Salivary iodide status as a measure of whole body iodine homoeostasis?

Iodine is a trace element required to produce the thyroid hormones, which are critical for development, growth and metabolism. To ensure appropriate population iodine nutrition, convenient and accurate methods of monitoring are necessary. Current methods for determining iodine status either involve a significant participant burden or are subject to considerable intra-individual variation. The continuous secretion of iodide in saliva potentially permits its use as a convenient, non-invasive assessment of status in populations. To assess its likely effectiveness, we reviewed studies analysing the association between salivary iodide concentration (SIC) and dietary iodine intake, urinary iodide concentration (UIC) and/or 24-h urinary iodide excretion (UIE). Eight studies conducted in different countries met the inclusion criteria, including data for 921 subjects: 702 healthy participants and 219 with health conditions. SIC correlated positively with UIC and/or UIE in four studies, with the strength of relationship ranging from r = 0·19 to r = 0·90 depending on sampling protocol, age, and if salivary values were corrected for protein concentration. Additionally, SIC positively correlated with dietary intake, being strongest when saliva was collected after dinner. SIC varied with external factors, including thyroid function, use of some medications, smoking and overall health status. Evidence provided here supports the use of SIC as a viable, low-burden method for determining iodine status in populations. However, small sample sizes and high variability indicates the need for more extensive analyses across age groups, ethnicities, disease states and dietary groups to clarify the relative accuracy and reliability in each case and standardise procedure.

Comparison of all-polyethylene and metal-backed modular tibial components in endoprosthetic reconstruction of the distal femur.

INTRODUCTION: All-polyethylene (AP) tibial components have demonstrated equivalent or improved long-term survivorship and reduced cost compared with metal-backed (MB) components in primary total knee arthroplasty; however, there is a lack of data comparing these outcomes in the setting of an oncologic endoprosthetic reconstruction. METHODS: A total of 115 (88 AP:27 MB) patients undergoing cemented distal femur endoprosthetic reconstruction following oncologic resection were reviewed. Mean age was 40 years and 51% were females. Cumulative incidences of all-cause revision, tibial component revision, reoperation, and infection were calculated utilizing a competing risk analysis with death as the competitor. Mean follow-up was 14 years. RESULTS: The 10-year cumulative incidence of all-cause revision was 19.9% in the AP group and 16.3% in the MB group (hazard ratio [HR] = 0.93, p = 0.88). The cumulative incidence of tibial component revision was significantly lower in AP compared with MB at 10 years (1.1% vs. 12.5%, HR = 0.18, p = 0.03). There was no difference in infection-free survival when comparing the two groups (p = 0.72). CONCLUSIONS: Reconstruction utilizing an MB or AP tibia component resulted in equivalent overall outcome; however, the tibial component in the AP group was less likely to be revised. AP tibial component should be considered for all primary oncologic reconstructions in the distal femur. LEVEL OF EVIDENCE: Level III Therapeutic.

Efficacy and toxicity of prolonged pegylated liposomal doxorubicin use in women with recurrent epithelial ovarian cancer.

