Secondary femur shaft fracture following treatment with cephalomedullary nail: a retrospective single-center experience.

AIM: Secondary femur fracture subsequent to treatment of trochanteric fractures with cephalomedullary nailing (i.e., a periprosthetic fracture related to the cephalomedullary nail) is a rare but very severe complication. As such, the aim of this study was to assess the impact of revision surgery and general state of health on mortality and functional outcomes in patients suffering femur fractures following treatment with cephalomedullary nails. MATERIALS AND METHODS: Between 2000 and 2015, 3549 patients presenting with OTA/AO 31A1-3 femur fractures were admitted to our department and subsequently treated with either a Gamma® Nail or PFNA®. Out of this sample population, 42 patients suffered 43 secondary femur shaft fractures (1.2%). The mean follow-up time was 26 ± 9.7 months. Fractures were classified according to the AO classification and the modified Vancouver classification. Treatment options included ORIF, removing the cephalomedullary nail and fixation with a long nail with or without cerclage wires. General health status was defined according to the ASA Score. Mortality, pre- and postoperative mobility, hospital stay and complications were assessed retrospectively. RESULTS: A total of 14.3% patients died within 90 days following surgery. At least 16.6% patients died due to medical complications strongly related to the surgery. The average time to secondary fracture following initial surgery for trochanteric fracture was 122.7 ± 32 weeks. The most common fracture types were AO 32A1 (53.5%) and AO 32B1 (23.3), as well as Vancouver C and B1. A time-to-secondary-fracture of less than or longer than 6 months following surgery for trochanteric fracture and ASA Score all had no significant influence on mortality, complications, duration of surgery and postoperative mobility. CONCLUSION: Femoral shaft facture subsequent to fixation of trochanteric fracture with cephalomedullary nails is a severe complication. It leads to prolonged hospital stays and delayed recovery. Postoperative hospital stay mortality rates may be as high as 16.6%.

Gender differences following computer-navigated single- and double-bundle anterior cruciate ligament reconstruction.

PURPOSE: Female patients not only demonstrate an increased risk for injury, but also a poorer response following anterior cruciate ligament (ACL) rupture. However, no study has investigated gender-related differences between computer-navigated single-bundle (SB) and double-bundle (DB) ACL reconstruction. The aim of this study was to evaluate the effects of gender on the outcome of computer-navigated SB and DB ACL reconstruction and to present reference values. METHODS: A retrospective review of 55 consecutive patients who underwent SB (15 males, 12 females) and DB (18 males, 10 females) ACL reconstruction with autogenous hamstring tendon grafts and showed a minimum follow-up of 24 months was conducted. Intraoperatively, the anteroposterior and rotational laxity were measured and the follow-up examination included pivot-shift testing, KT-1000 arthrometer testing, International Knee Documentation Committee (IKDC) form, the Lysholm score and Tegner score. RESULTS: Pre-operatively, female patients showed a significant higher internal rotation in (p < 0.001) both the SB and DB group. Regarding the post-operative reduction in internal rotation, females in the SB group revealed a greater reduction compared to males (p < 0.001), whereas females in the DB group revealed a significantly greater post-operative reduction in anterior-posterior translation (p = 0.04). Female patients following DB ACL reconstruction presented a significant worse IKDC score, Lysholm score and Tegner score compared to male patients. All score values of the female DB group were worse than in the female SB group. In contrast, male patients showed better results of all examined clinical scores following DB procedure compared to SB technique. CONCLUSION: Female patients who underwent computer-navigated DB ACL reconstruction exhibited significantly worse outcome scores than males who underwent DB ACL reconstruction. The gender-based relationship between joint function and outcome after ACL reconstruction remains unclear and requires further investigation. LEVEL OF EVIDENCE: Retrospective case-control series, Level III.

Avulsion fracture and complete rupture of the thumb radial collateral ligament.

