Study and development of encapsulated forms of 4, 5′, 8‐Trimethylpsoralen for topical drug delivery

Trimethylpsoralen (TMP) is often used to treat skin diseases (i.e., psoriasis, vitiligo, etc.). This drug permeates moderately the skin barrier. In the present study, we investigated the effect of formulation on the improvement of TMP skin bioavailability. Three formulations were performed. Each form (liposomes, nanospheres, and EtOH solution) contained 0.05% of TMP. For each preparation, the quantity deposited on the skin surface was 250 µg (Q₀). The TMP percutaneous penetration through ex‐vivo human skin was processed by Franz^® cells (n=4) using a human albumin solution (1.4% w/v) as receiver medium. The percentages of the extracted TMP that permeated through the skin and that were retained in the skin over 24 h, were calculated with respect to Q₀. The values obtained were reported, respectively, as follows: EtOH solution (1.33 vs. 0.08%), liposomes (0.93 vs. 0.93%), and PLG‐nanospheres (0.79 vs. 3.01%). So, considering the correlation between the cumulated amounts of TMP permeated through the skin and the TMP stocked in the skin, the nanosphere form showed the higher quantity of TMP accumulated in the skin structures. On the other hand, the maximum value of the flux (ng/cm²/h) in the steady state of TMP incorporated in each formulation was at 6 h for all formulations: 173.5±1.06 (EtOH solution) > 120.4±1.06 (liposomes) > 93.82±0.88 (PLG‐nanospheres). These results indicate that the controlled release of TMP by incorporation in PLG‐nanospheres may increase drug content in the skin, while maintaining a minimal percutaneous absorption. Finally, this work shows that the PLG‐nanospheres could constitute a promising approach for controlling TMP release in order to maintain its topical activity. Drug Dev. Res. 61:86–94, 2004. © 2004 Wiley‐Liss, Inc.     

Bladder tissue pharmacokinetics of intravesical taxol

Our previous studies have suggested that the ineffectiveness of intravesical mitomycin C or doxorubicin therapy against muscle-invading bladder cancer is in part because of the inability of these drugs to penetrate the urothelium (the urothelial drug concentration is <5% of the concentration in urine). The goal of the present study was to identify agents that are efficiently absorbed across the urothelium. To evaluate the potential use of taxol in intravesical therapy for bladder cancer, we examined the bladder tissue and systemic plasma pharmacokinetics of intravesical taxol in dogs. Animals (∼8 kg body weight) were given an instillation of taxol at 500 μg in 20 ml water. At 120 min postinstillation, the bladder was emptied and excised, and about 85% of the dose was recovered in the urine. The taxol concentration in the urothelium was about 50% of the concentration in the urine, the concentrations then declined logarithmically in the underlying capillary-perfused tissues. The average tissue concentration (∼2 μg/g) was two to three times the reported plasma concentration of 0.75 μg/ml in patients following intravenous infusion of the >100-fold higher dose of 250 mg/m². The steady-state plasma concentration was <0.02% of the average tissue concentration, and was <0.05% of the maximally tolerated plasma concentration in patients. The octanol:water partitioning coefficients of taxol, doxorubicin, and mitomycin were >99, 0.52, and 0.41, which parallels the rank order of the partitioning across urothelium, i.e. taxol (∼50%) >> doxorubicin ≈ mitomycin C (∼3%). In summary, the partitioning of taxol across the urothelium was more favorable than the partitioning of mitomycin C and doxorubicin, and the systemic concentration of taxol resulting from intravesical treatment was insignificant in spite of the extensive absorption into the bladder. We conclude that intravesical delivery of taxol provides a significant bladder tissue targeting advantage, and that taxol represents a viable candidate drug for intravesical bladder cancer therapy. Received: 20 September 1996 / Accepted: 2 December 1996     

Richter’s hernia occurring through a 5-mm laparoscopy sheath incision

We report a case of postoperative Richter’s hernia presenting through a 5-mm sheath incision. A 58-year-old woman having undergone laparoscopic hysterectomy 8 days before presented with severe left abdominal pain, nausea and light-headedness. The hypothesis of a sigmoid volvulus was suggested based on peroperative rectum and sigmoid release, the X-ray finding, and pain evolution. A secondary laparoscopic procedure allowed both diagnosis of a Richter’s hernia through a 5-mm sheath incision and surgical repair of the hernia. The use of this sheath during the laparoscopic vagina suture caused extension of the wound. Large 5-mm sheath defect sufficient for a Richter’s hernia can be created by multiple passes with small instruments and require surgical closure at the end of laparoscopy. Laparoscopy is useful in cases of postoperative complications, particularly when other complementary examinations are less informative.     