OBJECTIVE: To evaluate the efficacy and toxicity of extended duration pegylated liposomal doxorubicin (PLD) in women with recurrent epithelial ovarian carcinoma (rEOC). METHODS: Women with rEOC who received >7 cycles of PLD were retrospectively identified. Response was determined by RECIST 1.1. Progression free survival (PFS) and overall survival (OS) were calculated from PLD initiation. Toxicity was assessed by CTCAE v5.0. Kaplan Meier estimates and Cox proportional hazards were used to evaluate differences in time to recurrence or survival. RESULTS: 69 patients with rEOC received a median of 11.0 cycles (range, 7-115) at a median cumulative dose of 400 mg/m2 (range, 210-4600 mg/m2); 29.0% (n = 20) had platinum sensitive and 71.0% (n = 49) had platinum resistant disease. Of the observed grade ¾ toxicities (31.9%; n = 22), dermatologic were most frequent (n = 13; 18.8%). 41 women (59.4%) experienced clinical benefit; complete response in 17.4% (n = 12), partial response in 13.0% (n = 9) and stable disease in 29.0% (n = 20). Median PFS for all patients was 13.0 months (95% CI, 10.7, 15.2); there were no significant differences between platinum sensitive versus resistant disease (15.9 months vs. 12.3 months; HR 1.15, 95% CI, 0.66, 2.00; p = .61). With extended duration PLD, median OS was 40.2 months (95% CI 30.0, 49.0); no significant differences were noted for platinum sensitive versus resistant disease (44.7 months vs. 33.3 months; HR 1.85, 95% CI, 0.91, 3.78; p = .07). Four cases (5.8%) of oral squamous cell carcinoma occurred during treatment. CONCLUSIONS: Among women with both platinum sensitive and resistant rEOC who received >7 cycles of PLD, approximately one-half experienced sustained clinical benefit with acceptable toxicity. PLD may be considered for extended usage and maintenance in initially responding women with rEOC at least stable disease.

Incidence of squamous cell carcinomas of the head and neck following prolonged pegylated liposomal doxorubicin.

Despite numerous case reports, the incidence of a secondary diagnosis of head and neck squamous cell carcinoma (HNC) following pegylated liposomal doxorubicin (PLD) treatment is unknown. Computerized pharmacy records were searched at a large, multi-center healthcare system for patients who received PLD. Electronic medical records were searched to identify the patient's age at treatment initiation of PLD, diagnosis for which they were treated with PLD, number of courses and total cumulative dose of PLD (TCDPLD) and secondary malignancies. Published PLD associated HNC was utilized to determine the lowest and median TCDPLD doses associated with HNC. One thousand two hundred ninety eligible patients who had been treated with PLD were identified. The lowest TCDPLD associated HNC in the literature is 405 mg/m2. In our healthcare system, 275 patients received more than 400 mg/m2 yielding a risk of 0.004%. One hundred fifty-one patients received the lowest TCDPLD associated with HNC cancer in our series which was 640 mg/m2 yielding a risk of 0.007%. Four of 30 patients (13.3%) developed HNC who received the median TCDPLD associated with HNC in the literature of 1440 mg/m2. Five of 20 patients (25%) receiving 1650 mg/m2 developed HNC in our healthcare system. Prolonged therapy with PLD is associated with an increased risk of HNC. This risk appears to be related to the cumulative dose varying from 0.004 to 13.3% at the lowest and median TCDPLD of reported cases in the literature, respectively. Oncologists need to be aware of this risk and to screen patients appropriately.

Reduction in skin and mucosal toxicity with pegylated liposomal doxorubicin utilizing every 2-week dosing.

Four ovarian cancer patients with severe plantar palmar erythrodysesthesia or mucositis precluding further therapy from pegylated liposomal doxorubicin on the standard every 4 week schedule were able to be treated on every 2-week schedule without recurrence of plantar palmar erythrodysesthesia or stomatitis.

Long-Term Outcome of Hip Arthroplasty in the Setting of Pigmented Villonodular Synovitis.

BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare, benign, painful proliferation of the synovium previously treated successfully with total hip arthroplasty (THA). Published results come from small series; therefore, the purpose of this study is to investigate the outcomes of THA in the setting of PVNS. METHODS: We identified 25 patients with histologically confirmed, diffuse PVNS who underwent THA between 1971 and 2013. Mean follow-up and age was 10 years and 39 years. Before arthroplasty, 16 patients (64%) had at least 1 surgical procedure (mean, 1; range, 1-3) to treat PVNS. Twenty (80%) patients had "active" disease and underwent synovectomy. No constrained acetabular components were used. RESULTS: The 10-year disease free-survival was 100%. Recurrence occurred in 1 patient at 24 years postoperatively. Nineteen patients (76%) sustained a complication (most commonly component loosening (n = 12 [48%]), and 16 required revision surgery. The 10-year revision-free survival was 66% for conventional polyethylene implants and 100% for highly cross-linked polyethylene devices. Mean Harris Hip Score improved significantly from 48 (range, 23-69) preoperatively to 78 (range, 47-96) postoperatively (P < .001). CONCLUSION: THA in the setting of PVNS improves patient function with a low rate of local recurrence. Complication and revision rates are high in this series likely owing to the young and active patient population and the use of conventional polyethylene. Modern bearings theoretically reduce the risk of revision.

