Cement leakage and pulmonary embolism by bone cement-augmented pedicle screw fixation of the thoracolumbar spine - A case report.

Background: Few studies discuss the complication of pulmonary cement embolism (PCE) due to cement augmented pedicle screw instrumentation (CAPSI) of the thoracolumbar spine. Case Description: A 62 female with a history of multiple myeloma and Sjogren's syndrome on chronic steroids developed an osteoporotic L1 compression fracture and underwent posterior stabilization with a T10-L4 CAPSI. However, postoperatively, the patient developed a surgical site infection and a PCE, resulting in severe respiratory compromise and death 1 month later. Conclusion: When performing a T10-L4 thoracolumbar CAPSI (i.e., augmented pedicle screw instrumentation of the thoracolumbar spine) to address an L1 osteoporotic compression fracture, a 62 year old patient developed a life ending multi organ deficiency due to sepsis together with a PCE.

Surgical management and functional outcomes of perilunate dislocations and fracture dislocations through the dorsal approach.

BACKGROUND: Perilunate dislocations and perilunate fracture dislocations (PLD/PLFDs) are rare injuries of the wrist, with surgical management leading to acceptable functional results. PURPOSE: The purpose of this study was to assess the functional outcomes of the patients of our department who were treated with surgical management of PLDs/PLFDs through dorsal approach, as well as to report any complications on their follow-up. PATIENTS AND METHODS: In this retrospective study, 52 patients with PLD/PLFD, fulfilling the inclusion and exclusion criteria of the study, underwent surgical management of their injury. All patients were followed up at 6 weeks, 12 weeks, 6 months, 1 year postoperatively with radiographic imaging as well as functional scores measured with the modified mayo wrist score and the QuickDASH questionnaire. RESULTS: The mean postoperative modified Mayo score was 76.8 ± 8.8 and the mean QuickDASH score was 1.52 ± 2.18. Of the 52 cases, 20% had excellent results, 42% had good results, 29% had fair results and 9% had poor results as per the modified Mayo wrist score. No patient signed any symptoms of median nerve neuropathy. CONCLUSION: In conclusion, open reduction and internal fixation through dorsal approach is a reliable technique to manage perilunate injuries in spite of radiological evidence of wrist arthritis, as it also provides consistently good results in terms of functional outcomes. LEVEL OF EVIDENCE IV: Retrospective case series study.

Surgical Treatment of Congenital Kyphosis in Children: Report of a Rare Complication of Remote Cerebellar Haemorrhage.

Congenital deformities of the spine lead to an imbalance in the longitudinal growth of the spine. These growth abnormalities may lead to three main patterns of deformity: scoliosis (the most common), kyphosis or lordosis (the least common). Despite the recent improvements in imaging and the routine use of neuromonitoring in the surgical treatment of congenital kyphosis, this surgery may be associated with a high rate of complications such as neurologic deficit, pulmonary thromboembolic events, infection, deep vein thrombosis, implant failure, and dural injury. In this paper, we report a rare yet devastating complication to raise awareness about patients who have unexpected neurological deterioration after spinal surgery. Early recognition of remote cerebellar haemorrhage (RCH) symptoms is crucial since rapid diagnosis and management lead to a favourable outcome for this potentially life-threatening complication. To our knowledge, this is the first reported case in children.

White Cord Syndrome Following Cervical Surgery in a Patient With Klippel-Feil Syndrome: A Case Report.