PURPOSE: Acute grade III tears of the radial collateral ligament (RCL) of the thumb as well as certain bony avulsion fractures receive early surgical repair at our institution. The aim of this study was to evaluate if patients would benefit from this treatment algorithm at long-term. METHODS: 47 patients with RCL bony avulsion fracture or grade III RCL tear were evaluated at a median follow-up of 4.5 years (range 1-17.3 years). Grade III RCL tears were treated operatively when presenting >30° angulation in stress X-ray together with palmar subluxation of ≥3 mm. Further, avulsed bony fragments with diastasis >2 mm or fragment rotation >30°-45° in conventional X-ray underwent surgery. 6 patients with grade III RCL tear as well as 9 patients with bony avulsion underwent surgical repair. RESULTS: At follow-up, metacarpophalangeal joint stability and pain free ROM did not differ significantly between the groups. Subjective satisfaction based on the Catalano grading system revealed excellent results in operatively and conservatively treated patients. CONCLUSIONS: This retrospective analysis indicates that early surgical repair in severe RCL injuries is associated with unrestricted ROM, persistent joint stability, and subjective patient satisfaction. This data suggest that surgical treatment in certain RCL injuries might be a feasible therapeutic option in order to avoid chronic instability.

[Fractures of the thoracolumbar spine in childhood and adolescence]. / Frakturen des thorakolumbalen Übergangs im Kindes- und Jugendalter.

BACKGROUND: The aim of our study was to evaluate the clinical and radiological outcome after operative treatment of fractures of the thoracolumbar spine in children. PATIENTS AND METHODS: Over a period of 10 years, 14 patients (10 girls and 4 boys) with a mean age of 12.6 years were treated operatively. The mean follow-up was 47.4 months. At follow-up range of motion, residual pain, and activities of daily living were considered. Radiological X-rays were performed in anterior and lateral views, and kyphosis deformity as well as reduction of the height were determined. RESULTS: Most fractures were comprehension fractures (71.4%). In 13 patients dorsal decompression and internal fixation was performed. Off the six patients who had neurologic injuries, two had complete return of neurologic function. Five patients had no pain. Radiologically, five patients showed a mean kyphosis deformity of 12.7° as well as a mean height reduction of 2.7mm. Ten patients reported no problems in activities of daily living. Overall our patients showed good results in clinical outcome. CONCLUSION: Those patients who need operative therapy require prompt diagnosis and therapy to minimize permanent damage.

Thoracic Injuries in Pediatric Polytraumatized Patients: Epidemiology, Treatment and Outcome.

PURPOSE: The purpose of the present study was to assess the influence and contribution, epidemiology, treatment and outcome of thoracic injuries in a cohort of pediatric and adolescent polytraumatized patients. MATERIAL AND METHODS: All pediatric and adolescent (age < 18 years) polytraumatized patients with associated thoracic injuries were included in this study. Demographic data, mechanism of injury (MOI), injury severity score (ISS), Glasgow Coma Scale (GCS), hemodynamic parameters and pupillary response at ED admission, site of major injury (SOMI), associated chest and non-chest related injuries, length of hospital stay (LOS), procedures performed at the ED as well as outcome variables including mortality and cause of death. Stepwise logistic regression analysis was used to identify risk factors for a poor prognosis and outcome. RESULTS: The logistic regression found the following variables decreasing the odds for a "bad outcome": lack of a hemodynamically unstable condition (p = 0.009) and the absence of a pathological pupillary response (p < 0.001). CONCLUSIONS: The present study suggests that the severity of concomitant chest injuries in polytraumatized pediatric and adolescent patients contributes substantially to morbidity and mortality. Due to the anatomic features of the immature pediatric bones, careful attention should be drawn to possible severe chest injuries even in the absence of rib fractures. LEVEL OF EVIDENCE: A retrospective study (level - IV study).

Testing for colon neoplasia susceptibility variants at the human COX2 locus.

