Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.

Bioequivalence of two formulations of levetiracetam.

This study was conducted in order to compare the bioavailability of two tablet formulations containing 1,000 mg levetiracetam, (S)-a-ethyl-2-oxo-1-pyrrolidine acetamide, 102767-28-2 CAS registry number. 18 healthy subjects were enrolled in a single-center, randomized, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected up to 36.0 hours post-dosing. Levetiracetam levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection, LC-MS/MS method. Pharmacokinetic parameters used for bioequivalence assessment, area under the concentration-time curve from time 0 to time of last non-zero concentration (AUClast) and from time zero to infinitive (AUCinf) and maximum observed concentration (Cmax), were determined from the levetiracetam concentration data using non-compartmental analysis. The 90% confidence intervals obtained by analysis of variance were 88.98 - 108.75% for Cmax, 99.90 - 104.81% for AUClast and 100.11 - 105.23 %for AUCinf this is, within the predefined ranges. Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.

Soft-tissue expansion in lower extremity reconstruction.

Soft-tissue expansion in the lower extremities is typically well tolerated. The more proximal one is--that is, the closer to the thigh and buttocks--the easier and less complication prone the expansion will be. It is another valuable technique for resurfacing the lower extremity and for reconstructing defects in contour and in skin character. There are limitations to this technique, which generally is most useful in late reconstructions. Intraoperative expansion has no place in lower extremity reconstruction. Soft-tissue expansion may be limited by an unsuitable geometry or the sheer size of defects. It should not be used next to open wounds. Soft-tissue expansion offers significant advantage in that the coverage of a defect will be replaced with tissue like that lost. Seldom does one see necrosis of advanced flaps, so that there is little risk of tissue loss in using this modality. There is an excellent vascularity to the flaps and an excellent character to the skin. In addition, in this cost-conscious era, soft-tissue expansion is quite cost effective, and in many cases the procedures can be conducted on an outpatient basis with a minimum of hospitalization, if any. With care to select patients properly, design carefully, and conduct expansion in a leisurely fashion, soft-tissue expansion offers a valuable means of reconstructing both large and small lower extremity defects.

Treatment of extensive sternum keloid scar with surgical removal and immediate reconstruction with skin flaps from a combined mammaplasty.

We report the case of a 47-year-old woman with a large keloid scar on the sternum who was submitted to a simultaneous scar removal with bilateral breast-reduction mammaplasty. Breast reduction was performed to reduce local skin tension and to provide a skin flap for the full reconstruction of the scar-removal site. The association of these surgical procedures stands as a viable alternative for the reconstruction of the sternum region, producing less keloid scarring.

Assessing the role of presuturing on wound closure.

The efficacy of presuturing was tested by quantitating the tissue gains for standardized wounds in a white swine piglet (9 to 11-kg) model. Also measured were the changes in wound closure tension for the wounds. Measurements were carried out at 1, 4, 17, 24, 48, and 72 hours in a total of 20 piglets. Presuturing was carried out on one of the flanks and the opposite flank served as the control. Presuturing achieved a modest tissue gain, amounting to 67 mm at 4 hours and a maximum of 1.4 cm at 48 and 72 hours, for a 4-cm defect. The encouraging tissue gain was unfortunately not paralleled by a decrease in the tension required to approximate the wound edges. At 4 hours, the tension to close the wound was 1.2 N (only 120 g) less than the control wound. This initial small reduction in wound-closing tension was diminished thereafter, and at 72 hours the wounds were stiffer and harder to close than the control. This appeared to be due to tissue edema and was confirmed by an increase in measurable tissue water with increasing time. In this model, presuturing produces a minimal tissue advancement and even less reduction in wound-closing tension. It is concluded, from this work and from previously published work, that undermining will prove generally to be a more useful technique in closing broad defects.

CD82/KAI expression prevents IL-8-mediated endothelial gap formation in late-stage melanomas.

Melanoma cells facilitate endothelial gap formation, the first step during tumor transendothelial migration, which is mediated by both adhesion and endogenously produced chemokines (in particular, interleukin-8 (IL-8)). Tetraspanins are localized to the cell surface in cancer and participate in various functions including invasion of tissues mediated by secretion of cytokines and matrix metalloproteinases. However, little is known about the role of CD82 tetraspanins in malignant melanomas during cancer cell invasion. In this study, we investigated the functional importance of CD82 expression in melanoma-mediated gap formation by using cDNAs to induce CD82 expression in highly invasive melanoma cell lines. Results showed that CD82 expression inhibited melanoma cell-induced gap formation, melanoma cell extravasation in vitro and subsequent lung metastasis development in vivo. Mechanistic studies showed that inducible expression of CD82 in highly metastatic melanoma cells significantly increased p21 expression upon binding of Duffy antigen receptor group (DARC), inducing tumor cell senescence and interrupting IL-8-mediated vascular endothelial (VE)-cadherin disassembly. Taken together, these studies provide a rationale for using drug therapies that restore CD82 expression and inhibit IL-8 production to inhibit late-stage melanoma cell extravasation and subsequent metastasis development.

