Clinical relevance of screening checklists for detecting cancer predisposition syndromes in Asian childhood tumours.

Assessment of cancer predisposition syndromes (CPS) in childhood tumours is challenging to paediatric oncologists due to inconsistent recognizable clinical phenotypes and family histories, especially in cohorts with unknown prevalence of germline mutations. Screening checklists were developed to facilitate CPS detection in paediatric patients; however, their clinical value have yet been validated. Our study aims to assess the utility of clinical screening checklists validated by genetic sequencing in an Asian cohort of childhood tumours. We evaluated 102 patients under age 18 years recruited over a period of 31 months. Patient records were reviewed against two published checklists and germline mutations in 100 cancer-associated genes were profiled through a combination of whole-exome sequencing and multiplex ligation-dependent probe amplification on blood-derived genomic DNA. Pathogenic germline mutations were identified in ten (10%) patients across six known cancer predisposition genes: TP53, DICER1, NF1, FH, SDHD and VHL. Fifty-four (53%) patients screened positive on both checklists, including all ten pathogenic germline carriers. TP53 was most frequently mutated, affecting five children with adrenocortical carcinoma, sarcomas and diffuse astrocytoma. Disparity in prevalence of germline mutations across tumour types suggested variable genetic susceptibility and implied potential contribution of novel susceptibility genes. Only five (50%) children with pathogenic germline mutations had a family history of cancer. We conclude that CPS screening checklists are adequately sensitive to detect at-risk children and are relevant for clinical application. In addition, our study showed that 10% of Asian paediatric solid tumours have a heritable component, consistent with other populations.

Clinical Characteristics and efficacy of chemotherapy in sclerosing epithelioid fibrosarcoma.

BACKGROUND: Sclerosing epithelioid fibrosarcoma (SEF) is a very rare soft tissue sarcoma subtype. Clinically it is an aggressive tumour; however, to our knowledge there are no published reports regarding the efficacy of chemotherapy in SEF. Therefore, the aim of this study was to document the outcome of a series of patients with SEF treated at a single referral centre with reference to systemic therapy. METHODS: A retrospective search of a prospectively maintained database was performed to identify all patients diagnosed with SEF between 1990 and 2017. The diagnosis was confirmed in each case by a dedicated soft tissue sarcoma pathologist. We analysed those with recurrent disease and the effect of systemic chemotherapy in the metastatic setting. RESULTS: Thirteen patients were identified, median overall survival from diagnosis and metastasis were 47.3 (95% CI 25.0-131.9) and 16.3 (95% CI 5.3-20.6) months, respectively. In total, 12 (92.3%) patients developed metastatic disease of which 10 died of disease, 1 was lost to follow-up and 1 had recently commenced palliative treatment. Among the 10 patients with metastatic disease, 7 received palliative chemotherapy. Palliative chemotherapy resulted in partial response in 1 patient, stable disease in 3 patients and progressive disease in 3 patients. Median time to disease progression was 2.7 (95% CI 1.2-4.4) months. Two of 13 patients were treated with adjuvant chemotherapy, receiving 6 cycles of liposomal doxorubicin and 1 cycle of doxorubicin, respectively, with a metastasis-free survival of 28.2 and 7.1 months, respectively. CONCLUSION: SEF is an aggressive sarcoma subtype with a poor outcome and with limited responsiveness to conventional chemotherapy. Patients with this subtype should be considered for participation in clinical trials with novel agents. Further investigation into the biology of this rare disease is required to improve outcomes.

Biological significance and prognostic relevance of peripheral blood neutrophil-to-lymphocyte ratio in soft tissue sarcoma.

Peripheral blood indices of systemic inflammation such as the neutrophil-lymphocyte ratio (NLR) have been shown to be prognostic in various cancers. We aim to investigate the clinical significance of these indices in patients with soft tissue sarcoma (STS). Seven hundred and twelve patients with available blood counts at diagnosis and/or metastatic relapse were retrospectively examined. An optimal cutoff for NLR-high (>2.5) in predicting overall survival (OS) was determined using receiver operating curve analyses. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models. Our results show that NLR was significantly higher in patients with distant metastasis at diagnosis (n = 183) compared to those without (n = 529) (median: 4.36 vs 2.85, p < 0.0001). Progression of localized disease at diagnosis to metastatic relapse within the same patients was associated with an interval increase in NLR (median: 3.21 vs 3.74, p = 0.0003). In multivariate analysis, NLR-high was the only consistent factor independently associated with both worse OS (HR 1.53, 95% CI 1.10-2.13, p = 0.0112) and relapse-free survival (HR 1.41, 95% CI 1.08-1.85, p = 0.0125) in localized disease, as well as OS (HR 1.82, 95% CI 1.16-2.85, p = 0.0087) in metastatic/unresectable disease. In conclusion, high NLR is an independent marker of poor prognosis among patients with STS.

