Transcriptomic and clinical heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer.

BACKGROUND: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly classified into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes; however, less is known about any underlying biologic differences between these disease states. Herein, we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. PATIENTS AND METHODS: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous versus metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease timing. The median transcriptomic scores between groups were compared with the Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from the time of metastasis. Survival analysis was carried out with the Kaplan-Meier method and multivariable Cox regression. RESULTS: A total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-year OS (39% versus 79%; P < 0.01) and demonstrated lower median androgen receptor (AR) activity (11.78 versus 12.64; P < 0.01) and hallmark androgen response (HAR; 3.15 versus 3.32; P < 0.01). Multivariable Cox regression identified only high-volume disease [hazard ratio (HR) = 4.97, 95% confidence interval (CI) 2.71-9.10; P < 0.01] and HAR score (HR = 0.51, 95% CI 0.28-0.88; P = 0.02) significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; P < 0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; P = 0.56) disease were found to have better OS with AR and non-AR combination therapy as compared with monotherapy (P value for interaction = 0.05). CONCLUSIONS: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low-volume disease, those with metachronous low-volume disease have a more hormone-dependent transcriptional profile and exhibit a better prognosis than synchronous low-volume disease.

Adjuvant Radiotherapy After Radical Cystectomy for Patients with High-risk Muscle-invasive Bladder Cancer: Results of a Multicentric Phase II Trial.

BACKGROUND: High-risk muscle-invasive bladder cancer (MIBC) has a poor prognosis. Old trials showed that external beam radiotherapy (EBRT) after radical cystectomy (RC) decreases the incidence of local recurrences but induces severe toxicity. OBJECTIVE: To evaluate the toxicity and local control rate after adjuvant EBRT after RC delivered with volumetric arc radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: This is a multicentric phase 2 trial. From August 2014 till October 2020, we treated 72 high-risk MIBC patients with adjuvant EBRT after RC. High-risk MIBC is defined as ≥pT3-MIBC ± lymphovascular invasion, fewer than ten lymph nodes removed, pathological positive lymph nodes, or positive surgical margins. INTERVENTION: Patients received 50 Gy in 25 fractions with intensity-modulated radiotherapy to the pelvic lymph nodes ± cystectomy bed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome is acute toxicity. We report on local relapse-free rate (LRFR), clinical relapse-free survival (CRFS), overall survival (OS), and bladder cancer-specific survival (BCSS). RESULTS AND LIMITATIONS: The median follow-up is 18 mo. Forty-two patients (61%) developed acute grade 2 gastrointestinal (GI) toxicity. Four patients (6%) had acute grade 3 GI toxicity. One patient had grade 5 diarrhea and vomiting due to obstruction at 1 mo. Two-year probabilities of developing grade ≥3 and ≥2 GI toxicity were 17% and 76%, respectively. Urinary toxicity, assessed in 17 patients with a neobladder, was acceptable with acute grade 2 and 3 urinary toxicity reported in 53% (N = 9) and 18% (N = 3) of the patients, respectively. The 2-yr LRFR is 83% ± 5% and the 2-yr CRFS rate is 43% with a median CRFS time of 12 mo (95% confidence interval: 3-21 mo). Two-year OS and BCSS are 52% ± 7% and 62% ± 7%, respectively. Shortcomings are the nonrandomized study design and limited follow-up. CONCLUSIONS: Adjuvant EBRT after RC can be administered without excessive severe toxicity. PATIENT SUMMARY: In this report, we looked at the incidence of toxicity and local control after adjuvant external beam radiotherapy (EBRT) following radical cystectomy (RC) in high-risk muscle-invasive bladder cancer patients. We found that adjuvant EBRT was feasible and resulted in good local control. We conclude that these data support further enrollment of patients in ongoing trials to evaluate the place of adjuvant EBRT after RC.

Surgical repair of orbital fractures: how soon after trauma?