Bioequivalence studies for two different strengths of montelukast in healthy volunteers: 10 mg film-coated tablets and 5 mg chewable tablets.

In order to assess the bioequivalence of 2 different formulations of montelukast, a pivotal trial for the montelukast 10 mg film-coated tablets formulation and a pivotal trial for the montelukast 5 mg chewable tablets formulation were conducted.For the 10 mg study, 34 healthy subjects were enrolled in a single centre, randomised, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days, while for the 5 mg study, 42 healthy subjects were included in another study with a similar design. For both studies, plasma samples were collected up to 24 h post-dosing and drug levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection.Pharmacokinetic parameters used for bioequivalence assessment, area under the concentration-time curve from time zero to time of last non-zero concentration (AUC0-t) and from time zero to infinity (AUC0-inf) and maximum observed concentration (Cmax), were determined from the drug concentration data using non-compartmental analysis.In the 10 mg study, the 90% confidence intervals obtained by analysis of variance were 99.62-120.51% for Cmax, 102.25-117.37% for AUC0-t and 101.96-116.67% for AUC0-inf, which were within the predefined acceptable range of 80.00-125.00%.In the 5 mg study, the 90% confidence intervals were 91.14-98.46% for Cmax, 93.02-98.42% for AUC0-t and 93.09-98.63% for AUC0-inf, which were within the predefined acceptable range of 80.00-125.00%.Bioequivalence between formulations was concluded both in terms of rate and extent of absorption for both strengths.

Bioequivalence of two formulations of escitalopram.

Escitalopram, CAS registry number 128196-01-0 is an orally administrated selective serotonin reuptake inhibitor (SSRI).The objective of this trial was to assess bioequivalence between an escitalopram formulation manufactured by Grupo Tecnimede and that of a European reference formulation, while evaluating both formulations' tolerability as a secondary objective.24 healthy subjects were enrolled in a single centre, randomised, single-dose, open-label, 2-way crossover study. Drug levels were determined by reverse liquid chromatography and detected by tandem mass spectrometry detection, LC-MS/MS method. Pharmacokinetic parameters used for bioequivalence assessment were determined from the drug concentration data using non-compartmental analysis.Mean±Standard deviation (SD) Cmax values were 18.89±5.06 ng/mL and 18.45±5.05 ng/mL for reference and test, respectively. AUClast was 577.16±196.20 ng · h/mL after the administration of the reference and 577.69±220.88 ng · h/mL for the test. AUCinf was 595.66±203.80 ng · h/mL after the administration of the reference 596.19±235.47 ng · h/mL for the test.The 90% confidence intervals obtained by analysis of variance were 92.38-103.38% for Cmax, 94.10-104.37% for AUClast and 93.80-104.09% for AUCinf, which were within the predefined acceptable range of 80.00-125.00%. Both formulations were well tolerated, with no major side effects and no relevant differences in safety profiles observed between the preparations.The design of the study was adequate to determine the pharmacokinetic parameters of the test and the reference formulations. Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.

Long-term response of isolated limb perfusion with hyperthermia and chemotherapy for Merkel cell carcinoma.

INTRODUCTION: Merkel cell carcinoma (MCC) is a very rare and aggressive neoplasm. Due to its rarity, therapeutic guidelines are not well established, especially for regionally advanced disease. Hyperthermic isolated limb perfusion (HILP) with Melphalan and either with or without tumor necrosis factor-alpha (TNF-alpha) is becoming more common in clinical practice, yet the long-term response is not clear. Previous reports have established indications for treatment of unresectable MCC as well as the outcome of MCC patients receiving perfusion treatment in combination with other therapies (e.g., radiation). METHOD: A review was performed of the most important articles in MEDLINE from the last 20 years related to HILP and MCC. It was possible to collect all cases of HILP from the literature. Details of one case of MCC where HILP was administered was included in the literature review. RESULTS: A total of nine cases of MCC receiving ILP were identified in the literature; of these, seven achieved a complete response, one a partial response and one no response. All five patients treated without TNF-alpha had a complete response. Of the four patients treated with TNF-alpha, two had complete, one partial and one no response. CONCLUSION: Based on the cases described, isolated limb perfusion is an acceptable option to treat regional advanced cases of MCC, and the use of TNF-alpha does not impact the overall response.