BACKGROUND: Siblings and other first-degree relatives of patients with "sporadic" (i.e., apparently nonfamilial) colorectal cancer or precursor adenomatous colon polyps have an increased risk of developing colon neoplasia. This observation suggests the presence of inherited genetic determinants for sporadic colon neoplasia. Mice homozygous for a null cyclooxygenase 2 (COX2) (also called PTGS2) allele have a dramatically reduced susceptibility to the development of intestinal adenomas. In humans, use of pharmacologic inhibitors of COX2 enzyme activity are associated with reduced risk of colon neoplasia. This study examined whether the human COX2 locus may be linked to colon neoplasia in humans. METHODS: We used the affected sibling-pair method to test for linkage of the human COX2 locus to colon neoplasia. RESULTS: We examined 74 concordantly affected sibling pairs from 46 sibships with colon neoplasia. One hundred five siblings from these sibships were diagnosed with either colorectal cancer or colon adenomatous polyps before age 65 years. No linkage between COX2 and colon neoplasia was found by use of a multipoint model-free linkage analysis (estimate of allele sharing was 0.44; standard error = +/-0.04; 95% confidence interval = 0.36 to 0.52). Moreover, even allowing for heterogeneity, the potential that a COX2 colon neoplasia susceptibility variant was present within a substantial subset of these sibships was strongly excluded under either a recessive or a dominant inheritance model (95% confidence to exclude a model in which 2.7% or more of the sibling pairs harbor a dominant susceptibility allele). CONCLUSIONS: This study of concordantly affected sibling pairs thus demonstrates that variations in the COX2 gene are unlikely to be a source of individual susceptibility to colon neoplasia in humans.

A comparison of anterior screw fixation and halo immobilisation of type II odontoid fractures in elderly patients at increased risk from anaesthesia.

AIMS: We performed a retrospective, comparative study of elderly patients with an increased risk from anaesthesia who had undergone either anterior screw fixation (ASF) or halo vest immobilisation (HVI) for a type II odontoid fracture. PATIENTS AND METHODS: A total of 80 patients aged 65 years or more who had undergone either ASF or HVI for a type II odontoid fracture between 1988 and 2013 were reviewed. There were 47 women and 33 men with a mean age of 73 (65 to 96; standard deviation 7). All had an American Society of Anesthesiologists score of 2 or more. RESULTS: Patients who underwent ASF had a significantly better outcome than those who were treated by HVI. There was a rate of nonunion of 10% after ASF and 23% after HVI. Failure of reduction or fixation occurred in 11 patients (15%) but there was no significant difference between the two groups. Mortality rates were also similar: 9% (n = 3) after ASF and 8% (n = 4) after HVI. CONCLUSION: We conclude that ASF is the preferred method of treatment in this group of elderly patients, having a significantly higher rate of fusion, better clinical outcome and a similar rate of general and treatment-related complications. Cite this article: Bone Joint J 2016;98-B:1222-6.

Metabolism and biliary excretion of the novel anticancer agent 10-hydroxycamptothecin in the isolated perfused rat liver.

10-hydroxycamptothecin (HCPT), a natural analog of the alkaloid camptothecin (CPT), is a promising anticancer agent currently undergoing preclinical trials. Though HCPT is less toxic and more active in various human cancer cell lines and in animal tumor models than the clinically approved CPT-analog topotecan, little is known about its biotransformation products and their route of elimination. To investigate the metabolism and biliary excretion, livers of male Wistar rats were perfused with HCPT (5 microM). Bile and perfusate samples were collected for 60 min and quantified by reversed-phase high-performance liquid chromatography (HPLC). Besides HCPT, three metabolites, namely HCPT glucuronide (M1), hydroxyHCPT glucuronide (M2), and hydroxyHCPT (M3) could be identified by enzymatic hydrolysis with beta-glucuronidase and mass spectroscopy. Biliary secretion of HCPT and M1-M3 reached a peak secretion of 1532+/-124, 75+/-16, 5.8+/-1.6 and 2.1+/-0.5 pmoles/g liver.min, respectively, after 25 min. The total amount of HCPT and M1-M3 excreted into bile during the time of perfusion (60 min) was low and represented a mean of 9.9+/-3.2%, 0.44+/-0.17%, 0.041+/-0.010%, and 0.022+/-0.004% of the initial HCPT dose, respectively. In the perfusate, besides HCPT M1 and M2 but not M3 could be detected (maximum concentrations after about 20 min: 3248+/-210, 16.8+/-2.8 and 1.0+/-0.4 pmoles/g liver.min, respectively). The cumulative efflux of HCPT and M1 and M2 into the perfusate was 21.1+/-3.9%, 0.145+/-0.036% and 0.018+/-0.004% of the initial dose, respectively, indicating a preferable non-biliary secretion for HCPT and a predominant biliary elimination for conjugated HCPT biotransformation products. In conclusion, HCPT is biotransformed in a rat liver model to three metabolites, mainly excreted into bile, which may be of clinical relevance during cancer therapy.

