Nusinersen Treatment of Children with Later-Onset Spinal Muscular Atrophy and Scoliosis Is Associated with Improvements or Stabilization of Motor Function.

Nusinersen has been shown to improve or stabilize motor function in individuals with spinal muscular atrophy (SMA). We evaluated baseline scoliosis severity and motor function in nusinersen-treated non-ambulatory children with later-onset SMA. Post hoc analyses were conducted on 95 children initiating nusinersen treatment in the CHERISH study or SHINE long-term extension trial. Participants were categorized by baseline Cobb angle (first nusinersen dose): ≤10°, >10° to ≤20°, and >20° to <40° (no/mild/moderate scoliosis, respectively). Outcome measures included the Hammersmith Functional Motor Score-Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Regression analysis determined the relationships between baseline scoliosis severity and later motor function. For children with no, mild, and moderate scoliosis, the mean increase in HFMSE from baseline to Day 930 was 6.0, 3.9, and 0.7 points, and in RULM was 6.1, 4.6, and 2.3 points. In the linear model, a 10° increase in baseline Cobb angle was significantly associated with a -1.4 (95% CI -2.6, -0.2) point decrease in HFMSE (p = 0.02) and a -1.2 (95% CI -2.1, -0.4) point decrease in RULM (p = 0.006) at Day 930. Treatment with nusinersen was associated with improvements/stabilization in motor function in all groups, with greater response in those with no/mild scoliosis at baseline.

DEVOTE Study Exploring Higher Dose of Nusinersen in Spinal Muscular Atrophy: Study Design and Part A Results.

BACKGROUND: Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose. OBJECTIVE: Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A. METHODS: DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to higher doses. RESULTS: In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1-12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing. CONCLUSIONS: The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen.

A rare case of internal jugular vein dissection following central venous catheterization.

Background: Central venous catheterization (CVC) is an important and common procedure performed for the purpose of drug administration, hemodynamic monitoring, emergency venous access, and extracorporeal intervention. We report a rare case of CVC prior to cardiac surgery, complicated by internal jugular venous dissection. Case presentation: A 66-year-old female was undergoing central venous catheterization prior to cardiac surgery. During the procedure the guidewire could not be proceeded at which point an ultrasound was used to visualize the internal jugular vein, where a venous dissection was noted. Cannulation was, therefore, undertaken on the contralateral side, which was done uneventfully. Conclusion: Venous dissection is a rare complication of CVC, however the incidence is likely higher than the frequency of reporting suggests. Given the low pressures in the venous system the dissection will likely be self-limiting and can be monitored for complication. However, should continue expansion occur, surgery would be necessary.

Yolk Sac Tumor of the Omentum: A Case Report and Literature Review.

This is a case report of a rare finding of an extragonadal yolk sac tumor in a 37-year-old patient who presented with shortness of breath and abdominal bloating. During imaging and staging surgery, the findings were strongly suggestive of an extragonadal advanced tumor presenting with peritoneal dissemination, predominantly affecting omentum, with no clear primary origin. Histology revealed an extragonadal yolk sac tumor in a pure form outside the ovaries. Lacking an obvious origin elsewhere, the tumor was highly suspected to have truly originated from the omentum. The patient underwent surgery and four cycles of chemotherapy consisting of cisplatin, etoposide, and bleomycin. One-year outpatient follow-up thereafter showed no relapse. We herein discuss a possible site of the tumor origin and its development, as well as diagnostic challenges and disease prognosis.

Predictive Score of Nodal Involvement in Endometrial Cancer Patients: A Large Multicentre Series.

BACKGROUND: Sentinel lymph node (SLN) biopsy is considered the standard of care in early-stage endometrial cancer (EC). For SLN failure, a side-specific lymphadenectomy is recommended. Nevertheless, most hemipelvises show no nodal involvement. The authors previously published a predictive score of lymphovascular involvement in EC. In case of a negative score (value 3-4), the risk of nodal metastases was extremely low. This multicenter study aimed to analyze a predictive score of nodal involvement in EC patients. METHODS: The study enrolled patients with EC who had received comprehensive surgical staging with nodal assessment. A preoperative predictive score of nodal involvement was calculated for all the patients before surgery. The score included myometrial infiltration, tumor grading (G), tumor diameter, and Ca125 assessment. The STARD (standards for Reporting Diagnostic accuracy studies) guidelines were followed for score accuracy. RESULTS: The study analyzed 1038 patients and detected 155 (14.9%) nodal metastases. The score was negative (3 or 4) for 475 patients and positive (5-7) for 563 of these patients. The score had a sensitivity of 83.2%, a specificity of 50.8%, a negative predictive value of 94.5%, and a diagnostic value of 55.7%. The area under the curve was 0.75. The logistic regression showed a significant correlation between a negative score and absence of nodal metastasis (odds ration [OR], 5.133, 95% confidence interval [CI], 3.30-7.98; p < 0.001). CONCLUSION: The proposed predictive score is a useful test to identify patients at low risk of nodal involvement. In case of SLN failure, the application of the current score in the SLN algorithm could allow avoidance of unnecessary lymphadenectomies.

