Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

WNT-activated bone grafts repair osteonecrotic lesions in aged animals.

The Wnt pathway is a new target in bone therapeutic space. WNT proteins are potent stem cell activators and pro-osteogenic agents. Here, we gained insights into the molecular and cellular mechanisms responsible for liposome-reconstituted recombinant human WNT3A protein (L-WNT3A) efficacy to treat osteonecrotic defects. Skeletal injuries were coupled with cryoablation to create non-healing osteonecrotic defects in the diaphysis of the murine long bones. To replicate clinical therapy, osteonecrotic defects were treated with autologous bone graft, which were simulated by using bone graft material from syngeneic ACTB-eGFP-expressing mice. Control osteonecrotic defects received autografts alone; test sites received autografts treated ex vivo with L-WNT3A. In vivo µCT monitored healing over time and immunohistochemistry were used to track the fate of donor cells and assess their capacity to repair osteonecrotic defects according to age and WNT activation status. Collectively, analyses demonstrated that cells from the autograft directly contributed to repair of an osteonecrotic lesion, but this contribution diminished as the age of the donor increased. Pre-treating autografts from aged animals with L-WNT3A restored osteogenic capacity to autografts back to levels observed in autografts from young animals. A WNT therapeutic approach may therefore have utility in the treatment of osteonecrosis, especially in aged patients.

Accuracy of ultrasonography performed by examiners with varied training and experience in predicting specific pathology of adnexal masses.

OBJECTIVES: To assess the diagnostic performance of subjective assessment by Level II ultrasound examiners in predicting the specific histology of adnexal masses. METHODS: The women included in this prospective multicenter cross-sectional study were older than 16 years of age and had at least one adnexal mass. They underwent transvaginal sonography (TVS) performed by Level II examiners, all of whom were familiar with the International Ovarian Tumor Analysis (IOTA) group definitions of ultrasound features of ovarian masses. The final outcome was histology. Specific diagnoses were categorized into 16 groups. Agreement between subjective assessment and final histology was measured using unweighted kappa coefficients. Sensitivities and specificities were obtained for subjective assessment. RESULTS: Of the 1279 women who underwent TVS, 313 were included in the final analysis. Overall agreement (16 × 16 table) between subjective assessment and histology was moderate, with a Cohen's kappa coefficient of 0.59 (95% CI, 0.53-0.65). The specificity of subjective assessment ranged between 91% and 100% for all histological subgroups. Highest sensitivities were achieved in the diagnosis of simple cysts (100% (95% CI, 61-100%)), hydrosalpinges (100% (95% CI, 34-100%)), mature teratomas (88% (95% CI, 74-96%)), endometriomas (75% (95% CI, 61-85%)), ovarian fibromas (88% (95% CI, 47-100%)), tubo-ovarian abscesses (88% (95% CI, 47-100%)) and serous cystadenocarcinomas (82% (95% CI, 66-93%)). Serous cystadenomas were misdiagnosed most commonly (40.5%). The sensitivity of subjective assessment in diagnosing adnexal torsion was 54% (95% CI, 25-81%); the 17 confirmed and/or suspected cases of adnexal torsion were not included in the 313 cases examined and analyzed for diagnostic performance. CONCLUSION: Overall, subjective assessment by Level II examiners was good for the detection of simple cysts, endometriomas, mature teratomas, hydrosalpinges, fibroma, tubo-ovarian abscess and serous cystadenocarcinomas.

Cell viability after osteotomy and bone harvesting: comparison of piezoelectric surgery and conventional bur.

The aim of this study was to evaluate and compare the influence of a piezoelectric device versus a conventional bur on osteocyte viability and osteoblast and osteoclast activity using an in vivo mouse model. Osteotomies were created and bone grafts were harvested using either a conventional bur or a piezoelectric device; the resulting injuries and bone grafts were evaluated over an extended time-course using molecular and cellular assays for cell death (TUNEL assay), cell viability (4',6-diamidino-2-phenylindole (DAPI) staining), the onset of mineralization (alkaline phosphatase activity), and bone remodelling (tartrate-resistant acid phosphatase activity). Osteotomies created with a piezoelectric device showed greater osteocyte viability and reduced cell death. Bone grafts harvested with a piezoelectric device exhibited greater short-term cell viability than those harvested with a bur, and exhibited slightly more new bone deposition and bone remodelling. The difference in response of osteocytes, osteoblasts, and osteoclasts to bone cutting via a bur and via a piezoelectric device is negligible in vivo. Given the improved visibility and the margin of safety afforded by a piezoelectric device, they are the instrument of choice when cutting or harvesting bone to preserve soft tissue.