The role of free tissue transfer following oncologic resection in the lower extremity.

The current treatment of extremity sarcomas is multimodal, consisting of limb-sparing surgery, adjuvant radiotherapy, and/or chemotherapy. This approach has decreased the need for amputations and increased the demand for coverage of large composite defects. To date, the role of microsurgery in lower extremity reconstruction after oncologic resection has not been well defined. This study reviews a single center's experience with free tissue transfer for reconstruction of the lower extremity after oncologic resection. Fifty-nine free flaps were performed in 57 patients over a 5-year period. Forty-six patients (78%) underwent primary reconstruction and 35 patients (61%) received adjuvant therapy. Overall flap success rate was 96.6%. Most flaps were soft-tissue types including musculocutaneous (78%), skin only (11%), and muscle plus skin graft (4%). Osteocutaneous flaps were uncommon. There were major complications in 12% and minor complications in 7%. This study demonstrates that free tissue transfer for lower extremity reconstruction following oncologic resection has a high success rate that is similar to other free flap applications. It has become an integral part of lower extremity sarcoma management. Free flaps permit uninterrupted adjuvant therapy and enhance the efficacy of limb salvage surgery.

[Extensive trauma of the external ear: surgical management]. / Traumatismos extensos do pavilhão auricular: conduta cirúrgica.

Fifty nine patients with extensive traumatisms of the external ear, including 3 total amputations, 10 partial amputations with maintenance of reduced pedicle and 46 extensive lesions without further vascularization, have been attended in the Emergency Unit of Hospital das Clinicas at University of São Paulo Medical School from 1979 to 1989. Surgical behaviors performed in each case are described and explained in detail. The main purpose of the study was to show the outliving possibilities of the ear even in serious traumas and to emphasize the need of immediate repair of the ear in order to obtain a satisfactory result.

Tissue expansion of sensate skin for pressure sores.

The surgical treatment of pressure sores has improved with the development of many techniques to provide coverage of these defects. Few deliver sensate coverage. This report describes tissue expansion of back skin to provide definitive sensate coverage of a pressure sore, thereby preventing its recurrence. Follow-up of 5.5 years is presented with a review of the literature.

Penicillamine-induced pseudoxanthoma elasticum-like skin changes requiring rhytidectomy.

A 42-year-old woman with pronounced skin laxity of her neck underwent a rhytidectomy and was found to have pseudoxanthoma elasticum-like changes of her skin. Her medical history was significant for Wilson's disease, requiring that she take penicillamine for 26 years. In patients on long-term penicillamine therapy, 20% to 33% will develop a dermatopathy. The drug has been used to alter scar formation in various surgical conditions. Penicillamine is known to alter cross-linking of elastin and collagen fibers. A review of the literature reveals other penicillamine-related dermatopathies that may present to the surgeon.

A comparison of donor and recipient site sensation in free tissue reconstruction of the oral cavity.

In patients who undergo oral cavity reconstruction, loss of sensation plays a vital role in producing disturbances in postoperative oral function. Microsurgical techniques have provided a method of addressing this deficit through the use of sensate cutaneous free flaps in which microneural anastomoses are performed between a sensory nerve supplying the flap, and a recipient nerve in the head and neck. The purpose of this study was to compare the cutaneous sensation of the radial forearm flap and lateral arm flap donor sites, the two most commonly used intraoral sensate flaps. For comparison, sensation was also determined in five intraoral sites: the tip of tongue, lateral tongue, cheek, gingiva, and hard palate. Sensation was evaluated at the two potential donor sites in 66 random subjects using static and moving two-point discrimination, thermal sensation differences, and Semmes-Weinstein monofilament pressures. In the same subjects Semmes-Weinstein monofilament pressures were used to evaluate intraoral sensation. Information was recorded on age, sex, smoking and denture status. All four sensory evaluations demonstrated that the lateral arm flap donor site was more sensitive than the radial forearm donor site. Thermal sensitivity differentials (0.52 vs. 0.40 degrees C, p < 0.001), static two-point discrimination (15.4 vs. 15.0 mm, p < 0.2), moving two-point discrimination (5.8 vs. 4.8 mm, p < 0.03), and Semmes-Weinstein monofilament pressures (5.10 vs. 4.08 g per square millimeter, p < 0.001) all indicated a more sensitive lateral arm flap donor site. Older subjects had significantly decreased sensation at both donor sites based on static two-point discrimination and Semmes-Weinstein monofilament testing. No sex differences were noted. Based on Semmes-Weinstein monofilament testing in the mouth, the tip of the tongue is the most sensitive area (2.26 g per square millimeter), followed by the hard palate (3.60 g per square millimeter), the lateral tongue (4.08 g per square millimeter), the cheek (4.77 g per square millimeter), and the gingiva (8.06 g per square millimeter). Smokers had significantly decreased sensation at the tip of tongue and hard palate. Denture wearers had significantly diminished sensation in all intraoral locations except the lateral tongue. Older patients had significantly diminished sensation at all intraoral sites. No sex differences were noted. The lateral arm flap donor site is a more sensitive region than the radial forearm flap donor site. However, the lateral arm flap donor site is less sensitive than the tip of tongue and hard palate, while the radial forearm flap donor site is less sensitive than the tip of tongue, hard palate, lateral tongue, and cheek. This suggests that for certain locations, intraoral sensate flaps may require measures such as sensory reeducation protocols to approach normal recipient site sensation.