Long-term use of pegylated liposomal doxorubicin to a cumulative dose of 4600 mg/m2 in recurrent ovarian cancer.

Pegylated liposomal doxorubicin (PLD) is used widely in gynecologic oncology and other oncology disciplines. Native doxorubicin use is associated with the potential for significant toxicity. Cardiac toxicity in particular limits lifetime dose. PLD has not been shown to be associated with clinical cardiac toxicity. We report on the long-term use of PLD in a patient with recurrent high-grade serous ovarian cancer to a lifetime dose of 4600 mg/m. This therapy was associated with long-term stable disease, good performance status, and minimal adverse effects.

Efficacy of Pegylated Liposomal Doxorubicin in Low-Grade Serous Ovarian Carcinoma.

OBJECTIVE: The aim of this study was to assess the efficacy of pegylated liposomal doxorubicin (PLD) in low-grade serous ovarian carcinoma (LGSOC). METHODS: We retrospectively identified patients with LGSOC who were treated with PLD. Response to therapy was evaluated by RECIST 1.1 criteria. Progression-free survival (PFS) and overall survival were calculated. In addition, PFS on PLD was compared with the patient's most recent PFS on previous therapy. RESULTS: Twenty-four patients were treated with PLD. Three patients were not evaluable, leaving 21 patients evaluable for response. Pegylated liposomal doxorubicin was dosed at 40 mg/M every 28 days except in 7 patients (5 received PLD dosed at 30 mg/M in combination with carboplatin and 2 received PLD dosed at 20 mg/M, one of which was in combination with etoposide). Four of the patients who received PLD in combination subsequently received PLD alone for 4+, 12, 21, and 29 cycles, respectively. Three patients (14.3%) had a complete response and remained progression free at 8, 31, and 34 months, respectively. Two of these patients received PLD alone. The third complete response patient initially received PLD in combination with carboplatin and then went on to receive PLD alone during which a complete radiologic response was achieved. No difference in response or PFS by platinum sensitivity was noted (Ps = 0.73 and 0.62, respectively). Fourteen patients had stable disease for a median of 18 months. Among the 14 patients with stable disease, the PFS on PLD exceeded the previous PFS in 11 patients (78.6%) from 1.3 to 20.6 folds, with a median of 3.5 folds. The 2 of the 3 lowest increases in PFSs were seen in patients whose therapy was terminated despite stable disease. CONCLUSIONS: Pegylated liposomal doxorubicin is relatively active in LGSOC. The treatment of stable disease resulted in increase in PFS in 78.6% of patients by a mean of 350%.