White cord syndrome is a rare entity, as there are very few cases described in the current literature. Postoperative MRI examination reveals cord intrinsic changes, including edema and ischemia. It is also described as a reperfusion injury of the spinal cord. This report depicts a rare case of "white cord syndrome" with tetraplegia after posterior laminectomy and fusion of the cervical spine in a patient with Klippel-Feil syndrome. A 33-year-old male patient with Klippel-Feil syndrome presented to our department with cervical myelopathy, claudication, deteriorating neurological status, imbalance, and lower limb spasticity. Due to kyphotic malformation of the cervical spine, a two-stage surgical intervention was scheduled. The patient first underwent anterior spinal fusion of C4-C6 with corpectomy of C5, where many anatomical and visceral differentiations were signed, so the surgical team was enhanced by a vascular surgeon. The postoperative period was uneventful and the patient was discharged after a week of hospitalization without any neurological deterioration. A second surgical intervention was scheduled after two months where laminectomy of C5-C7 and posterior fusion of C5-T1 were carried out. However, due to intraoperative spinal instability and various anatomical spinal variations, a third surgery, which would be occipitocervical fusion, was decided as the final surgical solution. During the third surgical operation, after the laminectomy of C1 to C5 and the placement of the occipital plate, the screws, and the two rods in situ, complete nullification of the intraoperative neurophysiologic control was signed. The internal fixation was removed immediately, the wake-up test revealed tetraplegia below C5, and the patient was transferred to the ICU. Immediate MRI revealed no spinal cord hematoma; however, spinal cord edema was present. The patient underwent a tracheostomy and remained quadriplegic with a sensory level of T8 and motor level of C5 and was discharged to a rehabilitation center. The possibility of white cord syndrome should be explained by surgeons before any cervical decompression surgery, as well as a thorough neurological examination should be performed postoperatively. The early recognition and prompt management of white cord syndrome is recommended.

Efficacy of combined targeted therapy with PI3K and CDK4/6 or PARP and WEE1 inhibitors in neuroblastoma cell lines.

Neuroblastoma (NB), the most frequent solid extracranial tumor in children, is not always cured by current aggressive therapies that have notable adverse effects; therefore, novel treatments are necessary. Phosphoinositide 3­kinase (PI3K) and fibroblast growth factor receptor inhibitors exhibit synergistic effect in NB cell lines. In the present study, mono­ and combination therapy of the United States Food and Drug Administration­approved PI3K, cyclin­dependent kinase­4/6 (CDK4/6), poly­ADP­ribose­polymerase (PARP) and WEE1 G2 checkpoint kinase (WEE1) inhibitors (BYL719, PD­0332991, BMN673 and MK­1775, respectively), were used to treat NB cell lines SK­N­AS, SK­N­BE(2)­C, SK­N­DZ, SK­N­FI and SK­N­SH and viability (assessed by WST­1 assay), proliferation (incucyte analysis) and cell cycle (FACS) changes were assessed. Treatments with all single drugs presented dose­-dependent responses with decreased viability and proliferation and combining BYL719 with PD­0332991 or BMN673 with MK­1775 resulted in additive or synergistic effects in most cell lines., except for SK­N­SH for the former and for SK­N­AS for the latter. Moreover, combining MK­1775 and BMN673 decreased the numbers of cells in S phase to a greater extent than either drug alone, while when combining PD­0332991 and BYL719 the observed effect was close to that of PD­0332991 alone. To summarize, PI3K and CDK4/6 or PARP and WEE1 exhibited synergistic anti­NB effects and lower doses of the inhibitors could be utilized, thereby potentially reducing adverse side effects.

Surgical Site Infection Following the Correction of Adolescent Idiopathic Scoliosis With ApiFix: A Retrospective Study Analyzing Its Incidence and Recurrence.

Background and objective ApiFix (OrthoPediatrics, Warsaw, IN) is an internal brace used for the correction of adolescent idiopathic scoliosis (AIS) classified as Lenke 1 or 5 with a Cobb angle of 35-60 degrees that decreases to ≤30 degrees on lateral side-bending radiographs. Since the indications are very specific, it is not a common procedure. Our study aimed to evaluate the incidence of surgical site infection (SSI) and its recurrence following treatment with ApiFix. Materials and methods A retrospective study of 44 cases of AIS treated at our center from 2016 to 2022 with ApifiX was conducted. Two patients who presented with SSI were initially treated with irrigation and debridement (I&D) following antibiotic therapy.  Results A total of 44 patients with a mean age of 15.1 years were evaluated. Two of our patients presented with early-onset infection while one of them presented after the end of treatment with a skin ulcer due to septic screw loosening. The removal of the ApiFix implant revealed a pedicle abscess during the screw removal. Conclusions In this study of 44 patients, we observed two cases of infection and one case of reinfection. Given the limited muscle detachment and short operating time needed for Apifix, statistics suggest that the risk of SSI is always present. Further randomized trials are needed to gather more evidence on this subject.

