Unexpected bleeding following eyelid tumor resection leading to the rare diagnosis of acquired haemophilia.

BACKGROUND: Our goal is to report for the first time in the literature a case of uncontrolled bleeding after an oculoplastic surgical procedure leading to the diagnosis of acquired haemophilia. HISTORY AND SIGNS: An 82-year-old patient underwent tumor excision and reconstruction of his right lower eyelid. On the same day, uncontrolled bleeding occurred that resisted optimal blood pressure control, external compression, surgical haemostasis and wound revision. Usual coagulation screening tests were normal, except for a slightly prolonged activated partial thromboplastin time. THERAPY AND OUTCOME: Extensive coagulation check was performed, which showed a severely reduced factor VIII due to the presence of an inhibitor. The bleeding was immediately stopped after administration of recombinant factor VIIa. After healing of the wound, factor VIIa treatment was replaced by immunosuppressive therapy. The factor VIII inhibitor became unmeasurable and remained so for three months after stopping the immunosuppressive therapy. CONCLUSIONS: Ophthalmologists confronted with unexpected uncontrolled bleeding should think about the possibility of blood dyscrasia, in particular acquired haemophilia.

Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients.

PURPOSE: We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol. EXPERIMENTAL DESIGN: Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months. RESULTS: Eight dose levels (40-8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 μg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days. CONCLUSION: High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (≥30% PSA response: 85%; ≥50% PSA response: 76%). A randomized phase II study is planned.

Partial cricotracheal resection for congenital subglottic stenosis in children: the effect of concomitant anomalies.

OBJECTIVE: To review the surgical outcomes of partial cricotracheal resection in children with severe congenital subglottic stenosis and define the effect of concomitant anomalies or syndromes affecting outcome. METHODS: Forty-one children with subglottic stenosis of congenital and mixed (acquired on congenital) etiologies who underwent partial cricotracheal resection were identified from a prospectively collected database. Children with congenital subglottic stenosis and concomitant anomalies/syndromes were compared to children with congenital subglottic stenosis with no syndromes or concomitant anomalies. Operation-specific decannulation rates and complication rates were the primary outcome measures. We performed a two-sample test of proportion using the STATA-10 software for categorical variables to detect differences in proportions. Significance was set at p value<0.05. RESULTS: Twenty-seven (66%) of 41 children had concomitant anomalies/syndromes and 14 (34%) had congenital subglottic stenosis without concomitant anomalies/syndromes. Four patients needed revision surgery in the concomitant anomaly group and two patients needed revision surgery in the non concomitant anomaly group before achieving decannulation. The operation-specific decannulation rate in the concomitant anomaly group was 85% and 86% in the non anomaly group. When compared to children without concomitant anomaly, children with concomitant anomalies were more likely to have delayed decannulation following partial cricotracheal resection. However, this difference was not found to be statistically significant. The complication and operation-specific decannulation rates after partial cricotracheal resection were comparable to children without concomitant anomalies. Mortality rate was 11% (three of 27 patients) in the group with associated congenital anomalies or syndromes. Two patients succumbed to the primary pathology and one patient died due to tracheostomy-tube obstruction. There was no post-operative death in the non anomaly group. CONCLUSION: Partial cricotracheal resection can be done safely and effectively in children with concomitant anomalies/syndromes to achieve decannulation. The post-operative course may be prolonged but the decannulation and the complication rates are comparable to those children with congenital subglottic stenosis without concomitant anomalies.

Association of urethral toxicity with dose exposure in combined high-dose-rate brachytherapy and intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer.