A phase I trial of pegylated liposomal doxorubicin (PLD), carboplatin, bevacizumab and veliparib in recurrent, platinum-sensitive ovarian, primary peritoneal, and fallopian tube cancer: An NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of veliparib combined with PLD and carboplatin (CD) in patients with recurrent, platinum-sensitive epithelial ovarian cancer. To determine the tolerability at the MTD combined with bevacizumab. METHODS: Patients received PLD (30mg/m(2), IV) and carboplatin (AUC 5, IV) on day 1 with veliparib on days 1-7 (intermittent) or days 1-28 (continuous). Standard 3+3 design was used in the dose escalation phase with DLTs based on the first cycle. Once the MTDs were determined, cohorts of 6 patients were enrolled to each regimen with bevacizumab (10mg/kg on days 1 and 15) to assess feasibility. DLTs were based on the first 4cycles of treatment in the bevacizumab cohorts. RESULTS: In the dose-escalation phase, 27 patients were treated at 3 dose levels with DLTs noted in 6 patients including grade 4 thrombocytopenia (n=4), and prolonged neutropenia >7days (n=3). At the MTD of veliparib (80mg p.o. b.i.d. for both dosing arms), myelosuppression was the DLT. At MTD, 12 additional patients were treated with bevacizumab with 9 patients experiencing DLTs including grade 4 thrombocytopenia (n=4), prolonged neutropenia >7days (n=1), grade 3 hypertension (n=5), and grade 5 sepsis (n=1). CONCLUSIONS: The MTD of veliparib combined with CD is 80mg p.o. b.i.d. in women with recurrent, platinum-sensitive ovarian cancer. With bevacizumab, DLTs were noted in 9 out of 12 patients. Lower doses of veliparib will need to be considered when given in combination with platinum-based therapies.

Balloon-assisted osteoplasty of periacetabular tumors following percutaneous cryoablation.

PURPOSE: To describe the feasibility, safety, and effectiveness of a technique using vertebral augmentation balloons to promote delivery of cement into periacetabular tumors after cryoablation for fracture prevention. MATERIALS AND METHODS: A retrospective review was performed of seven consecutive patients (six men and one woman; mean age, 64 y ± 8) with unilateral periacetabular tumors (mean size, 4.2 cm ± 1.4) treated with cryoablation and balloon-assisted osteoplasty for fracture prevention. Cortical defects were seen in six (86%) tumors, and additional pathologic fractures occurred in five (71%) tumors before treatment. The cohort included six (86%) Harrington class I defects and one (14%) class II defect. Procedures were performed with computed tomography fluoroscopic guidance and general anesthesia. Vertebral augmentation balloons (mean, 2; range, 1-4) were inflated within the ablation cavity immediately before or during cement injection. RESULTS: All procedures were technically successful. Median percentage tumor fill was 63% (range, 17%-96%). Minor cement leakage occurred in two (29%) patients with no symptomatic or intraarticular extravasation. A new nondisplaced fracture occurred in one patient and was conservatively managed. No major complications occurred. Local tumor progression occurred in one (20%) of five patients with imaging follow-up. CONCLUSIONS: Balloon-assisted osteoplasty after cryoablation of periacetabular tumors appears feasible, safe, and effective for fracture prevention. This technique directs cement instillation into ablation defects with a high degree of filling and minimal leakage.

Tantalum acetabular cups provide secure fixation in THA after pelvic irradiation at minimum 5-year followup.

BACKGROUND: Pelvic radiation has been commonly used to treat gastrointestinal, genitourinary, or hematopoietic malignancies. Conventional THA in these patients reportedly have high rates of fixation failure. Although secure short-term fixation reportedly occurs with trabecular metal implants following pelvic radiation, it is unclear whether the fixation is durable. QUESTIONS/PURPOSES: We determined the survival of trabecular metal acetabular components in patients having THA following pelvic radiation and assessed function and radiographic loosening. METHODS: We retrospectively reviewed 29 patients with prior pelvic radiation who had 34 arthroplasties using trabecular metal acetabular components from 1998 and 2005. The mean pelvic radiation dose was 6300 cGy. We collected the following data: patient demographics, surgery and implant information, clinical and radiographic followup, and tumor and radiotherapy related details. We obtained Harris hip scores (HHS) on all patients. Ten patients died of disease prior to 5 years and two patients were excluded, leaving 17 patients (22 hips) with a minimum of 5 years of clinical (mean, 78 months; median, 71; range, 57-116) and radiographic (mean, 73; median, 65; range, 51-116) followup. RESULTS: All implants were in place in the surviving patients. The mean HHS improved from 36 preoperatively to 80 at latest followup. There were no reoperations for any reason, and we observed no implant loosening or migration at final followup in surviving or deceased patients. CONCLUSIONS: Tantalum trabecular metal acetabular components restored function and provided durable reconstruction in patients undergoing THA following prior pelvic radiation. We observed no clinical or radiographic failures at a minimum 5-year followup. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Recurrent giant cell tumor of long bones: analysis of surgical management.