Intraperitoneal hemorrhage following primary cytoreductive surgery for ovarian cancer: Successful treatment with superior epigastric artery embolization.

Hemoperitoneum often occurs due to abdominal trauma, abdominal tumors, gastro-intestinal perforation and more rarely it's spontaneous due to coagulopathies. Superior epigastric artery (SEA) iatrogenic damage is rarer than the Inferior epigastric artery injury, it may occur during laparotomy and, in most cases, it causes a rectus muscle hematoma. We present the case of a caucasian 44 years-old-woman with hemoperitoneum after cytoreductive surgery for ovarian cancer. Active bleeding from the distal branch of the SEA was diagnosed at computed tomography and coil embolization followed by surgical laparotomic drainage of the hemoperitoneum was performed. After initial resolution, active bleeding from the same vessel was observed. Further embolization of the same vessel was necessary to stop bleeding. Ultrasound follow-up showed a complete resolution of the hemoperitoneum.

Neuroendocrine small cell carcinoma of the cervix: A case report.

Merkel cell polyomavirus (MCPyV) has been found in patients with Merkel cell carcinoma and respiratory tract infections. Merkel cell carcinoma is a primary aggressive neuroendocrine carcinoma of the skin. It has been demonstrated that MCPyV can be transmitted during sexual activity and may be present in the oral and anogenital mucosa. The aim of the present study was to evaluate whether MCPyV coexisted with HPV in three cases of neuroendocrine small cell carcinoma of the cervix using PCR and immunohistochemical analysis Three cases of NSC of the cervix were identified in the pathology archives of Parma University (Italy). Of these, two cases were associated with an adenocarcinomatous component. A set of general primers from the L1 region (forward, L1C1 and reverse, L1C2 or L1C2M) was PCR amplified to detect the broad-spectrum DNA of genital HPV. The presence of MCPyV was investigated via immunohistochemistry using a mouse monoclonal antibody against the MCPyV LT antigen and through PCR analysis to separate viral DNA. HPV DNA was present in all three neuroendocrine carcinomas and in the adenocarcinoma component of the two mixed cases. None of the cases were immunoreactive to CM2B4 and did not contain viral DNA in either their neuroendocrine or adenocarcinomatous component. Whilst it is difficult to draw definitive conclusions from such a small sample size, these data suggested that MCPyV does not coexist with HPV in the cervix. However, in the present study, the absence of detectable MCPyV may have been due to the presence of a genotype that was not detected by the primers used in the PCR analysis or by the antibody used for the immunohistochemical study. MCPyV microRNA may also have been present, inhibiting LT expression. Additional studies with larger cohorts and more advanced molecular biology techniques are required to confirm the hypothesis of the current study.

Obstetrics outcomes after complete and partial molar pregnancy: Review of the literature and meta-analysis.

The hydatidiform mole is a rare gynecological disease rising from the trophoblastic. Post-molar pregnancies have an extremely variable course, varying from repeated abortions, stillbirths, preterm births, live births, or recurring in further molar pregnancies. Literature on obstetric outcomes following molar pregnancy is poor, often including monocentric studies, and with data collected from national databases. This review and meta-analysis aim to analyze the obstetric outcomes after conservative management of complete (CHM) and partial (PHM) molar pregnancies. The meta-analysis was performed following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and the preferred reporting items for systematic reviews and meta-analyses statement (PRISMA). Six studies met the inclusion. Of the total 25,222 patients, 13,129 complete (52.1 %) and 12,093 partial (47.9 %) molar pregnancies were included. Live births rate after CHM was statistically higher (p = 0.002) compared to the live births after PHM (53.6 % vs. 51.0 %, 3266 vs. 1807 cases, respectively). Studies showed heterogeneity I2 = 57.7 %, pooled proportion = 0.2 %, and 95 % Confidence Interval (CI) 0.6 to 0.9. No statistically significant difference was demonstrated for ectopic pregnancies (p = 0.633), miscarriage (p = 0.637), preterm birth (p = 0.865), stillbirth (p = 0.911), termination of pregnancy (p = 0.572), and complete molar recurrence (p = 0.580) after CHM and PHM. Partial molar recurrence occurred more frequently after PHM than CHM (0.4 % vs. 0.3 %, 52 vs. 37 cases, respectively, p = 0.002). Careful counseling on the obstetric subsequent pregnancies outcomes should be provided to patients eager for further pregnancy and further studies are needed to confirm these results.

Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study.

INTRODUCTION: The EMBRACE study (Clinical Trials No. NCT02462759) evaluated nusinersen in infants/children with infantile- or later-onset spinal muscular atrophy (SMA) who were ineligible for the ENDEAR and CHERISH studies. METHODS: Participants were randomized to intrathecal nusinersen (12-mg scaled equivalent dose; n = 14) or sham procedure (n = 7) in part 1 (~14 months) and subsequently received open-label nusinersen for ~24 months in part 2 of the study. RESULTS: Part 1 was stopped early after the demonstration of motor function benefit with nusinersen in ENDEAR. There were no nusinersen-related adverse events (AEs) and no study discontinuations due to nusinersen-related AEs. The most common AEs included pyrexia, cough, pneumonia, and upper respiratory tract infections. Motor milestone responder rates were higher in those receiving nusinersen at last available assessment (93%) than in those receiving sham procedure in part 1 (29%) or transitioned from sham to nusinersen in part 2 (83%). This functional improvement was observed despite the small sample size and shortened part 1 trial duration that undermined the power of the study to demonstrate such treatment effects at a significant level. DISCUSSION: Nusinersen demonstrated a favorable long-term benefit-risk profile in this broad population of individuals with infantile- or later-onset SMA.

Confounding factors of transvaginal ultrasound accuracy in endometrial cancer.

Endometrial cancer is the most frequently diagnosed gynecological tumour. Transvaginal ultrasound has a leading role in the preoperative evaluation of endometrial cancer patients. The study aimed to identify factors that can worsen the diagnostic accuracy of transvaginal ultrasound in endometrial cancer patients. We retrospectively analysed 290 patients with histological diagnosis of endometrial adenocarcinoma. Two-dimensional (2D) gray-scale ultrasound and power Doppler imaging were performed. Age, menopause status, obesity, parity, Figo stage and benign uterine disorders were evaluated as possible factors worsening the diagnostic accuracy of the ultrasonography. FIGO stage IB was the main significant confounding factor in the univariate analysis (p = .004). Furthermore, 2D transvaginal ultrasound showed worse diagnostic accuracy in endometrial cancer patients with concomitant benign uterine pathologies.Impact statementWhat is already known on this subject? Many studies have analysed the reliability and diagnostic accuracy of transvaginal ultrasound in predicting myometrial invasion, but few studies have underlined the importance of confounding factors. Shin et al. (2011) showed that diffuse fibromatosis is a quality ultrasound confounding factor. Furthermore, Fischerova et al. (2014) showed that body mass index (BMI) did not influence the diagnostic accuracy of ultrasound assessment.What do the results of this study add? FIGO stage IB is the main factor worsening the diagnostic accuracy of transvaginal ultrasound in endometrial cancer patients (p = .004). Among the 82 patients with histologically proven FIGO stage IB, 27 (32.9%) had a wrong ultrasound prediction of myometrial infiltration. Twenty-one (36.2%) patients in whom there was no agreement between ultrasound prediction of myometrial infiltration and pathological analysis had fibromatosis and/or adenomyosis (p = 0.04).What are the implications of these findings for clinical practice and/or further research? Two-dimensional ultrasound represents a useful tool in the correct pre-operative setting of patients with endometrial cancer. In FIGO stages IB endometrial cancer patients and in conjunction with benign uterine pathologies, 2D transvaginal ultrasound has less diagnostic accuracy. In these cases, MRI still plays a leading role.

Novel preoperative predictive score to evaluate lymphovascular space involvement in endometrial cancer: an aid to the sentinel lymph node algorithm.

