsorption kinetics data were also obtained at four different pH of 2, 4, 6, and 8 where the nonlinear pseudo-first-order model best fitted the kinetic at pH of 2 and the nonlinear pseudo-second-order model represented the kinetic best at the remaining higher pH, which suggests that tannin adsorption onto AC occurred by physisorption at pH of 2 and by chemisorption at pH of 4, 6, and 8.

Acquired Immunodeficiency from Maternal Chemotherapy and Severe Primary Pneumocystis Infection in an Infant.

Pneumocystis jirovecii is recognized as an opportunistic pathogen in immunosuppressed patients. We report a case of severe Pneumocystis pneumonia (PCP) in an infant with acquired combined immunodeficiency secondary to maternal chemotherapy exposure during the second and third trimesters of pregnancy. The infant required cardiorespiratory support with veno-venous extracorporeal membrane oxygenation (VV-ECMO) for severe respiratory failure. This case highlights the potential for severe acquired immunodeficiency in this patient cohort and further postnatal surveillance is highly recommended.

Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is widely used to treat inoperable stage 1 non-small-cell lung cancer (NSCLC), despite the absence of prospective evidence that this type of treatment improves local control or prolongs overall survival compared with standard radiotherapy. We aimed to compare the two treatment techniques. METHODS: We did this multicentre, phase 3, randomised, controlled trial in 11 hospitals in Australia and three hospitals in New Zealand. Patients were eligible if they were aged 18 years or older, had biopsy-confirmed stage 1 (T1-T2aN0M0) NSCLC diagnosed on the basis of 18F-fluorodeoxyglucose PET, and were medically inoperable or had refused surgery. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and the tumour had to be peripherally located. Patients were randomly assigned after stratification for T stage and operability in a 2:1 ratio to SABR (54 Gy in three 18 Gy fractions, or 48 Gy in four 12 Gy fractions if the tumour was <2 cm from the chest wall) or standard radiotherapy (66 Gy in 33 daily 2 Gy fractions or 50 Gy in 20 daily 2·5 Gy fractions, depending on institutional preference) using minimisation, so no sequence was pre-generated. Clinicians, patients, and data managers had no previous knowledge of the treatment group to which patients would be assigned; however, the treatment assignment was subsequently open label (because of the nature of the interventions). The primary endpoint was time to local treatment failure (assessed according to Response Evaluation Criteria in Solid Tumors version 1.0), with the hypothesis that SABR would result in superior local control compared with standard radiotherapy. All efficacy analyses were based on the intention-to-treat analysis. Safety analyses were done on a per-protocol basis, according to treatment that the patients actually received. The trial is registered with ClinicalTrials.gov (NCT01014130) and the Australia and New Zealand Clinical Trials Registry (ACTRN12610000479000). The trial is closed to new participants. FINDINGS: Between Dec 31, 2009, and June 22, 2015, 101 eligible patients were enrolled and randomly assigned to receive SABR (n=66) or standard radiotherapy (n=35). Five (7·6%) patients in the SABR group and two (6·5%) in the standard radiotherapy group did not receive treatment, and a further four in each group withdrew before study end. As of data cutoff (July 31, 2017), median follow-up for local treatment failure was 2·1 years (IQR 1·2-3·6) for patients randomly assigned to standard radiotherapy and 2·6 years (IQR 1·6-3·6) for patients assigned to SABR. 20 (20%) of 101 patients had progressed locally: nine (14%) of 66 patients in the SABR group and 11 (31%) of 35 patients in the standard radiotherapy group, and freedom from local treatment failure was improved in the SABR group compared with the standard radiotherapy group (hazard ratio 0·32, 95% CI 0·13-0·77, p=0·0077). Median time to local treatment failure was not reached in either group. In patients treated with SABR, there was one grade 4 adverse event (dyspnoea) and seven grade 3 adverse events (two cough, one hypoxia, one lung infection, one weight loss, one dyspnoea, and one fatigue) related to treatment compared with two grade 3 events (chest pain) in the standard treatment group. INTERPRETATION: In patients with inoperable peripherally located stage 1 NSCLC, compared with standard radiotherapy, SABR resulted in superior local control of the primary disease without an increase in major toxicity. The findings of this trial suggest that SABR should be the treatment of choice for this patient group. FUNDING: The Radiation and Optometry Section of the Australian Government Department of Health with the assistance of Cancer Australia, and the Cancer Society of New Zealand and the Cancer Research Trust New Zealand (formerly Genesis Oncology Trust).

Prostate cancer post-prostatectomy radiotherapy: CT vs MRI for vesico-urethral anastomosis target delineation.

BACKGROUND: Vesico-urethral anastomosis (VUA) is critical to the clinical target volume (CTV) in post-prostatectomy radiotherapy (PPRT), as it is the commonest site of recurrence. Typically, this is performed on a CT alone but guidelines recommend MRI. OBJECTIVE: To evaluate the VUA spatial differences between CT (ctVUA) and MRI (mrVUA) and analyse its impact on the CT defined CTV (ctCTV) as recommended by published guidelines. MATERIALS AND METHODS: We identified 34 patients with a co-registered simulation CT and T2 weighted MRI. The VUA was located on CT and MRI whilst blinded to the opposing scan. The differences were analysed using Wilcoxon's Signed Rank Test. The mrVUA coverage was investigated using three ctCTV margins of 5mm, 8mm and 12mm. RESULTS: Median age was 63years with 59% having pT3a disease and median Gleason score of 7. The mrVUA was coincident with the ctVUA in 12% and inferior in 88%. Median difference was 5mm (0-10mm) (P<0.0001). Only a ctCTV margin of 12mm would have encompassed all mrVUAs. A ctCTV margin of 8mm and 5mm resulted in 12% and 38% cases where the VUA was excluded from the ctCTV. CONCLUSIONS: MRI is important for the accurate delineation of VUA for PPRT.