Placental metastasis from maternal carcinoma of the lung.

A case of large cell undifferentiated carcinoma of the lung metastatic to the placenta and a review of the literature are presented. This is the 44th documented case of placental and/or fetal metastasis from maternal cancer in the past 113 years. Fifty percent of these cases are either malignant melanomas or hematopoietic malignancies. Evidence indicates that these 2 malignancies are more likely to metastasize to the products of conception than are other malignancies.

Metabolism of camptothecin, a potent topoisomerase I inhibitor, in the isolated perfused rat liver.

PURPOSE: Camptothecin (CPT) is a potent topoisomerase I inhibitor that has recently been undergoing phase I clinical trials. Though CPT shows high activity against various tumor cells, its biotransformation is still unknown. To investigate the metabolism and biliary excretion of CPT, an isolated perfused rat liver system was used. METHODS: CPT was added to the perfusion medium at a concentration of 20 microM, and bile and perfusate samples were collected for 90 min. CPT (lacton and carboxylate) and three novel metabolites were identified by mass spectroscopy and quantified by reversed-phase high-performance liquid chromatography (HPLC). Kinetic parameters of CPT and its biotransformation products were then estimated in bile and effluent perfusate. RESULTS: Biliary secretion of CPT and its three metabolites reached a peak secretion of 37.6 +/- 16.3, 0.94 +/- 0.29, 0.19 +/- 0.023 and 0.302 +/- 0.076 nmol/g liver/min, respectively, after 20 min. The total amount of CPT and M1-M3 excreted into bile during 90 min of perfusion was 63.5 +/- 15.4%, 1.8 +/- 0.37%, 0.43 +/- 0.06%, and 0.72 +/- 0.15% of CPT cleared from the perfusate during 90 min, respectively. In the perfusate, only one metabolite (M3) could be detected (cumulative release into the perfusion medium: 0.37 +/- 0.026 micromol/liver). Analysis of the biliary metabolites by mass spectroscopy supported the existence of dihydroxy-CPT derivatives (M1 and M2), whereas M3 appears to be a monohydroxy-analog. CONCLUSION: CPT is biotransformed to three novel metabolites, mainly excreted into bile. The possible pharmacological effects of these new metabolites need to be considered.

Poly(D,L-lactic-co-glycolic acid) microspheres for sustained delivery and stabilization of camptothecin.

Camptothecin (CPT) and its water-insoluble derivatives are known as topoisomerase-I inhibitors exhibiting high antitumoral activity against a wide spectrum of human malignancies. Until now clinical application of CPT is restricted by insolubility and instability of the drug in its active lactone form resulting in less antitumor potency and poor bioavailability. For these reasons CPT-loaded-microspheres were prepared by the solvent evaporation method using the H-series of poly(D,L-lactide-co-glycolide) (H-PLGA), which contain more carboxylic acid end chains and hydrate faster than the non-H-series. At 1.2% CPT-payload the drug was molecular dispersed throughout the matrix whereas at higher CPT-payload the amount of crystalline CPT-islets increased with the CPT content. The release pattern of CPT was biphasic comprising a first burst effect delivering 20-35% of the payload and increasing with drug-loading. This phase was followed by sustained delivery of CPT releasing 40-75% of the payload within 160 h. In comparison to PLGA-microspheres, the CPT-release rate from H-PLGA was twofold higher and accelerated. The active CPT-lactone was maintained during preparation, storage and release due to hindered diffusion of acidic oligomers among other mechanisms. Thus stabilization and sustained release of CPT from PLGA-microspheres might reduce local toxicity combined with prolonged efficacy offering new perspectives in CPT chemotherapy.