Prognostic value of residual node involvement in operable breast cancer after induction chemotherapy

The purpose of this retrospective study was to evaluate the influence of axillary disease on patients' survival after neoadjuvant chemotherapy and to assess patient and tumor characteristics associated with post-chemotherapy axillary involvement.After six induction cycles, 277 patients with operable breast cancer (stage II–III) underwent surgery with axillary dissection, followed by radiotherapy (n = 267) or additional chemotherapy (n = 63) and adjuvant tamoxifen therapy (n = 138). At a median follow-up of 8.5 years, overall survival (OS) and disease-free survival (DFS) were analyzed as a function of node involvement.The differences in OS and DFS according to the number of positive nodes were highly statistically significant with a decreased survival associated with the increasing number of nodes (p = 5 × 10^–6 and 9 × 10^–7, respectively). Upon multivariate analysis, the node number after chemotherapy appeared as the most significant prognostic factor (p = 7 × 10^–4 for OS and p = 3 × 10^–5 for DFS). All the other classical prognostic factors were insignificant, except post-chemotherapy Scarff–Bloom–Richardson (SBR) grading for OS (p = 8 × 10^–4) and adjuvant hormonotherapy for DFS (p = 1 × 10^–2).Although constituting a different parameter from primary surgery data, the number of positive nodes after chemotherapy could still remain a valuable prognostic factor at secondary surgery, raising the question for high risk patients of a second non-cross-resistant adjuvant regimen, or high dose chemotherapy with peripheral blood stem cells support.     

The Kernohan-Woltman Notch Phenomenon : A Systematic Review of Clinical and Radiologic Presentation,Surgical Management,and Functional Prognosis

The Kernohan-Woltman notch phenomenon (KWNP) refers to an intracranial lesion causing massive side-to-side mass effect which leads to compression of the contralateral cerebral peduncle against the free edge of the cerebellar tentorium. Diagnosis is based on “paradoxical” motor deficit ipsilateral to the lesion associated with radiologic evidence of damage to the contralateral cerebral peduncle. To date, there is scarce evidence regarding KWNP associated neuroimaging patterns and motor function prognostic factors. A systematic review was conducted on Medline database from inception to July 2021 looking for English-language articles concerning KWNP, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The research yielded 45 articles for a total of 51 patients. The mean age was 40.7 years-old and the male/female sex ratio was 2/1. 63% of the patients (32/51) suffered from head trauma with a majority of acute subdural hematomas (57%, 29/51). 57% (29/51) of the patients were in the coma upon admission and 47% (24/51) presented pupil anomalies. KWNP presented the neuroimaging features of compression ischemic stroke located in the contralateral cerebral peduncle, with edema in the surrounding structures and sometimes compression stroke of the cerebral arteries passing nearby. 45% of the patients (23/51) presented a good motor functional outcome; nevertheless, no predisposing factor was identified. A Glasgow coma scale (GCS) of more than 3 showed a trend (p=0.1065) toward a better motor functional outcome. The KWNP is a regional compression syndrome oftentimes caused by sudden and massive uncal herniation and leading to contralateral cerebral peduncle ischemia. Even though patients suffering from KWNP usually present a good overall recovery, patients with a GCS of 3 may present a worse motor functional outcome. In order to better understand this syndrome, future studies will have to focus on more personalized criteria such as individual variation of tentorial notch width.     