INTRODUCTION: To report acute and late toxicities in patients with intermediate- and high-risk prostate cancer treated with combined high-dose-rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: From March 2003 to September 2005, 64 men were treated with a single implant HDR-B with 21 Gy given in three fractions, followed by 50 Gy IMRT along with organ tracking. Median age was 66.1 years, and risk of recurrence was intermediate in 47% of the patients or high in 53% of the patients. Androgen deprivation therapy was received by 69% of the patients. Toxicity was scored according to the CTCAE version 3.0. Median follow-up was 3.1 years. RESULTS: Acute grade 3 genitourinary (GU) toxicity was observed in 7.8% of the patients, and late grades 3 and 4 GU toxicity was observed in 10.9% and 1.6% of the patients. Acute grade 3 gastrointestinal (GI) toxicity was experienced by 1.6% of the patients, and late grade 3 GI toxicity was absent. The urethral V(120) (urethral volume receiving &gt; or =120% of the prescribed HDR-B dose) was associated with acute (P=.047) and late &gt; or = grade 2 GU toxicities (P=.049). CONCLUSIONS: Late grades 3 and 4GU toxicity occurred in 10.9% and 1.6% of the patients after HDR-B followed by IMRT in association with the irradiated urethral volume. The impact of V(120) on GU toxicity should be validated in further studies.

Acute toxicity of curative radiotherapy for intermediate risk localized prostate cancer in the EORTC trial 22991

Introduction: EORTC trial 22991 randomly assessed the addition of concomitant and adjuvant short-term hormonal therapy to curative conformal/intensity-modulated radiotherapy (RT) for intermediate risk localized prostate cancer. We report the acute toxicity (assessed weekly during RT) for the organs at risk (genito-urinary (GU) and gastro-intestinal (GI)) in relation to radiation parameters. Material and Methods: Eligibility criteria were age _80 years, PSA _ 50 ng/ml, N0M0 and either tumour stage cT2a (1997 UICC TNM) or cT1b-c combined with PSA_10 ng/ml and/or Gleason score _7. We report toxicity for all eligible patients who received the planned RT with documented acute toxicity (CTCAEv.2) and RT-quality assurance parameters. The RT dose (70 Gy, 74 Gy or 78 Gy) and technique (3DCRT vs IRMT) were per institution choice, the randomization was stratified for institution. Statistical significance was set at 0.05. (ClinicalTrials.gov: NCT00021450) Results: Of 819 randomized patients, 28 were excluded from the analysis (3 with <60 Gy RT, 25 with missing information). Of the 791 analysed patients, 652 (82.4%) were treated with 3D-CRT, 139 with IMRT. In the 3DCRT group, 195 patients (29.9%) were treated with a total prescribed dose of 70 Gy; 376 (57.7%) with 74 Gy and 81 (12.4%) with 78 Gy. In the IMRT group, 28 (20.1%) were treated to a total dose of 74 Gy and 111 (79.9%) with 78 Gy. Overall, only 7 of 791 patients (0.9%) had grade 3 GI toxicity during RT: diarrhea (N = 6), rectal bleeding (N = 1) and proctitis (N = 1). Fifty patients (6.3%) had grade 3 GU toxicity: urinary frequency (N = 38, 4.6%), dysuria (N = 14, 1.7%), urinary retention (N = 11, 1.3%), urinary incontinence (N = 2) and hematuria (N = 1). No grade 4 toxicity was reported. Hormonal treatment did not influence the risk of side effects (p>0.05). The risk of grade _2 GI toxicity significantly correlated to D50%-rectum (p = 0.004) with a cut-of value of 44 Gy. The risk of grade _2 GU toxicity was moderately affected by Dmax-bladder (p = 0.051). Overall, only 14 patients (1.8%) had residual grade 3 toxicities one month after RT. Conclusion: 3D-CRT and IMRT up to 78 Gy is well tolerated. Dmaxbladder and D50%-rectum were related to the risk of grade_2 GU and GI toxicity, respectively. IMRT lowered D50% rectum and Dmax-bladder. An irradiated volume >400 cc for 3D-RT and a dose of 78 Gy, even for IMRT, negatively affected those parameters and increased the risk for toxicity.

