Case series: Immune checkpoint inhibitor-induced transverse myelitis.

Introduction: Increasing implementation of the highly efficacious immune checkpoint inhibitors (ICIs) has raised awareness of their various complications in the form of immune-related adverse events (irAEs). Transverse myelitis following ICIs is thought to be a rare but serious neurologic irAE and knowledge is limited about this distinct clinical entity. Cases: We describe four patients across three tertiary centers in Australia with ICI-induced transverse myelitis. Three patients had a diagnosis of stage III-IV melanoma treated with nivolumab and one patient had stage IV non-small cell lung cancer treated with pembrolizumab. All patients had longitudinally extensive transverse myelitis on magnetic resonance imaging (MRI) spine and clinical presentation was accompanied by inflammatory cerebrospinal fluid (CSF) findings. Half of our cohort had received spinal radiotherapy, with the areas of transverse myelitis extending beyond the level of previous radiation field. Inflammatory changes on neuroimaging did not extend to the brain parenchyma or caudal nerve roots, except for one case involving the conus medullaris. All patients received high dose glucocorticoids as first-line therapy, however the majority relapsed or had a refractory state (3/4) despite this, requiring escalation of their immunomodulation, with either induction intravenous immunoglobulin (IVIg) or plasmapheresis. Patients in our cohort who relapsed had a poorer outcome with more severe disability and reduced functional independence following resolution of their myelitis. Two patients had no progression of their malignancy and two patients had malignancy progression. Of the three patients who survived, two had resolution of their neurological symptoms and one remained symptomatic. Conclusion: We propose that prompt intensive immunomodulation is favored for patients with ICI-transverse myelitis in an attempt to reduce associated significant morbidity and mortality. Furthermore, there is a significant risk of relapse following cessation of immunomodulatory therapy. We suggest one treatment approach of IVMP and induction IVIg for all patients presenting with ICI-induced transverse myelitis based on such findings. With the increasing use of ICIs across oncology, further studies are required to explore this neurological phenomenon in greater detail to help establish management consensus guidelines.

Slit-Robo signalling establishes a Sphingosine-1-phosphate gradient to polarise fin mesenchyme.

Immigration of mesenchymal cells into the growing fin and limb buds drives distal outgrowth, with subsequent tensile forces between these cells essential for fin and limb morphogenesis. Morphogens derived from the apical domain of the fin, orientate limb mesenchyme cell polarity, migration, division and adhesion. The zebrafish mutant stomp displays defects in fin morphogenesis including blister formation and associated loss of orientation and adhesion of immigrating fin mesenchyme cells. Positional cloning of stomp identifies a mutation in the gene encoding the axon guidance ligand, Slit3. We provide evidence that Slit ligands derived from immigrating mesenchyme act via Robo receptors at the apical ectodermal ridge (AER) to promote release of sphingosine-1-phosphate (S1P). S1P subsequently diffuses back to the mesenchyme to promote their polarisation, orientation, positioning and adhesion to the interstitial matrix of the fin fold. We thus demonstrate the coordination of the Slit-Robo and S1P signalling pathways in fin fold morphogenesis. Our work introduces a mechanism regulating the orientation, positioning and adhesion of its constituent cells.

Label-free quantitative measurement of cardiovascular dynamics in a zebrafish embryo using frequency-comb-referenced-quantitative phase imaging.

SIGNIFICANCE: Real-time monitoring of the heart rate and blood flow is crucial for studying cardiovascular dysfunction, which leads to cardiovascular diseases. AIM: This study aims at in-depth understanding of high-speed cardiovascular dynamics in a zebrafish embryo model for various biomedical applications via frequency-comb-referenced quantitative phase imaging (FCR-QPI). APPROACH: Quantitative phase imaging (QPI) has emerged as a powerful technique in the field of biomedicine but has not been actively applied to the monitoring of circulatory/cardiovascular parameters, due to dynamic speckles and low frame rates. We demonstrate FCR-QPI to measure heart rate and blood flow in a zebrafish embryo. FCR-QPI utilizes a high-speed photodetector instead of a conventional camera, so it enables real-time monitoring of individual red blood cell (RBC) flow. RESULTS: The average velocity of zebrafish's RBCs was measured from 192.5 to 608.8 µm / s at 24 to 28 hour-post-fertilization (hpf). In addition, the number of RBCs in a pulsatile blood flow was revealed to 16 cells/pulse at 48 hpf. The heart rates corresponded to 94 and 142 beats-per-minute at 24 and 48 hpf. CONCLUSIONS: This approach will newly enable in-depth understanding of the cardiovascular dynamics in the zebrafish model and possible usage for drug discovery applications in biomedicine.