INTRODUCTION: Sentinel lymph node (SLN) dissection has been recognized as a valid tool for staging in patients with endometrial cancer. Several factors are predictors of recurrence and survival in endometrial cancer, including positive lymphovascular space invasion. The aim of this study is to formulate a pre-operative score that, in the event of no-SLN identification, may give an estimate of the true probability of lymphovascular space invasion and guide management. METHODOLOGY: This was a multi-institutional retrospective study conducted from January 2007 to December 2017. We included all patients with any grade endometrial tumor with a complete pathological description of the surgical specimen and with a minimum follow-up of 12 months. All patients underwent a class A hysterectomy according to Querleu and Morrow and bilateral salpingo-oophorectomy. Lymphadenectomy was performed based on patient risk of node metastases. In order to verify the predictive capacity of the parameters associated with lymphovascular space invasion status, grading, abnormal CA125 (>35 units/ml), myometrial invasion, and tumor size, a synthetic score was calculated. The score was introduced in the receiver operating characteristic curve model in which the binary classifier was represented by the lymphovascular space invasion status. The ideal cut-off was calculated with the determination of the Youden index. Sensitivity and negative predictive value of lymphovascular space invasion score was calculated in patients with lymph node metastasis. RESULTS: Six hundred and fourteen patients were included in the study. The average age and BMI of patients were 64.8 (range 33-88) years and 30.1 (range 17-64) respectively. Of the 284 patients who underwent lymphadenectomy, 231 (81.3%) patients had no lymph node metastases, 33 (11.6%) patients had metastatic pelvic lymph nodes, 12 (4.2%) patients had metastatic aortic lymph nodes, and eight (2.8%) patients had both pelvic and aortic metastatic lymph nodes. Lymphovascular space invasion was associated with deep myometrial infiltration (P<0.001), G3 grading (P<0.001), tumor size ≥25 mm (P=0.012), abnormal CA125 (P<0.001), recurrence (P<0.001), overall survival (P<0.001), and disease-free survival (P<0.01). Of all patients with lymphovascular space invasion, 79% had an lymphovascular space invasion score ≥5. The score ranged from a minimum score of 1 to a maximum of 7. The score shows 78.9% sensitivity (95% CI 0.6971 to 0.8594), 65.3% specificity (95% CI 0.611 to 0.693), 29.4% positive predictive value (95% CI 0.241 to 0.353), and 94.4% negative predictive value (95% CI 0.916 to 0.964). CONCLUSION: We found that when lymphovascular space invasion score ≤4, there is a very low possibility of finding lymph nodal involvement. The preoperative lymphovascular space invasion score could complement the SLN algorithm to avoid unnecessary lymphadenectomies.

Laparoscopy versus laparotomy for surgical treatment of obese women with endometrial cancer: A cost-benefit comparative analysis.

The aim of the present study was to demonstrate the cost of obese patients affected by endometrial cancer undergoing open surgery compared with minimally invasive surgery. In the retrospective cohort study (Canadian Task Force classification II-2), the economic expenditure in pre-operative, intra-operative and post-operative phases of the selected patients was evaluated. Costs were analyzed for all blood tests, instrumental examinations, consultations, operating materials, drugs, gynecological examinations, hospital stay, intensive care hospitalization and management of operative complications. The average length of stay was longer for patients who underwent laparotomy, with an almost double median hospitalization cost in the open abdominal group compared with the laparoscopic group (€4,805.37 vs. €2,589.25; P<0.0001). Evaluation by another specialist (cardiologist, diabetologist, internist) was necessary in 30.9% of laparotomies vs. 10.4% of laparoscopies (P=0.003). A respiratory support was applied to 38 patients (28.8%), of whom 23 (41.8%) were in the open abdominal arm (P=0.011). Antibiotic and pain-relief therapies resulted in a significantly higher cost for the open abdominal than for the minimally-invasive approach (P=0.027). Considering all the pre-, intra- and post-operative course, the expenses for an obese patient operated by laparoscopy was €4,412.41 vs. €7,323.17 by open surgery, with an average saving of €2,911.03 in favor of minimally-invasive surgery. This study revealed that in obese patients with endometrial cancer, minimally invasive surgery is more advantageous both in terms of costs and post-operative complications. To conclude, laparoscopic surgery in obese patients allows an economic saving of ~60% less than open surgery.

Endoscopic near infrared and indocyanine green to verify the viability of the subcutaneous flap for vulvar cancer.

INTRODUCTION: Vulvar cancer often requires radical vulvectomy with subsequent vulvar flap. Approximately in 20-60% of cases, there are post-operative complications ranging from infection to flap necrosis that often require reoperation. Several methods have been described to verify the vitality of the flap, but these are often expensive and require specific machinery that is not generally present in a gynecological clinic. In this case report, we present a viability verification of VY fasciocutaneous advancement flap for vulvar reconstruction by Endoscopic Near-Infrared and Indocyanine Green. METHODOLOGY: The patient was a 67-year-old woman with FIGO IB ≤ 4 cm squamous cell vulvar cancer with absence of inguinal lymphadenopathy. The lesion appeared about 35 mm from the lateral margin of the large left lip and extended to the left inguinocrural fold. The patient underwent left inguinal lymphadenectomy and left radical hemivulvectomy with a left fasciocutaneous medial-thigh advancement flap. For the flap evaluation, we endovenous administered 50 mg of Indocyanine Green diluted in 10 ml of saline solution. After 10 min we visualized the flap margin with a near-infrared laparoscopic view. The evaluation was repeated at the end of the surgical procedure and we confirmed the good vascularization of the flap. RESULTS: No early or late post-operative complications were obtained. There was no wound dehiscence, marginal necrosis or surgical site infection. CONCLUSIONS: Verifying the viability of the vulvar flap using near-infrared laparoscopic optics was easy to use, reproducible and highly economical technique. This could be a reproducible alternative to other more expensive techniques.

Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B-LONG): results from a multicentre, non-randomised phase 3 study.

BACKGROUND: Kids B-LONG was a multicentre, open-label, phase 3 study assessing the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) in previously treated paediatric patients younger than 12 years with severe haemophilia B. METHODS: The study enrolled 30 previously treated boys younger than 12 years with haemophilia B (≤2 IU/dL [≤2%] endogenous coagulation factor IX [FIX] activity). All patients were initially given rFIXFc prophylaxis (50-60 IU/kg) once per week with adjustments to dose (≤100 IU/kg per infusion) or dosing frequency (up to two times per week) as needed. The primary outcome measure was development of inhibitors (neutralising antibodies). Secondary outcomes were pharmacokinetics, annual bleeding rate (ABR), spontaneous joint ABR, the number of infusions and dose required to resolve a bleed, time from last infusion of rFIXFc to a bleeding episode, assessment of response to treatment, and total annualised rFIXFc consumption for prevention and treatment of bleeding episodes. All patients underwent sequential pharmacokinetic evaluations of their prestudy FIX and rFIXFc. The completed trial is registered with ClinicalTrials.gov, number NCT01440946. FINDINGS: No patients developed inhibitors to rFIXFc; in the 30 enrolled patients the most common adverse events were nasopharyngitis (n=7; 23%) and fall (n=6; 20%); four patients (13%) had serious adverse events. Overall, rFIXFc exhibited a prolonged half-life of 68·6 h (95% CI 61·8-76·0), reduced clearance, and similar recovery compared with prestudy FIX. The median ABR was 2·0 (0·0-3·1) overall and 0·0 (0·0-0·0) for spontaneous joint bleeds; ten (33%) of 30 patients reported no bleeding, and 19 (63%) reported no joint bleeding on-study. The median average prophylactic dose of rFIXFc was 58·6 IU/kg (IQR 52·3-64·8) per week. Throughout the study, 29 (97%) of 30 patients remained on once per week infusions. INTERPRETATION: Weekly infusions of rFIXFc were well tolerated and resulted in low bleeding rates in children with severe haemophilia B. FUNDING: Biogen, Sobi.

Remifentanil vs. meperidine for patient-controlled analgesia during colonoscopy: a randomized double-blind trial.

OBJECTIVES: The aim was to compare patients' and endoscopists' satisfaction in terms of efficacy and safety of remifentanil patient-controlled analgesia (PCA) during colonoscopy with that of a combination of midazolam and meperidine. METHODS: Sixty patients undergoing colonoscopy were randomly assigned to two groups. All of the patients received midazolam 0.03 mg/kg intravenously for premedication. In the remifentanil group, a bolus dose of remifentanil was given, and a patient-controlled sedation analgesia (PCSA) pump was set to inject further bolus doses with no "lockout" time. Patients in the meperidine group received a bolus of meperidine and sham PCSA. Non-invasive arterial blood pressure, electrocardiography, and pulse oximetry were monitored throughout the study. The Observer's Assessment of Alertness and Sedation Scale (OAA/S) was performed at baseline, every 5 min during, and after colonoscopy. Assessment of pain and satisfaction with sedoanalgesia was scheduled after colonoscopy and 24-72 h later by a 100 mm visual analog scale (VAS). The technical difficulty of the examination and the gastroenterologist's satisfaction were assessed similarly. RESULTS: The degree of pain, the level of satisfaction with sedoanalgesia by patients and gastroenterologists, and the degree of difficulty experienced by the endoscopist were not different in the two groups. The time to reach an Aldrete score > or = 9 was significantly shorter in the remifentanil group (P < 0.0001); discharge times did not differ between the groups (P = 0.36). There was no difference between the groups regarding the duration of colonoscopy (P = 0.82) and the stability of vital signs. At the end of the procedure, OAA/S was significantly higher in the remifentanil group (P = 0.03). CONCLUSIONS: Remifentanil PCA is safe and effective to induce sedoanalgesia during colonoscopy. Further studies should address the optimization of dosing and lock out setting.