Severe rhabdomyolysis from red-bellied black snake (Pseudechis porphyriacus) envenoming despite antivenom.

Envenoming by the Australian red-bellied black snake (Pseudechis porphyriacus) causes non-specific systemic symptoms, anticoagulant coagulopathy, myotoxicity and local effects. Current management for systemic envenoming includes administration of one vial of tiger snake antivenom within 6 h of the bite to prevent myotoxicity. We present a case of severe rhabdomyolysis in a 16 year old male which developed despite early administration of one vial of tiger snake antivenom. Free venom was detected after the administration of antivenom concurrent with rapidly decreasing antivenom concentrations. The case suggests that insufficient antivenom was administered and the use of larger doses of antivenom need to be explored for red-bellied black snake envenoming.

Sunitinib tissue distribution changes after coadministration with ketoconazole in mice.

Sunitinib is a multitargeted tyrosine kinase inhibitor approved for gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors. It is metabolized via CYP3A4 and has low brain penetration due to efflux transporters ABCB1B and ABCG2. We studied the interaction with ketoconazole (50 mg/kg), antifungal drug which shares metabolic pathways and efflux transporters, in ICR female mice after oral coadministration (30 min apart) of 60 mg/kg sunitinib (study group) versus sunitinib alone (control group). Plasma, liver, kidney and brain sunitinib concentrations were measured by HPLC at 2, 5, 10, 20, 40 min, 1, 2, 4, 6, 12 h post-sunitinib administration, and non-compartmental pharmacokinetic parameters estimated. In plasma, ketoconazole coadministration increased plasma maximum concentration (C MAX) 60 %, delayed time to C MAX (T MAX); 1.6-fold greater area under the curve AUC0→∞ (p < 0.001); lower apparent steady-state volume of distribution (V SS/F) and oral clearance (Cl/F) 40 and 61 %, respectively; and shorter elimination half-life (t 1/2). Sunitinib exhibited extensive tissue distribution which increased after ketoconazole coadministration: total area under the curve (AUC0→∞) increased 1.8-, 2.8- and 1.2-fold in kidney, liver and brain, respectively (all p < 0.001). Sunitinib presented high tissue-to-plasma AUC0→∞ ratio in liver (17.8 ± 1.2), kidney (14.6 ± 1.52) and brain (2.25 ± 0.18) which was modified after coadministration: AUC0→∞ ratio increased in liver (31.4 ± 4.7; p < 0.001), kidney (17.1 ± 2.2; p > 0.05) and decreased in brain (1.70 ± 0.23, p > 0.05). The results showed a significant ketoconazole-sunitinib interaction that affected plasma, tissue pharmacokinetics and tissue uptake mechanisms. The study portrays the risk to increase toxicity and potential clinical translatability to treat tumors in tissues.

Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.

Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue-to-plasma AUC0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue-to-plasma partial AUC ratio, the drug tissue targeting index, and the tissue-plasma hysteresis-like plots also showed sex-based ibuprofen-sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences.

Outcomes of chemoradiotherapy in cervical cancer--the Western Australian experience.

PURPOSE: A retrospective review of patients with Stage IB1-IVA cervical cancer treated with combined chemoradiotherapy in Western Australia was conducted with the aim of assessing outcomes and patterns of recurrence. Multivariate analysis was performed to identify potential prognostic factors. METHODS AND MATERIALS: Patients treated with radical chemoradiotherapy for cervical cancer in Western Australia between June 2005 and November 2008 were analyzed. Treatment consisted of external-beam radiotherapy with concurrent weekly cisplatin (40 mg/m(2)), followed by high-dose-rate brachytherapy. The Kaplan-Meier method was used to determine overall survival and disease-free survival, and Cox regression analysis was used to identify potential prognostic factors. RESULTS: Sixty-nine patients were included in the analysis. All patients completed external-beam radiotherapy; however, only 43.5% of patients completed the planned course of brachytherapy. At a median follow-up of 27 months, 24- and 48-month overall survival were 68.8% and 61.1%, respectively. Disease-free survival at 24 and 48 months was 59.4% and 56.7%, respectively. The 2-year local control rate was 70.1%. Nodal involvement resulted in increased risk of disease recurrence (hazard ratio [HR] 6.26, p = 0.002) and death (HR 5.15, p = 0.013). Pretreatment hemoglobin <120 g/L was a negative prognostic factor for disease recurrence (HR 4.20, p = 0.031) and death (HR 8.19, p = 0.020). Completion of brachytherapy improved overall survival (p = 0.039), with a trend to reducing disease recurrence (p = 0.052). The risk of relapse increased with treatment time over 8 weeks (HR 8.18, p = 0.019), however treatment time did not affect the risk of death (p = 0.245). CONCLUSION: The overall survival outcomes in this group of women with locally advanced cervical carcinomas treated with chemoradiotherapy are comparable to worldwide data. Despite the use of modern treatment protocols, a significant proportion of women developed locoregional recurrences and distant failures. Many poor prognostic factors have been identified as contributors to this, including pelvic nodal involvement, incomplete brachytherapy, pretreatment hemoglobin <120 g/L, and treatment time over 8 weeks.