Multicentre external validation of IOTA prediction models and RMI by operators with varied training.

BACKGROUND: Correct characterisation of ovarian tumours is critical to optimise patient care. The purpose of this study is to evaluate the diagnostic performance of the International Ovarian Tumour Analysis (IOTA) logistic regression model (LR2), ultrasound Simple Rules (SR), the Risk of Malignancy Index (RMI) and subjective assessment (SA) for preoperative characterisation of adnexal masses, when ultrasonography is performed by examiners with different background training and experience. METHODS: A 2-year prospective multicentre cross-sectional study. Thirty-five level II ultrasound examiners contributed in three UK hospitals. Transvaginal ultrasonography was performed using a standardised approach. The final outcome was the surgical findings and histological diagnosis. To characterise the adnexal masses, the six-variable prediction model (LR2) with a cutoff of 0.1, the RMI with cutoff of 200, ten SR (five rules for malignancy and five rules for benignity) and SA were applied. The area under the curves (AUCs) for performance of LR2 and RMI were calculated. Diagnostic performance measures for all models assessed were sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), and the diagnostic odds ratio (DOR). RESULTS: Nine-hundred and sixty-two women with adnexal masses underwent transvaginal ultrasonography, whereas 255 had surgery. Prevalence of malignancy was 29% (49 primary invasive epithelial ovarian cancers, 18 borderline ovarian tumours, and 7 metastatic tumours). The AUCs for LR2 and RMI for all masses were 0.94 (95% confidence interval (CI): 0.89-0.97) and 0.90 (95% CI: 0.83-0.94), respectively. In premenopausal women, LR2-RMI difference was 0.09 (95% CI: 0.03-0.15) compared with -0.02 (95% CI: -0.08 to 0.04) in postmenopausal women. For all masses, the DORs for LR2, RMI, SR+SA (using SA when SR inapplicable), SR+MA (assuming malignancy when SR inapplicable), and SA were 62 (95% CI: 27-142), 43 (95% CI: 19-97), 109 (95% CI: 44-274), 66 (95% CI: 27-158), and 70 (95% CI: 30-163), respectively. CONCLUSION: Overall, the test performance of IOTA prediction models and rules as well as the RMI was maintained in examiners with varying levels of training and experience.

Mucin immunohistochemistry in the diagnosis and mapping of extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare skin cancer of the genital region in which cancer cells with enlarged nuclei and pale cytoplasm are scattered singly in the affected epidermis. These cancer cells, called Paget cells, contain mucin, which is never found in normal epidermis. The oligosaccharide side chains of Paget cell mucin end with sialic acid. Sialic acid is easily detected by zirconyl haematoxylin or alcian blue. The other sugars in the oligosaccharide chains can be detected by the periodic acid-Shiff reaction. Rarely, the diagnosis of EMPD is complicated by the absence of mucin from the Paget cells. We have examined such an atypical case. The oligosaccharide side chains, including the sialic acids, are absent. In both this case and a typical case, the Paget cells contain epithelial membrane antigen mucin (MUC1) core protein and usually contain gastric surface-type mucin (MUC5AC) core protein, which can be stained by antibodies. Since neither core protein is found in normal epidermis, epithelial membrane antigen core protein may be the most reliable diagnostic marker for extramammary Paget's disease. In both the atypical case and the typical case of Paget's disease, some cells that look like keratinocytes contain mucin core proteins. These may be incipient Paget cells. We suggest that using th epithelial membrane antigen core protein as a marker for the true extent of extramammary Paget's disease could facilitate complete excision and reduce the rate of recurrence.

Intracranial germ cell tumors: a single institution experience and review of the literature.