PURPOSE: To determine the results of surgical exploration soon after orbital trauma in comparison with surgery half a year or longer after trauma. METHODS: A retrospective study was done on 41 patients with motility disorders after trauma. Full ophthalmologic and orthoptic investigation was done in all patients. CT-scans and/or X-ray photographs were also made. The 41 patients were divided into two groups. One group of 13 patients did not need surgical repair. One group of 28 patients needed an operation. RESULTS: In 13 patients there was an orbital fracture but no surgical repair was needed. In 28 patients surgical repair was done. In 8 patients the operation was performed half a year or longer after trauma, 15 patients underwent surgery within two weeks after trauma, and 5 patients within two months. CONCLUSION: The best final results were obtained when the operation was done soon after trauma; however, the results in the patients who were operated late were fairly good too.

Anxiety and autonomic regulation in major depressive disorder: an exploratory study.

Spectral analysis of fluctuations in heart rate and blood pressure was employed to explore sympathetic and parasympathetic cardiovascular control mechanisms in relation to trait anxiety in major depressive disorder Sixteen drug-free female depressed patients were divided into two groups: those who were high on trait anxiety (HTA, n = 9) and those who were normal or low on trait anxiety (LTA, n = 7). In patients and age-matched female controls (n = 10), heart rate (HR), blood pressure (BP; Finapres device) and respiration were recorded during a period of supine rest (10 min), orthostatic challenge (60 degrees head-up tilting, 8 min), and post-orthostatic supine rest (8 min). Power spectra were calculated over the last 4 min of these three situations for HR, systolic BP, as well as for respiration. Spectral density was assessed for three frequency bands: low (0.02-0.06 Hz), mid (0.07-0.14 Hz) and high (0.15-0.50 Hz). Patients did not differ from controls during supine rest. During orthostatic challenge, HTA patients showed significantly more HR increase and suppression of high-frequency fluctuations of HR (suggesting stronger vagal inhibition) in comparison with the controls; this effect was accompanied by a significant increase in respiratory frequency. Both patients groups did not show the normal increase in mid-frequency band fluctuations of BP during orthostatic challenge, indicating reduced sympathetic activation. Low-frequency fluctuations of HR, as well as respiratory frequency during post-orthostatic supine rest of the HTA patients were significantly increased versus controls. This exploratory study indicates that trait anxiety may be a relevant factor when evaluating parasympathetic and sympathetic dysbalances in the state of a major depressive disorder.

Cardiovascular variability in major depressive disorder and effects of imipramine or mirtazapine (Org 3770).

Spectral analysis of fluctuations in heart rate (HR) and blood pressure (BP) was applied to assess sympathetic and parasympathetic cardiovascular control mechanisms in patients with unipolar affective disorder before and after treatment with imipramine (IMI) or mirtazapine (MIR). In a double-blind randomized study, 10 patients received treatment with IMI and 10 patients received treatment with MIR. Cardiovascular parameters were studied before and after 4 weeks of treatment: HR and BP (Finapres) were recorded continuously during supine rest (SR) and orthostatic challenge (OC; 60-degrees head-up tilting). During SR and OC, power spectra were calculated for HR and systolic BP. Spectral density was assessed for three frequency bands: low (0.02-0.06 Hz), mid (0.07-0.14 Hz), and high (0.15-0.50 Hz). Before treatment, the depressed patients (N = 20) differed from age-matched controls (N = 20) only in their response to OC: the depressed patients showed more suppression of HR variability (both mid- and high-frequency band fluctuations), indicating stronger vagal inhibition, and a reduced increase of BP variability (mid-frequency band fluctuations), indicating reduced sympathetic activation. After 4 weeks of treatment, patients treated with either antidepressant drug showed significant changes of HR (increase) and HR variability (decrease) during SR and OC; the suppression of mid- and high-frequency fluctuations of HR was larger for IMI than for MIR. The increase in HR and decrease in HR variability may be attributed to the anticholinergic properties of IMI (strong) and MIR (weak), resulting in cardiac vagal inhibition. Whereas MIR had no effect on BP or BP variability, IMI specifically reduced mid-frequency band fluctuations of BP as the result of a suppression of central sympathetic activity. Our data confirm and extend previous observations on the presence of autonomic dysfunctions in unmedicated depressed patients: spectral analysis of HR and BP fluctuations suggested that both parasympathetic and sympathetic mechanisms are involved, specifically during OC. The preexisting autonomic cardiovascular dysfunctions were not normalized by antidepressant drugs. In fact, some of the components of the cardiovascular autonomic dysfunction were further aggravated, depending on the pharmacologic profile of the drug under investigation.