Biotransformation of topotecan in the isolated perfused rat liver: identification of three novel metabolites.

This study evaluates the metabolism of the anticancer drug topotecan (TPT) in the isolated perfused rat liver of male Wistar-rats. Using a sensitive high-performance liquid chromatography method, in bile TPT, its ring-opened hydroxycarboxylate form and three new metabolites could be quantified. Enzymatic hydrolysis of the metabolites with beta-glucuronidase and mass spectroscopy revealed the existence of glucuronidated TPT as well as unconjugated and glucuronidated bidesmethyl TPT. Biliary secretion of glucuronidated N-bidesmethyl TPT was fast reaching a maximum already after 15 min(30.6 +/- 15.1 pmol/g liver.min), whereas secretion of TPT, topotecan glucuronide and N-bidesmethyl TPT was delayed (maximum at 30 min: 431 +/- 19, 6.4 +/- 2.1 and 12.7 +/- 2.7 pmol/g liver.min, respectively). No release of TPT metabolites into the perfusate was detected. The amount of TPT, TPT glucuronide, N-bidesmethyl TPT and N-bidesmethyl TPT glucuronide excreted into bile during 60 min of perfusion was 2.10 +/- 0.483%, 0.031 +/- 0.006%, 0.058 +/- 0.013% and 0.108 +/- 0.012% of TPT cleared from the perfusate over 60 min, respectively. In conclusion we could identify three novel TPT metabolites, however, their overall metabolism in the rat liver is low.

Formation of a novel topotecan metabolite in the hormone-independent human prostate carcinoma cell lines DU-145 and PC-3.

To investigate the implications of drug metabolism on topotecan (TPT) resistance in prostate cancer cells, we measured the time-dependent uptake, metabolismrand efflux of TPT in the prostate cancer-derived cell lines DU-145 and PC-3 by HPLC. Exposure of DU-145 to 10 microM TPT resulted in a maximal intracellular concentration of TPT of 12.6 +/- 0.53 pmol/10(6) cells (t = 10 min) with a decrease to 4.4 +/- 0.25 pmol/10(6) cells after 2 hours. Incubation of PC-3 cells, however, revealed a more than 2-fold higher level of cytoplasmatic TPT (25.3 +/- 4.8 pmol/10(6) cells). In both cell lines, an intracellular metabolite was detectable after 30 minutes. Its concentration continuously increased reaching saturation after 6 hours (0.015 +/- 0.003 pmol/10(6) cells in DU-145 and 0.0059 +/- 0.0020 pmol/10(6) cells in PC-3 cells). Analysis of the culture supernatant of DU-145 and PC-3 cells revealed that this metabolite is secreted into the medium at increasing concentrations (0.220 +/- 0.025 and 0.079 +/- 0.008 pmol/10(6) cells, respectively). In accordance with the elevated formation of the TPT-metabolite in DU-145 cells, the expression of cytochrome P450 (CYP) isoenzymes CYP3A, CYP2B, CYP2D and CYP2E as measured by Western blot analysis was also higher in this cancer cell line. In conclusion, we found that TPT is rapidly taken up by the two prostate cancer cell lines and metabolized to a minor biotransformation product dependent on their content of cytochrome P450 isoenzymes. The structural identification of this TPT metabolite and the CYP isoenzyme(s) responsible for its formation remain to be elucidated.