There is little literature to guide therapy in children and young adults with intracranial germ cell tumors. We present 17 consecutively diagnosed intracranial germ cell tumors at The Children's Hospital, Denver, from 1995 to 2001. Of 17 patients, 3 had considerable delay in diagnosis. Two with suprasellar tumors presented with dementia, blindness and pan-hypopituitarism and another with recurrent subarachnoid hemorrhage. Seven had germinoma, three were metastatic at diagnosis. Ten had non-germinomatous germ cell tumors (NGGCT), 5/10 were alpha feto-protein (AFP) positive only, one beta-human chorionic growth (betaHCG) factor positive only, 3 positive for AFP and betaHCG, and 1 malignant teratoma. Therapy for metastatic patients consisted of chemotherapy followed by craniospinal radiation (CSI). Patients with localized disease received chemotherapy followed by focal radiation. Two patients received chemotherapy only, one because she died of sepsis while receiving chemotherapy and one because of neurologic injury incurred during surgery parents elected for no therapy. Three patients have died, one of tumor recurrence, one from a remote complication of surgery and one of sepsis. Twelve patients are alive without evidence of disease from 10 to 68 months (median 31.5 months). All five children with only AFP positivity, treated with chemotherapy and focal radiation are alive without evidence of disease at 10, 16, 22, 41 and 41 months. Thus, there is little evidence that CSI is necessary in non-metastatic germinomas and AFP positive NGGCTs when combined chemotherapy and radiation therapy is used. However, complications of delayed diagnosis, surgery and chemotherapy are important causes of mortality, with only one patient dying of tumor.

Specific staining of tissue components with metal-hematoxylin complexes.

The older metal-hematoxylin stains stain a broad spectrum of tissue components. Several recently introduced metal-hematoxylin stains are highly selective. This selectivity is usually bought at the price of severe limitations on the choice of fixative. A very dilute (2 x 10(-4)M) aluminum hematoxylin is selective for nucleic acids in tissues fixed in organic solvents alone. Vanadate hematoxylin is selective for basic proteins in tissues fixed in formaldehyde or mercuric salts. Bismuth hematoxylin is selective for arginine residues and thus for histones and myelin basic protein in tissues fixed in strong acids (Bouin's fluid or SUSA fluid). Zirconyl hematoxylin is selective for acidic mucins. Zirconyl hematoxylin does not restrict the choice of fixative.

Structural determinants for potent, selective dual site inhibition of human pp60c-src by 4-anilinoquinazolines.

The kinetic mechanisms for the inhibition of pp60(c-src) tyrosine kinase (Src TK) by 4-anilinoquinazolines, an important class of chemicals as protein kinase inhibitors, were investigated. 4-Anilinoquinazolines with a bulky group at the 4'-position of the anilino group were shown to be competitive with both ATP and peptide, whereas molecules lacking such a bulky group only displayed an inhibition pattern typical of those competitive with ATP and noncompetitive with peptide. Modifications of the substituents on the carbocyclic ring did not perturb the inhibition pattern although the affinities of these modified inhibitors for Src TK were affected. Structural modeling of Src TK with inhibitor and peptide substrate bound indicated a direct atomic conflict between the bulky 4-position group and the hydroxy of the peptide tyrosyl to which the gamma-phosphate of ATP is transferred during the kinase reaction. This atomic conflict would likely prevent simultaneous binding of both inhibitor and peptide, consistent with the observed kinetic competitiveness of the inhibitor with peptide. The dual site inhibitors appeared to have both enhanced potency and selectivity for Src TK. One such inhibitor, 4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline, had a 15 nM potency against Src TK and was selective over receptor tyrosine kinases VEGFR2 by 88-fold and C-fms by 190-fold.

Zirconyl hematoxylin: a new stain for acidic mucins.

Most stains for acidic mucins are time-consuming to prepare and have poor stability. Zirconyl hematoxylin is easily prepared and works for a year or more. It is made by adding 5 ml freshly-made 0.1% aqueous sodium iodate, 400 mg zirconyl chloride octahydrate, and 40 ml 25% aqueous glycerol, in that order, to 100 mg of hematoxylin in 5 ml of absolute ethanol and stirring for 5 min. Stain 10 min and do not "blue" the stain. Chlorazole black or kernechtrot and fast green are good counterstains. Zirconyl hematoxylin stains acidic mucins violet or red violet, regardless of how they are fixed. It stains the same mucins as alcian blue in mouse and sheep salivary glands. It shows goblet cells in mouse rectum as well as alcian blue. It stains the same stomach regions in a lizard as alcian blue. Like alcian blue and colloidal iron, zirconyl hematoxylin stains the mucin of cancerous prostate, but not normal prostate.