BACKGROUND: Treatment of giant cell tumor of bone (GCT) often is complicated by local recurrence. Intralesional curettage is the standard of care for primary GCTs. However, there is controversy whether intralesional curettage should be preferred over wide resection in recurrent GCTs. QUESTIONS/PURPOSES: We investigated the rerecurrence-free survival after surgical treatment of recurrent GCTs to determine the influence of the surgical approach, adjuvant treatment, local tumor presentation, and demographic factors on the risk of further recurrence. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 46 patients with recurrent GCTs of long bones treated with wide resection or intralesional curettage and compared these cohorts. Recurrence rates, risk factors for recurrence, and the development of pulmonary metastases were determined. The minimum followup was 37 months (mean, 134 months; range, 37-337 months). RESULTS: The rate of rerecurrence after wide resection was 6%. Intralesional curettage showed an overall rerecurrence rate of 32%. Implantation of polymethylmethacrylate (PMMA) instead of bone grafting was associated with a lower risk of subsequent recurrence in intralesional procedures (14% versus 50%). Extracompartmental disease did not increase the risk of rerecurrence. Pulmonary metastases occurred in seven patients and appeared independent of the surgical treatment modality chosen. CONCLUSIONS: Intralesional curettage with methylmethacrylate for recurrent GCT provided equivalent tumor control compared with resection in this retrospective study. If joint salvage is possible, we advocate this treatment over resection in recurrent GCTs to preserve the native joint articulation. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Giant cell tumor of bone: risk factors for recurrence.

BACKGROUND: Many surgeons treat giant cell tumor of bone (GCT) with intralesional curettage. Wide resection is reserved for extensive bone destruction where joint preservation is impossible or when expendable sites (eg, fibular head) are affected. Adjuvants such as polymethylmethacrylate and phenol have been recommended to reduce the risk of local recurrence after intralesional surgery. However, the best treatment of these tumors and risk factors for recurrence remain controversial. QUESTIONS/PURPOSES: We evaluated the recurrence-free survival after surgical treatment of GCT to determine the influence of the surgical approach, adjuvant treatment, local tumor presentation, and demographic factors on the risk of recurrence. METHODS: We retrospectively reviewed 118 patients treated for benign GCT of bone between 1985 and 2005. Recurrence rates, risk factors for recurrence and the development of pulmonary metastases were determined. The minimum followup was 36 months (mean, 108.4 ± 43.7; range, 36-233 months). RESULTS: Wide resection had a lower recurrence rate than intralesional surgery (5% versus 25%). Application of polymethylmethacrylate decreased the risk of local recurrence after intralesional surgery compared with bone grafting; phenol application alone had no effect on the risk of recurrence. Pulmonary metastases occurred in 4%; multidisciplinary treatment including wedge resection, chemotherapy, and radiotherapy achieved disease-free survival or stable disease in all of these patients. CONCLUSION: We recommend intralesional surgery with polymethylmethacrylate for the majority of primary GCTs. Because pulmonary metastases are rare and aggressive treatment of pulmonary metastases is usually successful, we believe the potential for metastases should not by itself create an indication for wide resection of primary tumors. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Randomized phase III study of canfosfamide in combination with pegylated liposomal doxorubicin compared with pegylated liposomal doxorubicin alone in platinum-resistant ovarian cancer.