Associations of gestational diabetes and proton density fat fraction of vertebral bone marrow and paraspinal musculature in premenopausal women.

Background and objective: Fat content in bones and muscles, quantified by magnetic resonance imaging (MRI) as a proton density fat fraction (PDFF) value, is an emerging non-invasive biomarker. PDFF has been proposed to indicate bone and metabolic health among postmenopausal women. Premenopausal women with a history of gestational diabetes (GDM) carry an increased risk of developing type 2 diabetes and an increased risk of fractures. However, no studies have investigated the associations between a history of GDM and PDFF of bone or of paraspinal musculature (PSM), composed of autochthonous muscle (AM) and psoas muscle, which are responsible for moving and stabilizing the spine. This study aims to investigate whether PDFF of vertebral bone marrow and of PSM are associated with a history of GDM in premenopausal women. Methods: A total of 37 women (mean age 36.3 ± 3.8 years) who were 6 to 15 months postpartum with (n=19) and without (n=18) a history of GDM underwent whole-body 3T MRI, including a chemical shift encoding-based water-fat separation. The PDFF maps were calculated for the vertebral bodies and PSM. The cross-sectional area (CSA) of PSM was obtained. Associations between a history of GDM and PDFF were assessed using multivariable linear and logistic regression models. Results: The PDFF of the vertebral bodies was significantly higher in women with a history of GDM (GDM group) than in women without (thoracic: median 41.55 (interquartile range 32.21-49.48)% vs. 31.75 (30.03-34.97)%; p=0.02, lumbar: 47.84 (39.19-57.58)% vs. 36.93 (33.36-41.31)%; p=0.02). The results remained significant after adjustment for age and body mass index (BMI) (p=0.01-0.02). The receiver operating characteristic curves showed optimal thoracic and lumbar vertebral PDFF cutoffs at 38.10% and 44.18%, respectively, to differentiate GDM (AUC 0.72 and 0.73, respectively, sensitivity 0.58, specificity 0.89). The PDFF of the AM was significantly higher in the GDM group (12.99 (12.18-15.90)% vs. 10.83 (9.39-14.71)%; p=0.04) without adjustments, while the CSA was similar between the groups (p=0.34). Conclusion: A history of GDM is significantly associated with a higher PDFF of the vertebral bone marrow, independent of age and BMI. This statistical association between GDM and increased PDFF highlights vertebral bone marrow PDFF as a potential biomarker for the assessment of bone health in premenopausal women at risk of diabetes.

Total Hip Replacement in Developmental Hip Dysplasia: A Narrative Review.

The reconstruction of the hip joint in patients suffering from developmental hip dysplasia (DDH) is a demanding procedure and presents many challenges to the reconstructive surgeon. Higher rates of mechanical complications are present in this group of patients. The results of cemented and uncemented implants used in DDH patients are very promising, according to recent outcomes. However, the surgeon has to be aware of several complications, in order to establish an uneventful surgical management of DDH. The specific article investigates the technical challenges and clinical results of total hip arthroplasty in patients with DDH.

Hepatocellular Carcinoma: An Overview of the Changing Landscape of Treatment Options.

The last three years have seen remarkable progress in comprehending predisposing factors and upgrading our treatment arsenal concerning hepatocellular carcinoma (HCC). Until recently, there were no means to withstand the progression of viral hepatitis-associated liver cirrhosis to HCC. A deeper understanding of the molecular mechanism of the disease, the use of biomarkers, and the follow-up, allowed us to realize that conventional chemotherapy failing to increase survival in patients with advanced HCC tends to be exiled from clinical practice. Multi-kinase inhibitors (TKIs) such as sorafenib, lenvatinib targeting mainly the vascular endothelial growth factor receptors 1-3 VEGFRs 1-3 provided until recently the standard of care for these patients, as first- or second-line treatment. Since May 2020, the atezolizumab plus bevacizumab combination (immunotherapy plus anti-VEGF) has become the new reference standard in first-line HCC treatment. Additionally, anti-programmed cell death protein 1 (anti-PD-1) immunotherapy can be used as a second-line treatment following first-line treatment's failure. Phase III clinical trials have recently suggested the efficacy of novel anti-angiogenic factors such as cabozantinib and ramucirumab as a second-line treatment option. With considerations about toxicity arising, clinical trials are investigating combinations of the aforementioned targeted therapies with immunotherapy as first-line treatment. This paper aims to perform a systematic review describing the evolving treatment options for HCC over the last decades, ranging from neoadjuvant treatment to systemic therapy of advanced-stage HCC. With the landscape of HCC treatment shifting towards novel agents the forming of a new therapeutic algorithm for HCC seems to be imperative.