Upper limb free flap reconstruction after tumor resection.

Free tissue transfer is the autologous transplantation of composite tissue and its arterial and venous blood supply to a distant site. Free tissue transfers, also called free flaps, may include skin, fascia, muscle, or bone. Free flaps were once considered highly complex procedures; now they are frequently used as the reconstructive option of choice. While several variables must be considered when one plans a free tissue transfer, the most important consideration is the size and location of the defect created by the tumor resection. Free tissue transfer is a multistep procedure, including preparation of the recipient site, harvesting of the flap, and transfer and revascularization of the flap. For upper extremity reconstruction, the gracilis muscle flap has been particularly useful, as has the lateral arm fasciocutaneous flap. Semin. Surg. Oncol. 19:246-254, 2000.

Upper extremity salvage using the tensor fascia lata flap: report of two cases.

The tensor fascia lata pedicled flap was successfully used to salvage 3 severely injured upper extremities in 2 patients. Both patients had undergone 3 prior free tissue transfers without complete closure of their wounds. All 3 tensor fascia lata flaps (2 myocutaneous, 1 myofascial) survived entirely. We believe this flap offers a distinct advantage compared with the groin flap when pedicled flap coverage of the upper extremity is required.

Lag-screw technique in free osseous mandibular reconstruction.

The surgical registry was reviewed for mandibular reconstruction from 1988 to 1992. During this time, 51 patients underwent mandibular reconstruction. Of this group, 17 patients had their microvascular bone grafts secured with lag-screw fixation. An AO technique, utilizing 2.7-mm cortical screws, was used to provide rigid fixation. Mandibular defects ranged from 6 to 20 cm. AO vascularized bone grafts were studied with bone scans and remained viable. Follow-up revealed no flap losses or oral cutaneous fistulae. Lag-screw fixation, in conjunction with mandibular reconstruction, results in rigid fixation, obviates the need for mandibulamaxillary fixation, has the advantage of ease of application, and is safe to use.

Muscle flap reconstruction aids in urethral regeneration.

Traditional methods of reconstructing full-thickness urethral defects have employed a cutaneous component utilized to replace the lining of the urethra. These methods have failed to take advantage of the regenerative ability of urethral epithelium. This epithelium is capable of regenerating, eliminating the need for urethral lining reconstruction. Muscle flap reconstruction provides an environment that allows for complete regeneration of the urethral epithelium. A 56-year-old male presented with a 12-cm defect of the bulbous and penile urethra involving 180 degrees of the urethral circumference secondary to Fournier's gangrene. A proximally pedicled gracilis muscle was used to reconstruct the urethral defect. This healed without stricture or leak. Urethral biopsies showed satisfactory migration of the uroepithelium across the urethral defect.

Field edge smoothing for multileaf collimators.

PURPOSE: To smooth the scalloped dose pattern that occurs for stepped leaves at a treatment field edge defined by a multileaf collimator. METHODS AND MATERIALS: Fields with centers shifted slightly in space were superimposed to blur the staggered dose distribution at the field edge. Film dosimetry was used to monitor changes. The dose distribution for a single field position was compared to the distribution for one and three shifts. Three depths were examined and divergent alloy blocks were included in the comparison. RESULTS: The structure that appears at an edge for a single field when leaves are staggered was nearly eliminated when the field was shifted three times to give a total of four different positions. However, shifting the field one time so that two fields were superimposed gave an intermediate result with only slight improvement in the undulating dose distribution. For the four superimposed fields, the 50% isodose pattern converged to a smoothed line running along the center of the original undulating pattern. The 80 and 20% isodoses did not converge to the center of their scalloped patterns. Instead, these isodose lines were spread leaving a larger penumbra width than a divergent alloy block. CONCLUSIONS: Shifting and adding fields is an effective method for smoothing the staggered dose distribution that results when the leaves of a multileaf collimator are stepped to form an irregular field pattern. However, the width of the penumbra for the combined fields is wider than the penumbra for a cerrobend block.