Lateral versus cross pinning in paediatric supracondylar humerus fractures: a meta-analysis of randomized control trials.

BACKGROUND: Supracondylar humerus fractures are common in children. Percutaneous pinning remains the mainstay in treatment; however, there is lack of consensus on the optimal configuration: lateral-only pinning or cross pinning. This study aims to investigate the differences in clinical and surgical outcomes between lateral-only and cross-pinning paediatric supracondylar humerus fractures. METHODS: A systematic search was performed using Medline Ovid, Embase and Cochrane databases for relevant randomized control trials comparing lateral and cross pinning of paediatric supracondylar humerus fractures, reporting at least one of the following: rate of iatrogenic ulnar nerve injury, loss of reduction, infection, loss of Baumann's angle and loss of carrying angle. Statistical analysis was performed using STATA 13.0. RESULTS: Eleven suitable randomized control trials involving 900 patients were reviewed. Loss of reduction was more common with lateral pinning (relative risk 1.44, 95% confidence interval 1.04-2.00, P = 0.027). Iatrogenic ulnar nerve injury was less common in lateral pinning with treatment-based analysis (relative risk 0.36, 95% confidence interval 0.14-0.92, P = 0.032). There was no statistically significant difference in loss of carrying angle, loss of Baumann angle or rate of infection. CONCLUSION: Cross pinning provides superior stability in the treatment of supracondylar humerus fractures in children; however, it carries greater risk of iatrogenic ulnar nerve injury.

The comparative impact of video consultation on emergency neurosurgical referrals.

OBJECTIVE: Neurosurgical resources are concentrated in tertiary referral centers, whereas emergencies identified from district general hospitals are traditionally referred by telephone consultation (TC). Recent advances in communication technology offer the alternative options of teleradiology (TR) and video consultation (VC). This study aimed to determine the differences among these three consultation methods on the basis of their process-of-care indicators, clinical outcomes, and cost-effectiveness. METHODS: Patients with emergency neurosurgical conditions (head injury, stroke, and miscellaneous) from a district general hospital were randomized to three different modes of consultation: TC, TR, or VC. Process-of-care indicators (postresuscitation Glasgow Coma Scale score, consultation time required, diagnostic accuracy, and transfer decision and safety), 6-month clinical outcome, and cost-effectiveness of the three consultation modes were correlated. RESULTS: In a 3-year period, 710 patients were recruited and randomized to the three consultation modes (n = 235, 239, and 236, respectively). Demographic and clinical data were comparable. TR and VC showed a definite advantage in diagnostic accuracy over TC (89.1 and 87.7% versus 63.8%; P < 0.001). However, duration of the corresponding consultation process was longer for TR and VC than TC (1.01 and 1.3 h versus 0.70 h). A high failure rate (30%) was noted in VC. Thirty-three percent of patients were transferred to the neurosurgical center after consultation. The difference in consultation modes did not have an impact on transfer rate and safety. There was a trend toward more favorable outcome (61%; P = 0.12) and a reduced mortality (25%; P = 0.025) in TR compared with TC (54 and 34%, respectively) and VC (54 and 33%, respectively). The mean cost per patient in the VC group was slightly higher than the other two groups (TC versus TR versus VC = 14,000 US dollars versus 14,400 US dollars versus 16,300 US dollars, respectively), but the differences were not statistically significant. CONCLUSION: Emergency neurosurgical consultation assisted by TR and VC achieved a higher diagnostic accuracy in comparison with conventional TC. Although VC did not show an advantage over TR in process-of-care indicators, clinical outcome, and cost, it has been proven to be a safe mode of consultation in emergency neurosurgery.

Laparoscopic resection of rectosigmoid carcinoma: prospective randomised trial.