Vascular Injury in Elective Anterior Surgery of the Lumbar Spine: A Narrative Review.

The incidence of anterior lumbar surgery is increasing as the population is aging. Although adverse events regarding vasculature injury are uncommon, several have been described in the current literature. Complications can be categorized based on the time of occurrence, more specifically intraoperative or postoperative, but also regarding the nature of vascular damage such as thrombosis, occlusion, or rupture. The rate of complications is higher in the setting of revision anterior surgery than with primary anterior lumbar surgery. Moreover, the incidence of revision anterior surgery is also increasing in contrast to the past. Through this narrative review, an effort is made for a thorough understanding of the complications associated with anterior lumbar surgery, which will aid in the prevention, recognition, and management of this rare complication.

Medium-Term Results after Surgical Treatment of High-Energy Tibial Plateau Fractures.

The aim of the article is to present the medium-term results of surgical treatment of Schatzker's IV, V, and VI tibial plateau fractures, in a retrospective study of 22 patients at a level-1 trauma center. Twenty-two of 34 patients with Schatzker's IV-VI fractures completed follow-up at a mean of 56 months (range: 7-103 months). Patients' mean age was 47.6 years (range: 18-76 years). Open reduction and internal fixation were performed in 16 patients, while external fixators were used in the remaining six patents. Patients were assessed radiologically for the presence of arthritis using the Kellgren-Lawrence scale. Functional outcomes were measured using the Lysholm's knee score, knee injury, and osteoarthritis outcome score (KOOS). Quality of life was also assessed postoperatively using the EuroQol-5D (EQ-5D) form and EQ-VAS (visual analogue scale) score. There were no postoperative infections and no fracture went on to nonunion. Absence of arthritic change was noted in only 6.3% of cases. The average KOOS score was 80 and the average Lysholm's score was 84.91. Regarding the postoperative quality of life, mobility was impaired in 45.5%, self-care in 27.3%, and usual activities in 36.3% of patients. Pain or discomfort was reported in 77.2% and anxiety or depression in 40.9% of cases. The mean VAS score was 77.8. Eighty percent of patients had returned to their previous activities at the time of last follow-up. Although complex tibial plateau fractures are associated with a high rate of complications and can have a severe impact on the injured knee, most patients had quite satisfactory results during their medium-term clinical evaluation, in our study. It is a Level IV case series study.

The effect of diabetes mellitus on in-hospital hyperglycemia, length of stay and survival in patients with brain tumor receiving dexamethasone: A descriptive and comparative analysis.

OBJECTIVES: To perform a comparative analysis on the impact of Type 2 Diabetes Mellitus (DM) on in-hospital hyperglycemia, length of stay (LOS) and survival of patients suffering from brain tumor who receive dexamethasone. PATIENTS AND METHODS: Patients with brain tumor hospitalized in a Neurosurgery department between 2011 and 2018, were studied. Data referring to medical history, clinical characteristics and in-hospital survival was collected and analyzed. Morning plasma glucose levels (PGL) were obtained for seven consecutive days after the start of dexamethasone. RESULTS: Fifty-six patients were identified. Of them, 21 (37.5%) were diabetic. During dexamethasone administration, a difference in morning PGL values during different days was noted (p = 0.003). No difference in glucose levels among different glucocorticoid doses was seen. DM was associated with higher average PGL (aMPGL), calculated as the mean of morning PGL values for the last six days (p = 0.001) and with higher rates of persistent hyperglycemia (p = 0.002). The change of aMPGL from the morning PGL value of day one did not differ between the two cohorts (p = 0.729). DM neither affected LOS nor in-hospital survival (p = 0.745 & p = 0.438, respectively). CONCLUSION: Although morning glucose values were higher in diabetic, compared to non-diabetic patients, their change from day one was similar between the two cohorts. LOS and in-hospital survival were not affected by DM.