Establishing Normative Dynamic Postural Control Values in Elite Female Handball Players

BackgroundLower extremity injuries among young female handball players are very common. The modified Star Excursion Balance Test (mSEBT) is a valid clinical tool to assess dynamic postural control and identify athletes with higher risk of injury. However, its interpretation is difficult since performance on this test is highly sport dependent. No normative values on the mSEBT exist in handball.PurposeThe aim of this investigation was to establish normative ranges of mSEBT performance in young, healthy female handball players to help practitioners when interpreting risk estimates.Study designCross-Sectional StudyMethodsAthletes from 14 elite teams were recruited during a national tournament and performed 3 trials in the anterior (ANT), posteromedial (PM), posterolateral (PL) directions of the mSEBT. Means, standard deviations and 95% confidence intervals (95%CI) of normalized reached distances were calculated for each direction and the composite score (COMP). Level of asymmetry between dominant and non-dominant limbs were calculated for each direction using Bland Altman analyses. Group differences were weighed against the established mSEBT minimum detectable differences (MDD) to compare scores between limbs and across different player positions.ResultsOne-hundred and eighty-eight females (16.8±0.9 years) were tested. Mean reach distances were 65.2±5% (64.7-65.7), 110.0±6.2% (109.3-110.6), 107.1±6.2% (106.5-107.8) and 94.1±4.9% (93.6-94.6) for the ANT, PM, PL directions and COMP score respectively. Bias and limits of agreement for limb asymmetry were -0.23% (-5.85%, 5.38%) for ANT, -0.83% (-8.80%, 7.14%) for PM, 0.33% (-8.51%, 9.17%) for PL and -0.27% (-4.88%, 4.33%) for COMP score. No meaningful differences were observed between limbs or across player positions since the values did not exceed the MDD and all 95%CIs overlapped.ConclusionThis study provides normative performance values for dynamic postural control as measured by the mSEBT among young, healthy, elite female handball players. Considering the high incidence of injury in this population, these values can be used for injury risk reduction and return to sport decisions. Further prospective studies are needed to established specific cut-off scores in this population.Level of evidence2c     

Posterior pelvic exenteration for ovarian cancer: surgical and oncological outcomes

ObjectivePosterior pelvic exenteration (PPE) can be required to achieve complete resection in ovarian cancer (OC) patients with large pelvic disease. This study aimed to analyze morbidity, complete resection rate, and survival of PPE.MethodsNinety patients who underwent PPE in our Comprehensive Cancer Center between January 2010 and February 2021 were retrospectively identified. To analyze practice evolution, 2 periods were determined: P1 from 2010 to 2017 and P2 from 2018 to 2021.ResultsA 82.2% complete resection rate after PPE was obtained, with rectal anastomosis in 96.7% of patients. Complication rate was at 30% (grade 3 in 9 patients), without significant difference according to periods or quality of resection. In a binary logistic regression adjusted on age and stoma, only age of 51–74 years old was associated with a lower rate of complication (odds ratio=0.223; p=0.026). Median overall and disease-free survivals (OS and DFS) from initial diagnosis were 75.21 and 29.84 months, respectively. A negative impact on OS and DFS was observed in case of incomplete resection, and on DFS in case of final cytoreductive surgery (FCS: after ≥6 chemotherapy cycles). Age ≥75-years had a negative impact on DFS for new OC surgery. For patients with complete resection, OS and DFS were decreased in case of interval cytoreductive surgery and FCS in comparison with primary cytoreductive surgery.ConclusionPPE is an effective surgical measure to achieve complete resection for a majority of patients. High rate of colorectal anastomosis was achieved without any mortality, with acceptable morbidity and high protective stoma rate.     

Quantitative glycoproteomics of high-density lipoproteins

In this work, we developed a targeted glycoproteomic method to monitor the site-specific glycoprofiles and quantities of the most abundant HDL-associated proteins using Orbitrap LC-MS for (glyco)peptide target discovery and QqQ LC-MS for quantitative analysis. We conducted a pilot study using the workflow to determine whether HDL protein glycoprofiles are altered in healthy human participants in response to dietary glycan supplementation.

The optimized HDL glycoproteomics method was sensitive enough to detect the effects of dietary supplements on HDL protein glycoprofiles even in a small sample size.