Safety and feasibility of hyperthermic intraperitoneal chemotherapy during interval cytoreductive surgery in patients with advanced high-grade serous ovarian, fallopian tube, peritoneal cancer in an Australian context.

AIMS: To assess the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreduction surgery (CRS) in advanced high-grade serous ovarian, fallopian tube and peritoneal cancer within an Australian context. METHODS: Data were collected from 25 consecutive patients undergoing CRS and HIPEC from December 2018 to July 2022 at the Peritoneal Malignancy Service at the Mater Hospital Brisbane, Australia. Data collected included demographics, clinical variables, surgical procedures and complications and intra-operative and post-operative indexes of morbidity. RESULTS: Twenty-five women who underwent CRS and HIPEC from December 2018 to July 2022 were included in analysis. Findings indicate that CRS with HIPEC is associated with low morbidity. CONCLUSION: While judicious patient selection is imperative, HIPEC during CRS was well tolerated by all patients and morbidity was comparable to results from the previously reported OVHIPEC-1 trial. HIPEC appears to be a safe and feasible addition to CRS for the treatment of advanced ovarian cancer in Australian practice.

Preclinical Evaluation of a Fluorescent Probe Targeting Receptor CDCP1 for Identification of Ovarian Cancer.

Optimal cytoreduction for ovarian cancer is often challenging because of aggressive tumor biology and advanced stage. It is a critical issue since the extent of residual disease after surgery is the key predictor of ovarian cancer patient survival. For a limited number of cancers, fluorescence-guided surgery has emerged as an effective aid for tumor delineation and effective cytoreduction. The intravenously administered fluorescent agent, most commonly indocyanine green (ICG), accumulates preferentially in tumors, which are visualized under a fluorescent light source to aid surgery. Insufficient tumor specificity has limited the broad application of these agents in surgical oncology including for ovarian cancer. In this study, we developed a novel tumor-selective fluorescent agent by chemically linking ICG to mouse monoclonal antibody 10D7 that specifically recognizes an ovarian cancer-enriched cell surface receptor, CUB-domain-containing protein 1 (CDCP1). 10D7ICG has high affinity for purified recombinant CDCP1 and CDCP1 that is located on the surface of ovarian cancer cells in vitro and in vivo. Our results show that intravenously administered 10D7ICG accumulates preferentially in ovarian cancer, permitting visualization of xenograft tumors in mice. The data suggest CDCP1 as a rational target for tumor-specific fluorescence-guided surgery for ovarian cancer.

Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma.

High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses-of more than 10-fold lower than previously reported for other cancers-significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.

Natural history of fetal trisomy 13 after prenatal diagnosis.

There are currently limited data describing the natural history and outcome for fetal trisomy 13 diagnosed prenatally. The aim of this study was to evaluate the fetal and neonatal outcome for pregnancies with an established prenatal diagnosis of fetal trisomy 13, and a parental decision for continuation of the pregnancy. To this end, the obstetric and neonatal outcome data for such pregnancies, diagnosed at two referral Fetal Medicine Centers, were retrospectively obtained and examined. During the study period, there were 45 cases of trisomy 13 diagnosed at both units, of which 26 (56%) continued with the pregnancy to its natural outcome. There were 12 intrauterine deaths in the cohort resulting in a rate of 46.2% of intrauterine lethality. Conversely, the live birth rate was 53.8%. For infants born alive, neonatal death on day 1 of life occurred in 78.6% of cases. The overall early neonatal mortality rate was 93%. There was one infant death at 6 weeks of age and no survival noted beyond this period. These data provide reliable information for parental counseling pertaining to risk of intrauterine death when trisomy 13 is diagnosed prenatally. These data also indicate that the survival outcome is worse than that previously accepted from studies of postnatal follow up of live born infants with this diagnosis.

Maternal weight and body composition in the first trimester of pregnancy.