A Retrospective Comparative Study of Different Methods of Blood Management in Total Knee Replacement.

Perioperative blood management is essential to minimize allogeneic blood transfusion in total knee replacement. The effect of preoperative administration of erythropoietin, intraoperative cell saver, tranexamic acid, and restrictive transfusion strategies on allogeneic transfusion is studied in total knee replacement. A retrospective comparative study of 106 patients who underwent total knee replacement in different time periods was performed. Group A (n 1 = 45) underwent restrictive strategies of transfusion between 2009 and 2010. Group B (n 2 = 24) includes patients where erythropoietin of either 10.000 IU or 20.000 IU was given preoperatively. Patients of Group C (n 3 = 21) underwent autologous washed erythrocytes transfusion through a cell saver. Lastly, in Group D (n 4 = 15) tranexamic acid dose of 1 gr IV was given intraoperatively. The preoperative and discharge hemoglobin together with total units of blood transfusion and creatinine levels was studied. Tranexamic acid noted the least units of blood transfusion (mean = 0.82 units/patient, p < 0.001, CI 95%) in contrast to the two regimens of erythropoietin (1.16 units/patient) OrthoPAT (1.43 units/patient) and restrictive strategies (1.92 units/patient). The mean preoperative hemoglobin was 13.37 g/dL with no statistical difference among the groups of patients. The postoperative mean hemoglobin was 10.59 with no statistical difference among the groups of patients too. Additionally, the mean creatinine level was 0.93 mg/dL; however, no statistical difference among the groups of patients was noted. Finally, tranexamic acid seemed to be the most cost-effective regime. In our study, tranexamic acid proved its superiority concerning the postoperative blood transfusion on patients undergoing total knee replacement, in comparison with the other existing methods of perioperative blood management. This is a Level III, retrospective comparative study.

Glutathione analogues as substrates or inhibitors that discriminate between allozymes of the MDR-involved human glutathione transferase P1-1.

Glutathione (GSH) structure-guided tripeptide analogues were designed and synthesized by solid phase technology, purified (≥95%) by RP and/or GF column chromatography, to identify those that, compared with GSH, exhibited similar or higher binding and catalytic efficiency toward the MDR-involved human GSTP1-1 isoenzyme, and could discriminate between the allozymic expression products of the polymorphic human GSTP1 gene locus, designated as hGSTP1*A (Ile(104) /Ala(113) ), hGSTP1*B (Val(104) /Ala(113) ), and hGSTP1*C (Val(104) /Val(113) ). The analogues bear single amino acid alterations as well as alterations in more than one position. Some analogues showed remarkable allozyme selectivity, binding catalytically to A (I, II, IV, XII), to C (V and XVI), to A and C (III, VII, XIV) or to all three allozymes (XV). A heterocyclic substituent at positions 1 or 2 of GSH favors inhibition of A, whereas a small hydrophobic/hydrophilic amide substituent at position 2 (Cys) favors inhibition of B and C. Heterocyclic substituents at position 1, only, produce catalytic analogues for A, whereas less bulky and more flexible hydrophobic/hydrophilic substituents, at positions 1 or 3, lead to effective substrates with C. When such substituents were introduced simultaneously at positions 1 and 3, the analogues produced have no catalytic potential but showed appreciable inhibitory effects, instead, with all allozymes. It is anticipated that when GSH analogues with selective inhibitory or catalytic binding, were conjugated to allozyme-selective inhibitors of hGSTP1-1, the derived leads would be useful for the designing of novel chimeric inhibitors against the MDR-involved hGSTP1-1 allozymes. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 330-344, 2016.