OBJECTIVE: To evaluate the safety and efficacy of canfosfamide in combination with pegylated liposomal doxorubicin (PLD) in platinum-resistant ovarian cancer (OC). METHODS: Patients with platinum-refractory or -resistant (primary or secondary) OC were randomized to receive canfosfamide at 1000 mg/m² and PLD at 50 mg/m² intravenously or PLD alone at 50 mg/m2 intravenously on day 1 every 28 days until tumor progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Other end points were objective response rate and safety. The study was originally planned for 244 patients. The trial was temporarily placed on hold after 125 patients were randomized while the results of another trial were being reviewed and the sponsor decided not to resume enrollment. The interim analysis became the final analysis. RESULTS: The median PFS was 5.6 months for canfosfamide + PLD (n = 65) versus 3.7 months for PLD (n = 60) (hazards ratio, 0.92; P = 0.7243). A preplanned subgroup analysis showed that 75 patients with platinum-refractory or primary platinum-resistant OC had a median PFS of 5.6 months for canfosfamide + PLD versus 2.9 months for PLD (hazards ratio, 0.55; P = 0.0425). Hematologic adverse events were 66% on the canfosfamide + PLD arm versus 44% on the PLD arm, manageable with dose reductions. Nonhematologic adverse events were similar for both arms. The incidence of palmar-plantar erythrodysesthesia and stomatitiswas lower on canfosfamide + PLD(23%, 31%, respectively) versus (39%, 49%, respectively) on PLD. CONCLUSIONS: Overall median PFS showed a positive trend but was not statistically significant. The median PFS in the platinum-refractory and primary platinum-resistant OC patients was significantly longer for canfosfamide + PLD versus PLD. Canfosfamide may ameliorate the palmar-plantar erythrodysesthesia and stomatitis known to be associated with PLD. Further study of this active well-tolerated regimen in platinum-refractory and primary platinum-resistant OC is planned. This study was registered at www.clinicaltrials.gov: NCT00350948.

A comparison of droplet and contact contamination using 3 simulated barrier techniques for COVID-19 intubation: a quality assurance study.

BACKGROUND: The intubation of patients with coronavirus disease 2019 (COVID-19) puts health care workers at risk of infection through aerosol, droplet and contact contamination. We evaluated the risk of droplet and contact contamination for health care workers using 3 intubation barrier techniques as part of a quality assurance study at our institution. METHODS: This randomized quality assurance study was completed at a tertiary academic hospital in Vancouver, British Columbia, Canada, on Apr. 4, 2020. Participants in personal protective equipment performed simulated intubations on a manikin with (a) no barrier, (b) a clear plastic sheet covering the manikin and (c) a plexiglass intubation box over the manikin, in random order. Fluorescein was ejected from inside the manikin's mouth to simulate droplet and contact spread during a standard intubation sequence. Two blinded independent assessors evaluated the location and degree of contamination on the intubator and assistant using an ultraviolet light. Contamination severity was rated in a standard fashion (0 = none; 1 = minor; 2 = major). The primary outcome was total contamination score and secondary outcomes were scores between intubator and assistant, anatomic areas contaminated and qualitative feedback on ease of intubation. RESULTS: Five participants completed this study. Total contamination score was different between the 3 groups for the intubator (p = 0.02) but not the assistant (p = 0.2). For the intubator, the total contamination score was higher when the sheet was used (median 29 [interquartile range (IQR) 25-34]) than when the box was used (median 17 [IQR 15-22]) or when no barrier was used (median 18 [IQR 13-21]). All 5 participants reported challenges during intubation using the sheet. INTERPRETATION: Use of a plastic sheet while intubating patients with COVID-19 may increase the risk of droplet and contact contamination during intubation and impede intubation. Further study should be undertaken before implementing barrier techniques in practice.

Comparison of Porous Tantalum Acetabular Implants and Harrington Reconstruction for Metastatic Disease of the Acetabulum.