The potential of metastatic lymph nodes to predict positive resection margins in patients with resectable pancreatic cancer

Objective: Despite progress during recent decades, long-term outcome¦of patients with pancreatic cancer remains dismal. Since positive resection¦margins and metastatic lymph nodes are known risk factors for early tumor¦recurrence, patients at risk should be identified and could potentially benefit¦from preoperative radio-chemotherapy. This study aimed to assess whether the¦presence of lymph node metastasis could be used to predict positive resection¦margins in patients with pancreatic cancer.¦Methods: A series of 146 patients (82 male, 64 female, median age 68 years)¦underwent pancreatic head resection for various malignant diseases (pancreatic¦ductal adenocarcinoma, biliary cancer, periampullary cancer) at our institution¦from 2000 to 2011. Patients were identified from our prospective database¦that collects more than 60 single items of all patients undergoing pancreatic¦resection. Lymph node metastasis and positive resection margins were all¦confirmed by histological evaluation. Positive predictive value (PPV), negative¦predictive value (NPV), sensitivity and specificity were calculated to assess¦the predictive value of metastatic lymph nodes regarding tumor-free (R0) and¦tumor-involved (R1) resection margins.¦Results: There were 110 specimens (76%) with tumor-positive lymph nodes¦and 36 specimens with tumor-negative lymph nodes. Resection margins were¦positive in 47 specimens (32%) and negative in 99 specimens. Sensitivity of¦tumor-positive lymph nodes to detect positive resection margins was 96%, and¦the NPV was 94%. In contrast, specificity was 34% and the PPV was 41%.¦Conclusion: Patients with resectable pancreatic cancer, who have no lymph¦node metastasis, are at very low risk to have positive resection margins (2 of¦36 patients, NPV 94%). In contrast, more than one third of patients with¦metastatic lymph nodes are at increased risk for an incomplete tumor resection¦(sensitivity 96%). If lymph nodesmetastases are highly suspected at preoperative¦staging, a neoadjuvant treatment strategy should be considered to increase the¦R0 resection rate.

Partial cricotracheal resection for paediatric subglottic stenosis: update of the Lausanne experience with 129 cases.

OBJECTIVES: Partial cricotracheal resection (PCTR) is widely accepted for treating severe paediatric laryngotracheal stenosis (LTS). However, it remains limited to a few experienced centres. Here we report an update of the Lausanne experience in paediatric PCTR performed or supervised by a senior surgeon (Philippe Monnier). METHODS: An ongoing database of 129 paediatric patients who underwent PCTR for benign LTS between March 1978 and July 2012 at our hospital was retrospectively reviewed. Demographic characteristics and information on preoperative status, stenosis and surgery were collected. Primary outcomes were measured as overall and operation-specific decannulation rates (ODR and OSDR, respectively), and secondary outcomes as morbidity, mortality and postoperative functional results. RESULTS: A total of 129 paediatric patients [79 males and 50 females; mean age, 4.1 years (1 month-16 years, median age of 2 years old)] underwent PCTR during the study period. ODR and OSDR were 90 and 81%, respectively. The decannulation rates were significantly superior for single-stage PCTR compared with double-stage PCTR in both ODR and OSDR. Eight patients died postoperatively for reasons unrelated to surgery. Partial anastomotic dehiscence was seen in 13 patients, 9 of whom were successfully treated by revision surgery. Respiratory, voice and swallowing functions were near normal or only minimally impaired in 86, 65 and 81% of patients, respectively. CONCLUSIONS: PCTR is effective and feasible with good ODR and OSDR for highgrade / severe LTS. Glottic involvement and the presence of comorbidities were negative predictive factors of decannulation. Early detection and reintervention of postoperative incipient dehiscence contribute to avoiding the progress to late restenosis; however, voice improvement remains a challenge.

Detection of Clinically Significant Prostate Cancer Using Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy: A Systematic Review.