Stereoselective metabolism of the monoterpene carvone by rat and human liver microsomes.

The large amounts of carvone enantiomers consumed as food additives and in dental formulations justifies the evaluation of their biotransformation pathway. The in-vitro metabolism of R-(-)- and S-(+)-carvone was studied in rat and human liver microsomes using chiral gas chromatography. Stereoselective biotransformation was observed when each enantiomer was incubated separately with liver microsomes. 4R, 6S-(-)-Carveol was NADPH-dependently formed from R-(-)-carvone, whereas 4S, 6S-(+)-carveol was produced from S-(+)-carvone. Metabolite formation followed Michaelis-Menten kinetics exhibiting a significant lower apparent Km (Michaelis-Menten Constant) for 4R, 6S-(-)-carveol compared with 4S, 6S-(+)-carveol in rat and human liver microsomes (28.4+/-10.6 microM and 69.4+/-10.3 microM vs 33.6+/-8-55 microM and 98.3+/-22.4 microM). The maximal formation rate (Vmax) determined in the same microsomal preparations yielded 30.2+/-5.0 and 32.3+/-3.9 pmol (mg protein)(-1) min(-1) in rat liver and 55.3+/-5.7 and 65.2+/-4.3 pmol (mg protein)(-1) min(-1) in human liver microsomes. Phase II conjugation of the carveol isomers by rat and human liver microsomes in the presence of UDPGA (uridine S'-diphosphogluaronic acid) only revealed glucuronidation of 4R, 6S-(-)-carveol. Vmax for glucuronide formation was more than 4-fold higher in the rat liver compared with human liver preparations (185.9+/-34.5 and 42.6+/-7.1 pmol (mg protein)(-1) min(-1), respectively). Km values, however, showed no species-related difference (13.9+/-4.1 microM and 10.2+/-2.2 microM). This study demonstrated stereoselectivity in phase-I and phase-II metabolism for R-(-)- and S-(+)-carvone and might be predictive for carvone biotransformation in man.

The kininase activity of Ehrlichs' ascites solid tumor after treatment with oncolytic clostridia.

For the first time the effect of bacterial kininases of Cl. oncolyticum M 55 ATCC 13.732 could be demonstrated in the tumor itself. This is shown by an increased degradation of kinins by spore-treated tumor tissue in comparison with respective controls. The results indicate the influence of kininases on the capillary circulation of the tumor tissue as one of the fundamental reactions of oncolysis.

Treatment of toxoplasmosis in pregnancy: concentrations of spiramycin and neospiramycin in maternal serum and amniotic fluid.

Toxoplasma infection during pregnancy is widely treated with oral spiramycin to reduce the risk of congenital toxoplasmosis in the infant. Failures of therapy have been observed, however. In this study, a sensitive high-performance liquid chromatography technique was used to measure concentrations of spiramycin and neospiramycin, one of the major metabolites of spiramycin, in maternal serum and amniotic fluid. Samples were obtained from 18 women who underwent amniocentesis for polymerase chain reaction (PCR) diagnosis of fetal infection 5-109 days following the prescription of spiramycin therapy (3 g/day). Concentrations of spiramycin and neospiramycin in both serum and amniotic fluid were highly variable, ranging from nondetectable values to 1 microg/ml. None of the concentrations measured were within the range reported to inhibit growth of the parasite in vitro. Consistent with previous reports, part of the observed variability in maternal and fetal drug concentrations could be explained by individual differences in several pharmacokinetic parameters: intestinal absorption, tissue distribution, cellular uptake, metabolism, transfer across the placenta, drug accumulation in fetal tissue, and maternal and fetal drug elimination. The heterogeneity of the data could also be related to differences in patient compliance with the medication prescribed. By addressing factors that could impair adequate treatment of toxoplasmosis during pregnancy, the data presented call for a larger-scale controlled study to determine individual and diurnal variations in maternal drug levels, patient compliance, and outcomes of the offspring. The activity of neospiramycin against Toxoplasma gondii should be assessed.