OBJECTIVE: Previous studies on weight gain in pregnancy suggested that maternal weight on average increased by 0.5-2.0 kg in the first trimester of pregnancy. This study examined whether mean maternal weight or body composition changes in the first trimester of pregnancy. DESIGN: Prospective observational study. POPULATION: We studied 1,000 Caucasian women booking for antenatal care in the first trimester of pregnancy. SETTING: Large university teaching hospital. METHODS: Maternal height and weight were measured digitally in a standardized way and Body Mass Index (BMI) was calculated. Maternal body composition was measured using segmental multifrequency Bioelectrical Impedance Analysis (BIA). Sonographic examination confirmed the gestational age and a normal ongoing singleton pregnancy in all subjects. MAIN OUTCOME MEASURES: Maternal weight, maternal body composition. RESULTS: The mean BMI was 25.7 kg/m(2) and 19.0% of the women were in the obese category (> or =30.0 kg/m(2)). Cross-sectional analysis by gestational age showed that there was no change in mean maternal weight, BMI, total body water, fat mass, fat-free mass or bone mass before 14 weeks gestation. CONCLUSIONS: Contrary to previous reports, mean maternal weight and mean body composition values remain unchanged in the first trimester of pregnancy. This has implications for guidelines on maternal weight gain during pregnancy. We also recommend that calculation of BMI in pregnancy and gestational weight gain should be based on accurate early pregnancy measurements, and not on self-reported or prepregnancy measurements.

Tracheomalacia in adults with cystic fibrosis: determination of prevalence and severity with dynamic cine CT.

PURPOSE: To determine the prevalence and severity of tracheomalacia in adults with cystic fibrosis (CF) by using dynamic cine multidetector computed tomography (CT) and to correlate these findings with pulmonary function test (PFT) results and the severity of parenchymal lung disease. MATERIALS AND METHODS: In this institutional review board-approved HIPAA-compliant study, 40 patients with CF (22 men, 18 women; mean age, 28 years +/- 8 [standard deviation]; age range, 18-54 years) prospectively underwent PFTs, standard thin-section CT, and two dynamic cine multidetector CT acquisitions. Ten control subjects underwent dynamic cine multidetector CT. After standard thin-section CT was completed, dynamic cine multidetector CT was performed during a forced expiratory maneuver and during coughing. Dynamic cine multidetector CT images in nine patients were excluded. Maximal inspiratory, dynamic expiratory, and end-expiratory tracheal luminal areas were compared (Student t test) and correlated (Spearman rank) with PFT results and severity of parenchymal lung disease. RESULTS: Mean predicted forced expiratory volume in 1 second (FEV(1)) was 70.6% +/- 20.7, and mean Bhalla CT score was 41.8% +/- 13.6. In patients with CF, dynamic cine mean tracheal cross-sectional area reduction was 51.7% +/- 18.4 (range, 9%-89%) for forced expiratory maneuvers and 68.8% +/- 11.7 (range, 18%-88%) for coughing (P = .001). Tracheomalacia was demonstrated in 24 (69%) patients and no control subjects during forced expiratory maneuvers (P = .001) and in 10 (29%) patients and one (10%) control subject during coughing. For end-expiration images, mean tracheal luminal reduction was 16.1% +/- 14.0% (range, 0.0%-53.0%), with one patient demonstrating tracheal luminal reduction of more than 50%. There was no correlation between tracheal cross-sectional luminal reduction and either predicted FEV(1) or CT Bhalla score. CONCLUSION: Tracheomalacia depicted at dynamic cine multidetector CT is a highly prevalent finding in adults with CF. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/2522081956/DC1.

Bone mineral density in cystic fibrosis: benefit of exercise capacity.

The aim of this study was to evaluate the association between bone mineral density (BMD) and objective maximal exercise measurements in adults with cystic fibrosis (CF). Twenty-five CF patients (19 males, 6 females, mean age 25.5 yr, range: 17-52) underwent BMD assessment and maximal-cycle ergometer exercise testing. We examined the relationship between gas exchange (% peak-predicted O(2) uptake, CO(2) output, O(2) saturation), exercise performance (maximum power, exercise duration), and respiratory mechanics (tidal volume, rate) with lumbar spine and total proximal femur BMD. The strongest clinical correlate with BMD was forced expiratory volume at 1s (lumbar spine Z-score, r=0.36; total proximal femur Z-score, r=0.68, p<0.01). The strongest exercise correlate was % peak-predicted O(2) uptake (lumbar spine Z-score, r=0.44, p<0.01; total proximal femur Z-score, r=0.59, p<0.01). There was a closer association between exercise parameters and total proximal femur BMD (r=0.43-0.60) than with lumbar spine BMD (r=0.04-0.45). Multiple regression analysis revealed VO(2) to be the strongest independent predictor of BMD (R(2)=0.86, p<0.001) followed by petCO(2) and body mass index (R(2)=0.7 and 0.5, respectively, p<0.01). Exercise appears to influence total proximal femur BMD more than lumbar spine BMD in CF. Exercise rehabilitation programs focusing on peripheral strength training may benefit those CF patients with low total proximal femur BMD.

The repeatability of submaximal endurance exercise testing in cystic fibrosis.