CONTEXT: The current standard for diagnosing prostate cancer in men at risk relies on a transrectal ultrasound-guided biopsy test that is blind to the location of the cancer. To increase the accuracy of this diagnostic pathway, a software-based magnetic resonance imaging-ultrasound (MRI-US) fusion targeted biopsy approach has been proposed. OBJECTIVE: Our main objective was to compare the detection rate of clinically significant prostate cancer with software-based MRI-US fusion targeted biopsy against standard biopsy. The two strategies were also compared in terms of detection of all cancers, sampling utility and efficiency, and rate of serious adverse events. The outcomes of different targeted approaches were also compared. EVIDENCE ACQUISITION: We performed a systematic review of PubMed/Medline, Embase (via Ovid), and Cochrane Review databases in December 2013 following the Preferred Reported Items for Systematic reviews and Meta-analysis statement. The risk of bias was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. EVIDENCE SYNTHESIS: Fourteen papers reporting the outcomes of 15 studies (n=2293; range: 13-582) were included. We found that MRI-US fusion targeted biopsies detect more clinically significant cancers (median: 33.3% vs 23.6%; range: 13.2-50% vs 4.8-52%) using fewer cores (median: 9.2 vs 37.1) compared with standard biopsy techniques, respectively. Some studies showed a lower detection rate of all cancer (median: 50.5% vs 43.4%; range: 23.7-82.1% vs 14.3-59%). MRI-US fusion targeted biopsy was able to detect some clinically significant cancers that would have been missed by using only standard biopsy (median: 9.1%; range: 5-16.2%). It was not possible to determine which of the two biopsy approaches led most to serious adverse events because standard and targeted biopsies were performed in the same session. Software-based MRI-US fusion targeted biopsy detected more clinically significant disease than visual targeted biopsy in the only study reporting on this outcome (20.3% vs 15.1%). CONCLUSIONS: Software-based MRI-US fusion targeted biopsy seems to detect more clinically significant cancers deploying fewer cores than standard biopsy. Because there was significant study heterogeneity in patient inclusion, definition of significant cancer, and the protocol used to conduct the standard biopsy, these findings need to be confirmed by further large multicentre validating studies. PATIENT SUMMARY: We compared the ability of standard biopsy to diagnose prostate cancer against a novel approach using software to overlay the images from magnetic resonance imaging and ultrasound to guide biopsies towards the suspicious areas of the prostate. We found consistent findings showing the superiority of this novel targeted approach, although further high-quality evidence is needed to change current practice.

Prostate Cancer Unit Initiative in Europe: A position paper by the European School of Oncology.

The Prostate Cancer Programme of the European School of Oncology developed the concept of specialised interdisciplinary and multiprofessional prostate cancer care to be formalized in Prostate Cancer Units (PCU). After the publication in 2011 of the collaborative article "The Requirements of a Specialist Prostate Cancer Unit: A Discussion Paper from the European School of Oncology", in 2012 the PCU Initiative in Europe was launched. A multiprofessional Task Force of internationally recognized opinion leaders, among whom representatives of scientific societies, and patient advocates gathered to set standards for quality comprehensive prostate cancer care and designate care pathways in PCUs. The result was a consensus on 40 mandatory and recommended standards and items, covering several macro-areas, from general requirements to personnel to organization and case management. This position paper describes the relevant, feasible and applicable core criteria for defining PCUs in most European countries delivered by PCU Initiative in Europe Task Force.

Accuracy of cognitive MRI-targeted biopsy in hitting prostate cancer-positive regions of interest.