BACKGROUND: The periacetabular region is a common location for metastatic disease. Although large lytic acetabular defects are commonly treated with a hip arthroplasty with a cemented component according to a Harrington-style reconstruction, the use of highly porous uncemented tantalum acetabular components has been described. Currently, there are no direct comparisons of these reconstructive techniques. The purpose of this study was to compare the outcomes of the Harrington technique and tantalum acetabular component reconstruction for periacetabular metastases. METHODS: From 2 tertiary sarcoma centers, we retrospectively reviewed 115 patients (70 female and 45 male) with an acetabular metastatic defect who had been treated between 2002 and 2015 with a total hip arthroplasty using either the cemented Harrington technique (78 patients) or a tantalum acetabular reconstruction (37 patients). The mean patient age was 61 years, and the most common Eastern Cooperative Oncology Group status was 3 (39 patients). The mean follow-up for surviving patients was 4 years. RESULTS: An additional surgical procedure was performed in 24 patients (21%). Harrington-style reconstructions were more likely to require a reoperation compared with tantalum reconstructions (hazard ratio [HR], 4.59; p = 0.003). The acetabular component was revised in 13 patients (11%); 5 patients (4%) underwent revisions that were due to loosening of the acetabular component. The 10-year cumulative incidence of revision of the acetabular component for loosening was 9.6% in the Harrington group and 0% in the tantalum group (p = 0.09). The mean Harris hip score significantly improved following reconstruction (31 to 67 points; p < 0.001), with no significant difference (p = 0.29) between groups. CONCLUSIONS: In patients with periacetabular metastatic disease treated with total hip arthroplasty, an acetabular reconstruction strategy utilizing highly porous tantalum acetabular components and augments successfully provided patients with a more durable construct with fewer complications compared with the cemented Harrington-style technique. LEVELS OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A Novel Liposomal S-Propargyl-Cysteine: A Sustained Release of Hydrogen Sulfide Reducing Myocardial Fibrosis via TGF-ß1/Smad Pathway.

PURPOSE: S-propargyl-cysteine (SPRC; alternatively known as ZYZ-802) is a novel modulator of endogenous tissue H2S concentrations with known cardioprotective and anti-inflammatory effects. However, its rapid metabolism and excretion have limited its clinical application. To overcome these issues, we have developed some novel liposomal carriers to deliver ZYZ-802 to cells and tissues and have characterized their physicochemical, morphological and pharmacological properties. METHODS: Two liposomal formulations of ZYZ-802 were prepared by thin-layer hydration and the morphological characteristics of each liposome system were assessed using a laser particle size analyzer and transmission electron microscopy. The entrapment efficiency and ZYZ-802 release profiles were determined following ultrafiltration centrifugation, dialysis tube and HPLC measurements. LC-MS/MS was used to evaluate the pharmacokinetic parameters and tissue distribution profiles of each formulation via the measurements of plasma and tissues ZYZ-802 and H2S concentrations. Using an in vivo model of heart failure (HF), the cardio-protective effects of liposomal carrier were determined by echocardiography, histopathology, Western blot and the assessment of antioxidant and myocardial fibrosis markers. RESULTS: Both liposomal formulations improved ZYZ-802 pharmacokinetics and optimized H2S concentrations in plasma and tissues. Liposomal ZYZ-802 showed enhanced cardioprotective effects in vivo. Importantly, liposomal ZYZ-802 could inhibit myocardial fibrosis via the inhibition of the TGF-ß1/Smad signaling pathway. CONCLUSION: The liposomal formulations of ZYZ-802 have enhanced pharmacokinetic and pharmacological properties in vivo. This work is the first report to describe the development of liposomal formulations to improve the sustained release of H2S within tissues.

The degradation of lignocellulose in a chemically and biologically generated sulphidic environment.

Acid mine drainage waters are characterised by a low pH, high concentrations of heavy metals, high levels of sulphate salts and low concentrations of organic material. The biological treatment of these waters has been a subject of increasing focus as an alternative to physico-chemical treatment. The utilisation of lignocellulose as a carbon source has been restricted by the amount of reducing equivalents available within the lignocellulose matrix. This present study demonstrated that lignocellulose could be utilised as a carbon source for sulphate reduction. It was shown that the initial reduction of sulphate observed using lignocellulose as a carbon source was due to the easily extractable components. This degradation resulted in the production of sulphide ( approximately 500 mg/l), which further aided in the degradation of lignin (observed as a release of aromatic compounds), allowing greater access to cellulose (and release of reducing sugars).