Influence of age on the management of blow-out fractures of the orbital floor.

This study concerns 50 patients with blow-out fractures of the orbital floor, including 15 children, and was designed to evaluate the influence of age on clinical presentation and postoperative results. Fourteen of the 15 children were found to have a trap-door fracture. This type of fracture was not found in adults, who usually present with a large "open-door" fracture. In trap-door fractures, orbital tissues are liable to become trapped and even strangulated. It is therefore suggested that young patients with severely restricted eyeball motility, an unequivocal positive forced duction test, and findings indicating blow-out fracture of the orbital floor on CT, should undergo operative treatment as soon as possible after injury. A "wait and see" policy, keeping the patient under observation, seems to be appropriate for blow-out fractures in adults. Surgical treatment is recommended only in those adult patients who demonstrate impairment of vertical eyeball motility within the mainfield of view after the haemorrhage and oedema have resolved and in whom change in motility is no longer seen and Hertel measurements have stabilized.

Use of blocks of hydroxylapatite for secondary reconstruction of the orbital floor.

Malposition of the globe and failure to fuse images may be the result of orbital trauma. Five patients are reviewed in whom secondary correction of enophthalmos, sunken globe and diplopia was performed by implantation of blocks of dense hydroxylapatite.

CT diagnosis of synovial chondromatosis of the temporomandibular joint.

Synovial chondromatosis of the temporomandibular joint (TMJ) is a very rare condition. It is characterised by the presence of loose bodies in the joint space. Clinical signs, histopathological findings and radiography play an important role in the diagnostic process. Conventional X-rays have shown to be of limited value, for they fail to depict the intra-articular loose bodies in a significant amount of cases. Axial as well as coronal computer tomography (CT) is extremely useful in detecting loose bodies in the temporomandibular joint (TMJ). In this report we present and discuss a further case, and the use of CT in the diagnosis of TMJ-synovial chondromatosis is illustrated.

Bimaxillary hyperplasia: the facial expression of homozygous beta-thalassemia.

A boy born in Curaçoa, who was 6 years old at his initial visit and known to have homozygous beta-thalassemia, is described. Emphasis is directed to the typical facial expression. The possibility of surgical treatment of the maxillary hypertrophy is discussed. However, in view of the limited life expectancy of these patients, correction should not be performed before adolescence.

Carotid-cavernous sinus fistula following maxillofacial trauma and orthognathic surgery.

The presence of a carotid-cavernous sinus fistula after maxillofacial trauma or orthognathic surgery is uncommon. 2 patients are described who developed a carotid-cavernous sinus fistula. Early diagnosis is important, since delay in treatment may cause irreversible neurological and/or ophthalmological damage. The etiology of the carotid-cavernous sinus fistulas is discussed, in the cases described.

The influence of the mode of treatment of zygomatic bone fractures on the healing process of the infraorbital nerve.

Several authors have described the influence of the method of treatment of a fracture of the zygomatic complex on the recovery of the infraorbital nerve. In this study, the results of treatment of 106 patients with an isolated, non-comminuted, unstable fracture of the zygomatic bone are presented. Thirty-eight patients underwent fixation with interosseous wiring and 68 patients were treated with a miniplate osteosynthesis across the frontozygomatic suture. In the group with wire fixation, 50% suffered persistent reduced sensitivity in the infraorbital region at follow-up examination, whereas in the group with a miniplate osteosynthesis only 22.1% had persistent neurological sequelae. On the basis of these findings we recommend a miniplate osteosynthesis in all unstable zygomatic bone fractures with displacement.