PURPOSE: Prostate cancer (PCa) diagnosis relies on clinical suspicion leading to systematic transrectal ultrasound-guided biopsy (TRUSGB). Multiparametric magnetic resonance imaging (mpMRI) allows for targeted biopsy of suspicious areas of the prostate instead of random 12-core biopsy. This method has been shown to be more accurate in detecting significant PCa. However, the precise spatial accuracy of cognitive targeting is unknown. METHODS: Consecutive patients undergoing mpMRI-targeted TRUSGB with cognitive registration (MRTB-COG) followed by robot-assisted radical prostatectomy were included in the present analysis. The regions of interest (ROIs) involved by the index lesion reported on mpMRI were subsequently targeted by two experienced urologists using the cognitive approach. The 27 ROIs were used as spatial reference. Mapping on radical prostatectomy specimen was used as reference to determine true-positive mpMRI findings. Per core correlation analysis was performed. RESULTS: Forty patients were included. Overall, 40 index lesions involving 137 ROIs (mean ROIs per index lesion 3.43) were identified on MRI. After correlating these findings with final pathology, 117 ROIs (85 %) were considered as true-positive lesions. A total of 102 biopsy cores directed toward such true-positive ROIs were available for final analysis. Cognitive targeted biopsy hit the target in 82 % of the cases (84/102). The only identified risk factor for missing the target was an anterior situated ROI (p = 0.01). CONCLUSION: In experienced hands, cognitive MRTB-COG allows for an accuracy of 82 % in hitting the correct target, given that it is a true-positive lesion. Anterior tumors are less likely to be successfully targeted.

A cast of shadow on adjuvant radiotherapy for prostate cancer: A critical review based on a methodological perspective.

OBJECTIVE: To perform a critical review focusing on the applicability in clinical daily practice of data from three randomized controlled trials (RCTs): SWOG 8794, EORTC 22911, and ARO/AUO 96-02. METHODS AND MATERIALS: An analytical framework, based on the identified population, interventions, comparators, and outcomes (PICO) was used to refine the search of the evidence from the three large randomized trials regarding the use of radiation therapy after prostatectomy as adjuvant therapy (ART). RESULTS: With regard to the inclusion criteria: (1) POPULATION: in the time since they were designed, in two among three trial (SWOG 8794 and EORTC 22911) patients had a detectable PSA at the time of randomization, thus representing de facto a substantial proportion of patients who eventually received salvage RT (SRT) at non-normalised PSA levels rather than ART. (2) INTERVENTIONS: although all the trials showed the benefit of postoperative ART compared to a wait-and-see approach, the dose herein employed would be now considered inadequate; (3) COMPARATORS: the comparison arm in all the 3 RCTs was an uncontrolled observation arm, where patients who subsequently developed biochemical failure were treated in various ways, with up to half of them receiving SRT at PSA well above 1ng/mL, a level that would be now deemed inappropriate; (4) OUTCOMES: only in one trial (SWOG 8794) ART was found to significantly improve overall survival compared to observation, with a ten-year overall survival rate of 74% vs. 66%, although this might be partly the result of imbalanced risk factors due to competing event risk stratification. CONCLUSIONS: ART has a high level of evidence due to three RCTs with at least 10-year follow-up recording a benefit in biochemical PFS, but its penetrance in present daily clinics should be reconsidered. While the benefit of ART or SRT is eagerly expected from ongoing randomized trials, a dynamic risk-stratified approach should drive the decisions making process.

"Hit the primary": A paradigm shift in the treatment of metastatic prostate cancer?

Patients with metastatic prostate cancer (PC) represent a heterogeneous group with survival rates varying between 13 and 75 months. The current standard treatment in this setting is hormonal therapy, with or without docetaxel-based chemotherapy. In the era of individualized medicine, however, maximizing treatment options, especially in long-term surviving patients with limited disease burden, is of capital importance. Emerging data, mainly from retrospective surgical series, show survival benefits in men diagnosed with metastatic PC following definitive therapy for the prostate. Whether the irradiation of primary tumor in a metastatic disease might improve the therapeutic ratio in association with systemic treatments remains investigational. In this scenario, modern radiation therapy (RT) can play a significant role owing to its intrinsic capability to act as a more general immune response modifier, as well as to the potentially better toxicity profile compared to surgery. Preclinical data, clinical experience, and challenges in local treatment in de novo metastatic PC are reviewed and discussed.