Functional lower limb salvage with an osteocutaneous filet flap of the foot.

An osteocutaneous foot filet flap based on the posterior tibial vessels was successfully used to provide tibial coverage in a patient requiring a below-knee amputation following a high-voltage electrical injury. Addition of the calcaneus to the standard foot filet flap provided a vascularized bone graft that served to both lengthen the tibia and secure the flap via a tibial-calcaneal synostosis. The synostosis provided firm anchoring of the flap and allowed for a partial end-bearing, below-knee prosthesis.

Postpericardiotomy syndrome: its diagnosis and treatment after muscle flap closure of an infected sternal wound.

After nearly any form of cardiac surgery, an acute febrile illness characterized by leukocytosis, pericarditis with pericardial effusion, and pleural effusion may occur. In some instances, this postpericardiotomy syndrome may suggest the presence of mediastinal infection. Treatment of postpericardiotomy syndrome is conservative, and symptoms typically resolve with nonsteroidal antiinflammatory medication. We report a case of postpericardiotomy syndrome that mimicked recurrent mediastinal infection and developed after muscle flap closure of an infected sternal wound. Pericardial, pleural, and periflap fluid accumulated postmuscle flap closure and was sterile on culture. A diagnosis of postpericardiotomy syndrome was made, and the patient improved while receiving oral indomethacin. She has remained free of infection as of the 2-year follow-up.

Preliminary soft tissue distraction in congenital forearm deficiency.

Four patients (five limbs) were treated with preliminary soft tissue distraction using an Orthofix external distractor. The patient's ages ranged from 6 months to 14 years. Forearm deficiencies treated included partial absence of the radius (one patient), radial aplasia (two patients, three limbs), and partial absence of the ulna (one patient). Soft tissue distraction (mean, 55 days) was continued in radial deficiency until the hand could be passively centralized without residual radial deviation, allowing centralization to be accomplished through a single mid-dorsal incision. Mean measurement of distraction for the radial deficiencies was 1 cm. In the ulnar deficiency, soft tissue distraction was carried out until the cut radius was distal to the partially absent ulna (98 days) allowing for the creation of a one-bone forearm using the entire radius. Distraction (1 mm/day) was done by the children's parents with no distractor removed because of patient intolerance. All radial deficiency limbs remained centralized at a mean followup period of 14 months.

Supplemental oxygen: ensuring its safe delivery during facial surgery.

Electrosurgical coagulation in the presence of blow-by oxygen is a potential source of fire in facial surgery. A case report of a patient sustaining partial-thickness facial burns secondary to such a flash fire is presented. A fiberglass facial model is then used to study the variables involved in providing supplemental oxygen when an electrosurgical unit is employed. Oxygen flow, oxygen delivery systems, distance from the oxygen source, and coagulation current levels were varied. A nasal cannula and an adapted suction tubing provided the oxygen delivery systems on the model. Both the "displaced" nasal cannula and the adapted suction tubing ignited at a minimum coagulation level of 30 W, an oxygen flow of 2 liters/minute, and a linear distance of 5 cm from the oxygen source. The properly placed nasal cannula did not ignite at any combination of oxygen flow, coagulation current level, or distance from the oxygen source. Facial cutaneous surgery in patients provided supplemental oxygen should be practiced with caution when an electrosurgical unit is used for coagulation. The oxygen delivery systems adapted for use are hazardous and should not be used until their safety has been demonstrated.

Distal foot coverage with a reverse dorsalis pedis flap.

A reverse dorsalis pedis flap based on the proximal communicating branch of the dorsalis pedis artery was successfully used to close distal forefoot defects in two patients. The skin paddle was oriented transversely across the ankle crease, allowing for direct closure of the flap donor site. Both patients maintained full active ankle motion without bowstringing of the dorsal foot tendons and did not require special footwear. Both flaps maintained sensation to light touch and pinprick. We believe that this flap offers a viable alternative when faced with the challenge of a small soft-tissue defect requiring flap reconstruction in the distal foot.