BACKGROUND: Although laparoscopic resection of colorectal carcinoma improves post-operative recovery, long-term survival and disease control are the determining factors for its application. We aimed to test the null hypothesis that there was no difference in survival after laparoscopic and open resection for rectosigmoid cancer. METHODS: From Sept 21, 1993, to Oct 21, 2002, 403 patients with rectosigmoid carcinoma were randomised to receive either laparoscopic assisted (n=203) or conventional open (n=200) resection of the tumour. Survival and disease-free interval were the main endpoints. Patients were last followed-up in March, 2003. Perioperative data were recorded and direct cost of operation estimated. Data were analysed by intention to treat. FINDINGS: The demographic data of the two groups were similar. After curative resection, the probabilities of survival at 5 years of the laparoscopic and open resection groups were 76.1% (SE 3.7%) and 72.9% (4.0%) respectively. The probabilities of being disease free at 5 years were 75.3% (3.7%) and 78.3% (3.7%), respectively. The operative time of the laparoscopic group was significantly longer, whereas postoperative recovery was significantly better than for the open resection group, but these benefits were at the expense of higher direct cost. The distal margin, the number of lymph nodes found in the resected specimen, overall morbidity and operative mortality did not differ between groups. INTERPRETATION: Laparoscopic resection of rectosigmoid carcinoma does not jeopardise survival and disease control of patients. The justification for adoption of laparoscopic technique would depend on the perceived value of its effectiveness in improving short-term post-operative outcomes.

Sentinel lymph node dissection in papillary thyroid carcinoma.

BACKGROUND: Occult lymph node (LN) metastasis is common in papillary thyroid carcinoma. Sentinel lymph node (SLN) biopsy has been proven to be successful and accurate to predict the nodal status in melanoma and breast cancer. We investigate the use of SLN in papillary thyroid carcinoma. METHODS: Patients of previously untreated papillary thyroid carcinoma, diagnosed preoperatively by fine-needle cytology without any palpable cervical LN are prospectively studied. Blue dye injection was utilized for the SLN biopsy followed by central compartment lymphadenectomy. The histopathological results of the SLN and lymphadenectomy specimens were compared. RESULTS: Fifteen consecutive patients underwent surgery including SLN biopsy for papillary thyroid carcinoma. Occult nodal metastases were identified in 10 patients (67%). The other five cases had no nodal metastasis. SLN were found in 10 cases. One, two and three SLN were present in three, three and four patients, respectively. SLN were located in the central compartment in eight cases. The SLN were found in the lateral compartment in one case. In the remaining one case, the SLN were found in both the central and lateral compartments. Of the group with found SLN, false negative occurred in one case. The overall accuracy of the SLN in predicting the nodal status was 90%. The sensitivity, specificity, positive predictive value and negative predictive value were 88%, 100%, 100% and 67%, respectively. No complications were directly related to SLN biopsy. CONCLUSION: Occult nodal spread is frequently encountered in papillary thyroid carcinoma. SLN biopsy is safe and feasible in papillary thyroid cancer, however further studies are necessary to improve the diagnostic accuracy prior to routine clinical use.

Introduction of night shift call system for surgical trainees: a prospective self-controlled trial.

OBJECTIVE: The number of hours worked by specialty trainees has come under scrutiny recently. One approach aimed at decreasing the number of consecutive hours worked is the night shift call system (NSCS). This study aimed to determine the advantages and disadvantages of an NSCS compared with those of the conventional overnight call system (ONCS). SUBJECTS AND METHODS: Sixteen basic surgical trainees (BSTs) from our unit participated in this prospective, self-controlled trial. During April 2000, the conventional 1-in-4 ONCS with a post-call half-day off was instituted. From May to June 2000, each BST rotated to work 1 week of night duty (20.00-08.00) and 7 weeks of daytime duty. A battery of neuropsychological tests were administered to the group after call during the study period. RESULTS: On average the numbers of consecutive hours worked during the NSCS and ONCS periods were 12 and 28 hours, respectively. There was no difference in numbers of errors committed and no difference in discrepancy between diagnoses made on admission and discharge. Two of the simple neuropsychological tests (memory scanning and addition tests) showed a significant fall-off in performance during the ONCS period (P < 0.05). Most specialists preferred the ONCS, while the majority of the BSTs preferred the NSCS (P < 0.05). This was because without extra manpower, the overall workloads of senior staff were increased. CONCLUSIONS: The NSCS is 1 way of reducing work hours, and was associated with significantly less impaired cognition on the part of our BSTs. It is only feasible if extra relieving staff are available to cover daytime duties.

Screening for colorectal cancer in Chinese: comparison of fecal occult blood test, flexible sigmoidoscopy, and colonoscopy.