[Use of the gracilis muscle in reconstructing the perineum]. / Utilização do músculo grácil na reconstrução do períneo.

Ten patients had their vulvar and perineal areas reconstructed using musculocutaneous flaps of the gracilis muscle. Seven patients had extensive resections done for skin carcinomas, two due to traumas and one due to a sequel of Fournier's Syndrome. Reconstruction in tumor cases were performed primarily and the other secondarily. The skin island measured 12 x 8 centimeters and the muscle was taken entirely. The results were satisfactory in all cases. The muscle survived completely, but there was partial skin island loss in 8 instances. In 3 of those cases, there was need for a revision of the flap and skin grafting. The authors concluded that there is always a risk to take the skin island together with the gracilis muscle and the use of the isolated muscle with skin grafting should be considered im most cases.

[Use of tissue expanders on the scalp]. / Uso de expansores de tecido no couro cabeludo.

Tissue expanders have emerged recently as a new option for the treatment of alopecia. The method consists in expanding the scalp beyond the defective area. In this way, some disadvantages like the alterations in the donor area and low density of hair follicles, that may result from other techniques, are avoided. We present our experience with tissue expanders in the treatment of 32 patients with alopecia. The extent of these areas varied from 30 to 150 cm2, and the causes were: burn sequels in 12 patients; trauma sequels in ten; tumoral resections in ten; giant nevus pilosus in four and baldness (male standard) in two patients. The resection of the area with alopecia and the replacement by normal adjacent tissue was possible without any complications in all cases. However some disadvantages were observed. They included the necessity for a second surgical procedure because of marked deformity of the cephalic segment.

Effects of retinoic and glycolic acids on neoangiogenesis and necrosis of axial dorsal skin flaps in rats.

Retinoic acid (RA) and glycolic acid (GA) are frequently used in the treatment of acne and skin aging, as well as improving skin healing after dermabrasion and in photoaged skin. Examples of histologic alterations caused by these substances are vascularization increase and interference with inflammatory as well as regenerative skin processes. The objective of this study was to evaluate the possible decrease of skin flap necrosis areas in rats, by applying both substances to the skin 14 and 30 days before surgery, and analyzing histopathologic skin alterations after treatment. Fifty Wistar rats were divided into five groups of 10 animals each. They received daily retinoic acid application for 14 and 30 days, daily glycolic acid application for 14 and 30 days, and vehicle application (control group) for 14 days. After treatment, each rat was submitted to random dorsal skin flap (10 x 3 cm) elevation; flaps were sutured back in place over isolating plastic strips. The rats were sacrificed after 7 days and flap necrosis areas were measured through transparency and then analyzed using computer scanning. Statistical analysis was carried out using monocaudal nonpaired t tests and histopathologic examination was performed in all cases. Compared with the control group, treatment with both acids did not decrease average flap necrosis areas. Though groups RA 30 days and GA 14 days presented larger necrosis area averages (p < 0.05), groups RA 14 days and GA 30 days showed no statistically significant difference (p > 0.05) when compared to the control group. Both substances caused spongiosis, stratum corneum thickening, and vascularization increase, with GA inducing greater granulomatous reaction and RA more spongiosis and queratinization. Group RA 30 days showed the most significant dermo-epithelial (including vascular) regenerative and proliferative effects. Retinoic and glycolic acid treatment led to significant and well-known skin alterations, with group RA 30 days showing most notable dermo-epithelial proliferative effects. In our experimental model, preoperatory RA and GA application did not decrease rat dorsal skin flap necrosis area when compared to the control group.