Submaximal endurance cycle ergometer exercise tests are used to measure the efficacy of an exercise intervention, but the repeatability of these tests in patients with cystic fibrosis (CF) has not been established. The purpose of this study was to examine the repeatability of submaximal endurance testing in stable CF. Fifteen adults with CF underwent two submaximal endurance tests carried out over a 7-day period. A subset of six subjects returned 28 days later for a third submaximal endurance test. Workload was set at 80% of maximum workload and exercise was performed to exhaustion. Oxygen consumption, minute ventilation, tidal volume, carbon dioxide output, respiratory rate, heart rate, and oxygen saturation were measured at rest, at end exercise and at four matched times during the submaximal endurance tests (20, 40, 60, and 80% of exercise duration calculated from the first endurance test). Submaximal endurance test time was highly repeatable with no significant learning effect identified on multiple testing. Submaximal endurance exercise time demonstrated a variability of 5.7% which is consistent with high levels of repeatability. Metabolic, ventilatory and cardiac variables were all also highly reproducible between test days. Submaximal endurance testing is repeatable in stable CF, confirming that submaximal endurance tests are a reliable tool for assessment of therapeutic benefit in patients with CF.

Thin-section CT in patients with cystic fibrosis: correlation with peak exercise capacity and body mass index.

PURPOSE: To evaluate whether thin-section chest computed tomographic (CT) findings correlate with exercise capacity, body mass index (BMI), dyspnea, and leg discomfort in patients with cystic fibrosis (CF). MATERIALS AND METHODS: Institutional ethics committee approval was obtained, and patients provided written informed consent. Twenty-two patients (13 male and nine female patients; mean age, 22 years +/- 5.9; age range, 17-41 years) with stable CF underwent thin-section CT and exercise testing on a cycle ergometer. Three radiologists blinded to the clinical severity of disease and the spirometric findings of all patients independently and randomly scored all scans with a modified Bhalla scoring system. The primary measurement of the outcome of exercise testing was percentage of predicted peak O2 uptake. Univariate (Spearman rank correlation) and multivariate analyses were used to compare thin-section CT, clinical (age, sex, spirometric data, and BMI), and exercise measurements. RESULTS: The correlation between total thin-section CT score and percentage of predicted peak O2 uptake was stronger than the correlation between the percentage of predicted peak O2 uptake and any clinical measurement (R = -0.60, P < .01). The thin-section CT structural abnormalities that had the strongest correlation with percentage of predicted peak O2 uptake were severity of bronchiectasis and presence of sacculations or abscesses (R = -0.70 and -0.71, respectively; P < .01). Multivariate analysis showed total thin-section CT score to be the only significant predictor of exercise capacity, accounting for 42% of the variance in percentage of predicted peak O2 uptake. CONCLUSION: In patients with CF, the correlation between thin-section CT score and exercise limitation is stronger than that between spirometry results or BMI and exercise limitation.

Respiratory factors do not limit maximal symptom-limited exercise in patients with mild cystic fibrosis lung disease.

To evaluate whether respiratory factors limit exercise capacity in patients with mild cystic fibrosis (CF) lung disease (mean FEV(1) = 76 +/- 7.7% predicted) we stressed the respiratory system of seven patients using added dead space (V(D)). Primary outcomes were exercise duration (Ex(dur)) and maximal oxygen uptake (VO(2max)). Dyspnoea/leg-discomfort were assessed at end-exercise. Ex(dur) was identical between control and V(D) studies (520 +/- 152 versus 511 +/ -166 s, p = NS) as was VO(2max)(1.6 +/- 0.5 versus 1.6 +/- 0.6 L/min, p = NS). Significant resting, sub-maximal and maximal workload increases in minute ventilation (V(E)) were detected (70.8 +/- 13.7 versus 79.5 +/- 16.9 L/min, p < 0.05). Analysis of breathing pattern revealed increases in V(E) were attributable to increases in tidal volume (2.0 +/- 0.5 versus 2.2 +/- 0.6 L, p < 0.05) with no change in respiratory frequency. There was no difference in dyspnoea/leg discomfort between tests. The increase in V(E) in response to V(D), with no change in [Exdur/VO(2max) suggests maximal symptom-limited exercise limitation is not primarily limited by respiratory factors in mild CF lung disease. Focused investigation and treatment of non-respiratory factors contributing to exercise limitation may improve exercise rehabilitation in this patient group.

Inhaled beta-agonists improve lung function but not maximal exercise capacity in cystic fibrosis.