Sarcoidosis with maxillary involvement.

A case of sarcoidosis with maxillary involvement is presented. The patient complained of loose teeth in the upper anterior region, while radiographs revealed a poorly defined radiolucent area round the midline of the anterior maxilla. The diagnosis was verified by histopathologic examination.

Hyperbaric oxygen treatment of chronic osteomyelitis of the jaws.

A review of the literature on treatment of chronic osteomyelitis of the jaws shows that hyperbaric oxygen is often recommended as an adjunct in treatment of this disease. Definite criteria to indicate this treatment and to evaluate the results have not been reported. The results of hyperbaric oxygen treatment of chronic osteomyelitis of the jaws in 16 patients are presented. In contrast to the good results reported in the literature, only 7 of our patients could be considered as cured. The reasons for this discrepancy are discussed. Our results, as well as the data from the literature, indicate that a combined antibiotic and surgical approach is the treatment of choice in chronic suppurative osteomyelitis. However, in chronic diffuse sclerosing osteomyelitis and in patients in whom decortication and antibiotic therapy have failed, hyperbaric oxygen treatment in combination with antibiotics and surgery seems to be indicated.

Fractures of the orbital floor: indications for exploration and for the use of a floor implant.

Fractures of the orbital floor are frequently treated by exploratory surgery and by the insertion of a floor implant, because of the possibility of late diplopia and enophthalmos. The findings of this study would suggest that this fear is not justified and that there is no indication for an early diagnostic exploration of the fractured orbital floor, if there are no clinical or radiological signs of orbital floor fracture within 14 days of the accident. The significance of the status of the periorbita in the method of treatment of the fractured orbital floor is stressed. The suggestion is made, contrary to what is generally found in the literature, that a linear or a comminuted floor fracture and an orbital floor with a defect do not require a floor implant, if the periorbita is intact.

Downward displacement of the eye resulting from orbital emphysema (case report).

A case is reported of unusual downward displacement of the eye, occurring in a patient with fractures of the orbital floor and rim. On the basis of the clinical, roentgenological and computerized tomographic scan findings this is interpreted as resulting from a subperiosteal pneumatocoele above the eye ball.

Abnormal root development, probably due to erythema multiforme (Stevens-Johnson syndrome).

A case report is presented of a patient in whom nearly all teeth of the permanent dentition still present had short roots, while some teeth had never been formed at all. It may be concluded from the typical differences in length between the roots of the various teeth that this condition must be due to complete cessation of the growth of the teeth at the age of 7 or 8 years. Since the patient suffered a fulminant attack of erythema multiforme (STEVENS-JOHNSON syndrome) at this age, and since no other possible explanation of the short roots has been found, it is concluded that this clinical condition may have been the reason for the short root anomaly found. Damage or even destruction of the epithelial root sheath during the disease may be assumed to be the direct cause of the failure of full root development.

Antigenic properties of Bioplast.

The influence of heat treatment (at 150 +/- 2 degrees C for 2 hours) on the antigenicity of human Bioplast fibrin powder and human fibrin Bioplast plates was tested in an experimental study. Untreated and heat-treated fibrin powder with incomplete Freund's adjuvant was subcutaneously injected in rabbits. In addition, untreated and heat-treated plates, to which incomplete Freund's adjuvant was added, were subcutaneously implanted. A booster dose was given 8 weeks after the start of the experiment. Blood samples were collected up to 4 weeks after the second injection or implantation, and the sera were tested for precipitating antibodies by the double diffusion technique (OUCHTERLONY'S method). Unlike previous investigators, we found antibodies in sera from rabbits injected or implanted with heat-treated Bioplast products. Thus, the claim that the antigenic properties of all kinds of fibrin can be fully eliminated by heat treatment does not appear to be tenable. In order to avoid the risk of sensitization in man, it is probably advisable to use only human fibrin for the production of Bioplast fibrin powder and Fibrin Bioplast plates for clinical use in human beings.