Structural studies and cytotoxicity assays of "aggregation-prone" IAPP(8-16) and its non-amyloidogenic variants suggest its important role in fibrillogenesis and cytotoxicity of human amylin.

Amyloid deposits to the islets of Langerhans are responsible for the gradual loss of pancreatic ß-cells leading to type II diabetes mellitus. Human mature islet amyloid polypeptide (hIAPP), a 37-residue pancreatic hormone, has been identified as the primary component of amyloid fibrils forming these deposits. Several individual segments along the entire sequence length of hIAPP have been nominated as regions with increased amyloidogenic potential, such as regions 8-20, 20-29, and 30-37. A smaller fragment of the 8-20 region, spanning residues 8-16 of hIAPP has been associated with the formation of early transient α-helical dimers that promote fibrillogenesis and also as a core part of hIAPP amyloid fibrils. Utilizing our aggregation propensity prediction tools AmylPred and AmylPred2, we have identified the high aggregation propensity of the 8-16 segment of hIAPP. A peptide analog corresponding to this segment was chemically synthesized and its amyloidogenic properties were validated using electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy, and polarized microscopy. Additionally, two peptides introducing point mutations L12R and L12P, respectively, to the 8-16 segment, were chemically synthesized. Both mutations disrupt the α-helical properties of the 8-16 region and lower its amyloidogenic potential, which was confirmed experimentally. Finally, cytotoxicity assays indicate that the 8-16 segment of hIAPP shows enhanced cytotoxicity, which is relieved by the L12R mutation but not by the L12P mutation. Our results indicate that the chameleon properties and the high aggregation propensity of the 8-16 region may significantly contribute to the formation of amyloid fibrils and the overall cytotoxic effect of hIAPP.

Feasibility of Induction Docetaxel, Cisplatin, 5-Fluorouracil, Cetuximab (TPF-C) Followed by Concurrent Cetuximab Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: To report our experience with a sequential regimen of induction TPF-C followed by radioimmunotherapy with cetuximab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Toxicity and outcome was retrospectively analyzed in 22 patients receiving sequential therapy with induction TPF-C followed by radioimmunotherapy between October 2008 and December 2011. Outcome was estimated using Kaplan-Meier analyses. In addition, we performed mutation analysis for PIK3CA genes and high risk HPV DNA detection using PCR. RESULTS: Mean time of follow-up was 16 months. Six patients were TNM Stage III, 15 patients IV (IVA or IVB), and one patient Stage II with bulky disease. During TPF-C, Grade 3 and 4 toxicities occurred in eight patients, dose modifications in seven, delays in one, and unplanned admissions in five. Clinical tumor response was documented in 18 of the 21 patients who completed at least three cycles of TPF-C with three patients developing complete response and 15 partial responses. Grade 3/4 mucositis was observed in six patients. At a median follow-up of 19 months, 13 patients were alive and nine had died including seven patients as a result of disease persistence or recurrence and two as a result of unrelated causes. PIK3CA mutations were not identified and our two oropharynx cases were HPV negative. CONCLUSION: The combination of induction TPF-C with concurrent cetuximab radioimmunotherapy in patients with locally advanced HNSCC is tolerable, with encouraging efficacy.

Structure-activity studies of lGnRH-III through rational amino acid substitution and NMR conformational studies.

Lamprey gonadotropin-releasing hormone type III (lGnRH-III) is an isoform of GnRH isolated from the sea lamprey (Petromyzon marinus) with negligible endocrine activity in mammalian systems. Data concerning the superior direct anticancer activity of lGnRH-III have been published, raising questions on the structure-activity relationship. We synthesized 21 lGnRH-III analogs with rational amino acid substitutions and studied their effect on PC3 and LNCaP prostate cancer cell proliferation. Our results question the importance of the acidic charge of Asp6 for the antiproliferative activity and indicate the significance of the stereochemistry of Trp in positions 3 and 7. Furthermore, conjugation of an acetyl-group to the side chain of Lys8 or side chain cyclization of amino acids 1-8 increased the antiproliferative activity of lGnRH-III demonstrating that the proposed salt bridge between Asp6 and Lys8 is not crucial. Conformational studies of lGnRH-III were performed through NMR spectroscopy, and the solution structure of GnRH-I was solved. In solution, lGnRH-III adopts an extended backbone conformation in contrast to the well-defined ß-turn conformation of GnRH-I.

Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis.

BACKGROUND: A high incidence of adverse skin reactions following long-term oral administration of voriconazole in children with cystic fibrosis and allergic bronchopulmonary aspergillosis (ABPA). The aim was to study the pharmacokinetics of voriconazole in these patients and to determine a possible association between drug levels and adverse effects. METHODS: Multiple venous blood samples were collected for HPLC determination of voriconazole concentrations and routine blood tests. Adverse events were recorded. RESULTS: No significant correlation was found between incidence of photosensitivity and voriconazole serum levels in 6 of 8 children with ABPA. 80% of patients had trough voriconazole concentrations<1000 ng/mL and were highly variable. CONCLUSIONS: Long-term voriconazole therapy and greater sun exposure in Greece appear to play a major role in the occurrence of photosensitivity. Steady-state plasma drug concentrations were found to be highly variable and below the recommended therapeutic range in most patients, without any apparent negative influence on outcome.

Enzymatic stability, solution structure, and antiproliferative effect on prostate cancer cells of leuprolide and new gonadotropin-releasing hormone peptide analogs.

Analogs of GnRH, including [DLeu6, desGly1o]-GnRH-NHEt (leuprolide, commercial product), have been widely used in oncology to induce reversible chemical castration. Several studies have provided evidence that, besides their pituitary effects, GnRH analogs may exert direct antiproliferative effects on tumor cells. To study the effect of modifications in positions 4 and 6 of leuprolide on prostate cancer cell proliferation, we synthesized 12 new leuprolide analogs. All GnRH analogs lacked the carboxy-terminal Gly10-amide of GnRH, and an ethylamide residue was added to Pro9. Gly6 was substituted by DLys, Nepsilon-modified DLys, Glu, and DGlu. To improve the enzymatic stability, NMeSer was incorporated in position 4, and the rate of hydrolysis by alpha-chymotrypsin and subtilisin was investigated. Our results demonstrate that this incorporation increases enzymatic stability in all analogs of GnRH, whereas the antiproliferative effect on PC3 and LNCaP prostate cancer cells is similar to that of leuprolide. Conformational studies were performed to elucidate structural changes occurring on substitution of native residues and to study structure-activity relationship for these analogs. The solution models of [DLeu6, desGly10]-GnRH-NHEt (leuprolide), [NMeSer4, DGlu6, desGly10]-GnRH-NHEt, [Glu6, desGly10]-GnRH-NHEt, and [DGIu6, desGly10]-GnRH-NHEt peptides were determined through two-dimensional nuclear magnetic resonance spectroscopy in dimethylsulfoxide. Nuclear magnetic resonance data provide experimental evidence for the U-turn-like structure appeared in all four analogs, which could be characterized as beta-hairpin conformation. The most stable analog [NMeSer4, DGlu6, desGly10]-GnRH-NHEt against proteolytic cleavage forms a second extra backbone turn observed for residues 1-4.

A retrospective review of malignant minor salivary gland tumors and a proposed protocol for future care.

Malignant tumors affecting minor salivary glands present a wide range of histopathologic types. The present study sought to design a protocol for management of patients with malignancy of minor salivary glands. The data of 22 patients with malignant tumors of the minor salivary glands, surgically treated at our department in the past 10 years, were accumulated and studied. All patients underwent a diagnostic workup prior to surgery. The most useful examinations were magnetic resonance imaging of the head and neck and computerized tomography of the thorax. Wide local excision was sufficient for the majority of patients. Adjuvant treatment is indicated for high-grade, tumor-positive lymph nodes and residual disease. Malignant tumors of minor salivary glands are very rare. Therefore, design of management protocols is challenging. Management of the neck is necessary in evidence of metastasis and in high-grade and advanced-stage disease. Adjuvant treatment should be included in the treatment protocol in certain indications. Most importantly, long-term follow up is very important for all patients with malignant minor salivary tumors.