BACKGROUND: To investigate the effects of inhaled beta-agonists on sub-maximal and maximal exercise capacity, breathing pattern, dyspnoea, leg-discomfort and spirometry in patients with cystic fibrosis (CF). OBJECTIVES: Eight patients performed two maximal incremental cycle-ergometry tests on separate days with inhaled placebo or salbutamol (600 microg) administered before each test in a randomized, double-blind, placebo-controlled crossover trial. Primary outcomes were exercise duration (Exdur) in seconds (s) and maximal oxygen uptake (VO2max) in litres/minute (L/min). Forced expiratory volume in 1 s (FEV1) was measured immediately pre-inhaler, post-inhaler and post-exercise. Dyspnoea and leg-discomfort were assessed post-exercise. RESULTS: Within-day FEV1 comparisons demonstrated that the placebo test day FEV1 improved significantly post-exercise (0.11 L, p<0.05) and the salbutamol test day FEV1 improved significantly post-inhaler (0.22 L, p<0.001) and post-exercise (0.07 L, p<0.01). Between-day FEV1 comparisons demonstrated significant improvements in post-inhaler (0.17 L, p<0.05) and post-exercise (0.13 L, p<0.05) FEV1 following salbutamol. Sub-maximal and maximal exercise showed no significant difference as shown by Exdur (547+/-154 s vs. 529+/-127 s) and VO2max (1.9+/-0.5 L/min vs. 1.9+/-0.6 L/min). No significant change in breathing pattern, dyspnoea or leg-discomfort was detected. The study had a power of 92% to detect a 10% improvement in Exdur. CONCLUSIONS: In adults with CF, salbutamol improves post-exercise FEV1 and is safe when administered immediately before exercise but does not improve exercise capacity, exercise-induced dyspnoea or leg-discomfort.

Role of arterial hypoxemia and pulmonary mechanics in exercise limitation in adults with cystic fibrosis.

We tested the hypothesis that maximal exercise performance in adults with cystic fibrosis is limited by arterial hypoxemia. In study 1, patients completed two maximal exercise tests, a control and a test with 400 ml of added dead space. Maximal O2 consumption was significantly lower in the added dead space study vs. control (1.04 +/- 0.15 vs. 1.20 +/- 0.11 l/min; P < 0.05), with no difference in peak ventilation. There was significant O2 desaturation during exercise that was equal in both control and added dead space studies. The decrease in maximal O2 consumption with added dead space suggests that maximal exercise in cystic fibrosis is limited by respiratory factors. We subsequently examined whether pulmonary mechanics or arterial hypoxemia limits maximal exercise performance. In study 2, patients completed two maximal exercise tests, a control and a test with 400 ml of added dead space while also breathing 38% O2. Added dead space was used to overcome the suppressive effects of hyperoxia on minute ventilation. Maximal O2 consumption was significantly higher with added dead space and 38% O2 vs. control (1.62 +/- 0.16 vs. 1.43 +/- 0.14 l/min; P < 0.05). Peak ventilation and O2 saturation were significantly greater in the added dead space and 38% O2 test vs. control. The increase in maximal O2 consumption and peak ventilation with added dead space and 38% O2 suggests that maximal exercise in cystic fibrosis is limited by arterial hypoxemia.

Corticosteroids and skeletal muscle function in cystic fibrosis.

Patients with cystic fibrosis (CF) have reduced peripheral muscle strength. We tested the hypothesis that steroid treatment contributes to muscle weakness in adults with CF. Twenty-three stable CF patients were studied. Measurements included knee extensor (KE), knee flexor (KF), elbow flexor (EF), handgrip (HG), expiratory (Pemax), and inspiratory (Pimax) muscle strengths. Spirometry, body mass index (BMI), and days spent in hospital over the preceding 12 mo (DH) were also measured. Average daily dose of prednisolone over the preceding 12 mo (ADD) was 5.1 mg/day. Pearson's correlation analysis revealed that ADD correlated significantly with skeletal muscle strengths (KF%, r = -0.63, P < 0.01) with the exception of HG%. These findings are independent of age, BMI, pulmonary function, and DH. Multiple-regression analysis revealed that ADD was the most significant predictor of all measures of skeletal muscle function except HG%. It was independently responsible for 54% of the variance in Pimax%, for 46% of the variance in Pemax%, for 45% of the variance in KE%, for 39% of the variance in KF%, and for 41% of the variance in EF%. Concomitant medications (e.g., theophylline) were shown to have no causative effect. Corticosteroids contribute to the skeletal muscle weakness seen in CF patients. The correlation of proximal muscle strength, but not HG strength, with steroid dosage further supports a cause-effect relationship.