BACKGROUND AND AIMS: Fecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), and colonoscopy are the most commonly recommended screening tests for colorectal cancer. The aim of this study was to compare the accuracy and safety of these 3 screening procedures in a general population of ethnic Chinese. METHODS: Asymptomatic adults older than 50 years were recruited from the general public through health exhibitions. All enrolled subjects were offered FOBT and full colonoscopy under sedation. Advanced colonic lesions (defined as adenoma > or = 10 mm, villous adenoma, adenoma with moderate or severe dysplasia, or invasive cancer) were recorded. Lesions at the distal 40 cm in the left colon and rectum were taken as findings of FS. RESULTS: A total of 505 subjects (56% women; mean age +/- SD, 56.5 +/- 5.4 years) were enrolled, and 476 (94.3%) had a complete colonoscopy. Advanced colonic neoplasms were documented in 63 subjects (12.5%), of which 45 had lesions in the distal colon and 26 in the proximal colon. Among the 385 subjects with a normal distal colon, 14 (3.6%) had advanced lesions in the proximal colon that would be missed by FS alone. The sensitivity and specificity of FOBT for advanced colonic lesions were 14.3% and 79.2% and the sensitivity and specificity of FS were 77.8% and 83.9%, respectively. Combining FOBT with FS would not significantly improve the results of FS alone. Among these 505 subjects who underwent colonoscopy and 148 who underwent polypectomy, there was no perforation and only one occurrence of postpolypectomy bleeding recorded. CONCLUSIONS: Colonoscopy is a safe and accurate method for the screening of colorectal neoplasms in Chinese subjects.

Acupuncture anaesthesia in inguinal hernia repair.

BACKGROUND: The present study was undertaken to evaluate the efficacy of acupuncture anaesthesia in inguinal hernia repair. METHODS: Twelve patients with non-recurrent inguinal hernia had Lichtenstein mesh repair under acupuncture anaesthesia. Selected acupuncture loci were stimulated with fine needles connected to low frequency current. Supplementary local anaesthetic was given when required. RESULTS: Four (33%) patients reported satisfactory analgesic effect throughout the operation without need for additional medication, eight (67%) patients experienced mild discomfort during the operation requiring 1-4 mL of 1% lignocaine injection. Blood pressure and heart rate were stable during the procedure. All patients were able to sit up and resume their diet immediately post-operatively. All but one patient were discharged on day one after the procedure, with no early or late complications reported. Most patients were satisfied with the analgesic effect of acupuncture anaesthesia. CONCLUSIONS: Acupuncture anaesthesia is a feasible anaesthetic option. It reduces the amount of local anaesthetic required, and thus the associated potential complications. It is effective in pain relief and inhibiting gastrointestinal upset. Postoperative recovery was rapid and complication free.

On-table cecoscopy : a novel diagnostic method in acute diverticulitis of the right colon.

PURPOSE: Controversies abound regarding the optimal surgical management in noncomplicated diverticulitis of the right colon, ranging from a conservative approach to diverticulectomy to right hemicolectomy. One of the arguments for resection is to exclude carcinoma. However, there is significant morbidity associated with resection. We aim to introduce on-table cecoscopy as a tool to improve the diagnosis of acute diverticulitis of the right colon, exclude carcinoma, and reduce the rate of resection. METHODS: From October 1999 to June 2000, five patients presented to our unit with suspected acute appendicitis. Intraoperatively, we found a colonic inflammatory mass at either the cecum or the ascending colon. The cecum and ascending colon were mobilized, and bowel clamps were applied to the ascending colon and ileum. A bronchoscope (Olympus(R) BF-P200) was introduced through the appendix stump. To achieve a good endoscopic view, a limited volume of air was introduced through the working channel. RESULTS: After on-table cecoscopy, all the patients were diagnosed as having acute nonperforated diverticulitis of the right colon. They received appendicectomy, and the diverticulitis was managed conservatively. They were treated with a course of cephalosporin and metronidazole. We performed colonoscopy four weeks later and confirmed that none of them had carcinoma of the colon. CONCLUSIONS: On-table cecoscopy is a new, safe, and effective means of diagnosing acute diverticulitis of the right colon. We can confidently exclude carcinoma and reduce the amount of colonic resection in patients with noncomplicated diverticulitis of the right colon.