A phase I study of oral topotecan and pegylated liposomal doxorubicin (doxil) in platinum-resistant ovarian and peritoneal cancer.

OBJECTIVES: The feasibility, safety, and preliminary efficacy of a second-line combination therapy for oral topotecan and pegylated liposomal doxorubicin in patients with platinum-resistant or refractory epithelial ovarian, peritoneal, or tubal carcinoma were investigated in this phase I trial. METHODS: A fixed dose of oral topotecan 2.3 or 1.53 mg/m(2) on days 1 through 5 and escalating doses of pegylated liposomal doxorubicin on day 1 of a 28-day cycle were administered. Dose-limiting toxicities and maximum tolerated doses were recorded. Safety was assessed by adverse event monitoring, and complete and partial responses were recorded. RESULTS: Twenty-two patients received a total of 61 courses of therapy. The maximum tolerated dose of combination therapy was 1.53 mg/m(2) of topotecan on days 1 through 5 and 40 mg/m(2) of pegylated liposomal doxorubicin on day 1 of a 28-day cycle. Because of cumulative thrombocytopenia, the dose of topotecan was decreased by one-third from 2.3 to 1.53 mg/m(2) in an effort to increase the dose of pegylated liposomal doxorubicin. Only 5 patients completed >4 cycles of therapy. The most common grade 4 adverse events at dose level 4 were neutropenia (5/9 patients) and leukopenia (2/9 patients). Overall responses were observed in 2 of 22 patients. CONCLUSIONS: Oral topotecan and pegylated liposomal doxorubicin can be combined at doses that are active as monotherapies. However, the overall response rates after monotherapy in patients with platinum-resistant ovarian cancer are comparable to or higher than those observed in this phase I study of combination therapy.

Paclitaxel, carboplatin and pegylated liposomal doxorubicin in ovarian and peritoneal carcinoma: a phase I study of the Gynecologic Oncology Group.

PURPOSE: Based on the activity and tolerability of liposomal doxorubicin in platinum- and paclitaxel-resistant ovarian carcinoma, we conducted a phase I trial of pegylated liposomal doxorubicin with paclitaxel and carboplatin to determine the maximum tolerated dose (MTD) in chemotherapy naive ovarian, peritoneal and tubal carcinoma patients. METHODS: Three schedules were studied: paclitaxel, carboplatin and pegylated liposomal doxorubicin every 28 days; paclitaxel and carboplatin every 21 days with liposomal doxorubicin every 42 days; and weekly paclitaxel, carboplatin (AUC=5) every 21 days and liposomal doxorubicin every 42 days. The paclitaxel dose was 175 mg/m(2) over 3 h on an every 3-4 week schedule and 60 mg/m(2) when administered weekly. Based on the frequency of neutropenic sepsis, grade 4 thrombocytopenia and > or =grade 3 non-hematologic toxicity, the starting dose of liposomal doxorubicin of 20 mg/m(2) was escalated to determine the MTD. RESULTS: A total of 210 (21-day) cycles were administered to 37 patients. Dose-limiting toxicity (DLT) occurred when liposomal doxorubicin was administered at 40 mg/m(2). Because of treatment-related delays resulting in decreased paclitaxel/carboplatin dose intensity, administration was modified to be given every 21 days, with liposomal doxorubicin given every 42 days. Since neutropenia was the DLT of this schedule, the schema was further modified to administer paclitaxel weekly; however, weekly administration was inconsistent because of toxicity. CONCLUSION: Paclitaxel 175 mg/m(2), carboplatin (AUC=5) and pegylated liposomal doxorubicin 30 mg/m(2) are tolerable without supportive therapy. The usual dose intensity of paclitaxel/carboplatin was maintained by administering liposomal doxorubicin every other cycle.