Evaluation of the relative effectiveness of the 2017 updated Manchester scoring system for predicting BRCA1/2 mutations in a Southeast Asian country.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes have significant clinical implications for both risk-reducing and early surveillance management. The third and most recent revision of the Manchester scoring system (MSS3) used to distinguish patients indicated for germline BRCA1/2 testing included further adjustments for triple negative breast cancer, high-grade serous ovarian cancer and human epidermal growth factor 2 (HER2) receptor status. This study aims to evaluate the relative effectiveness of MSS3 in a Southeast Asian population. METHODS: All patients in our centre were tested using next-generation sequencing (NGS) panels that included full gene sequencing as well as coverage for large deletions/duplications in BRCA1/2. We calculated MSS1-3 scores for index patients between 2014 and 2017 who had undergone BRCA1/2 genetic testing and recorded their genetic test results. MSS1-3 outcomes were compared using receiver operating characteristic analysis, while associations with predictors were investigated using Fisher's exact test and logistics regression. Calculations were performed using Medcalc17. RESULTS: Of the 330 included patients, 47 (14.2%) were found to have a germline mutation in BRCA1 or BRCA2. A positive HER2 receptor was associated with a lower likelihood of a BRCA1/2mutation (OR=0.125, 95% CI 0.016 to 0.955; P=0.007), while high-grade serous ovarian cancer was conversely associated with an increased likelihood of a BRCA1/2 mutation (OR=5.128, 95% CI 1.431 to 18.370; P=0.012). At the 10% threshold, 43.0% (142/330) of patients were indicated for testing under MSS3, compared with 35.8% (118/330) for MSS1% and 36.4% (120/330) for MSS2. At the 10% threshold, MSS3 sensitivity was 91.5% and specificity 65.0%, significantly better than the previous MSS1 (P=0.037) and MSS2 (P=0.032) models. CONCLUSION: Our results indicate that the updated MSS3 outperforms previous iterations and relative to the Manchester population, is just as effective in identifying patients with BRCA1/2 mutations in a Southeast Asian population.

Clinical management of pheochromocytoma and paraganglioma in Singapore: missed opportunities for genetic testing.

BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors of the adrenal glands and paraganglia, occurring sporadically or as a range of hereditary tumor syndromes. About 30% of PPGLs are attributed to germline mutations. Clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background. Genetic testing for PPGLs is not well studied in Southeast Asia. We reviewed clinical management of PPGLs in Singapore, highlighting current gaps in clinical practice. METHODS: Medical records of patients with PPGLs between 2005 and 2016 were reviewed. Diagnosis was confirmed histologically and stratified into sporadic or familial/syndromic (FS). RESULTS: Twenty-seven (21.8%) patients were referred to the Cancer Genetics Service (CGS). FS PPGLs (18.5%) and extra-adrenal PPGLs (58.1%) incidences were higher than previous studies. Referrals were lower for sporadic PPGLs compared to FS PPGLs (3.7% vs. 100%). Referrals were highest at diagnosis age <20 years old (80%) and decreased with increasing age; ≥20-<40 years old (32.1%), ≥40-<60 years old (10.6%). Genetic testing was taken up in 12/27 (44.4%) patients of which 7/12 (58.3%, 3 SDHB, 2 SDHD, 2 VHL) had germline mutations. CONCLUSION: Opportunities for genetic testing are frequently missed due to low referral rates in patients with apparently sporadic PPGLs, particularly between ages 20-60.

Percutaneous Trigger Release in Non-Triggering Digits: Infiltration of Normal Saline into Tendon Substance to Induce Triggering.

Percutaneous trigger release is recognized as an effective minimally invasive procedure with a low complication rate. One prerequisite for percutaneous trigger release is a trigger of Quinnell Type II or higher; that is, a digit that is actively triggering. We describe an additional step in percutaneous trigger release, which enables the surgeon to perform the procedure in digits that are not actively triggering at the point of surgery. This step involves the infiltration of normal saline into the tendon substance distal to the A1 pulley in order to induce triggering.

Reconstruction of Extensive Soft-Tissue Defects with Concomitant Bone Defects in the Lower Extremity with the Latissimus Dorsi-Serratus Anterior-Rib Free Flap.

BACKGROUND: The combined latissimus dorsi-serratus anterior-rib (LD-SA-rib) free flap provides a large soft-tissue flap with a vascularized bone flap through a solitary vascular pedicle in a one-stage reconstruction. METHODS: Seven LD-SA-rib free flaps were performed in seven patients to reconstruct concomitant bone and extensive soft-tissue defects in the lower extremity (tibia, five; femur, one; foot, one). The patients were all male, with an average age of 34 years (range, 20-48 years). These defects were secondary to trauma in five patients and posttraumatic osteomyelitis in two patients. RESULTS: All flaps survived and achieved bony union. The average time to bony union was 9.4 months. Bone hypertrophy of at least 20% occurred in all flaps. All patients achieved full weight-bearing ambulation without aid at an average duration of 23.7 months. Two patients developed stress fractures of the rib flap. There was no significant donor site morbidity, except for two patients who had pleural tears during harvesting of the flap. CONCLUSION: The LD-SA-rib flap provides a large soft-tissue component and a vascularized bone flap for reconstruction of composite large soft-tissue defects with concomitant bone defects of the lower extremity in a one-stage procedure.

Posterior interosseous artery flap: our experience and review of modifications done.

This is a report on the 14 PIA flaps done in our centre for traumatic hand defects over both volar and dorsal aspects, as well as thumb reconstruction over a six-year period from 2000 to 2007. We were able to achieve reach to the DIPJ with the use of fascia extension and better flap survival with more perforators captured in the flap.

Comparison between cast immobilization versus volar locking plate fixation of distal radius fractures in active elderly patients, the Asian perspective.

Displaced distal radius fractures in active elderly patients with high functional demand present a clinical dilemma because current evidence is equivocal in the recommendation of treatment. Internal fixation is an increasingly popular option with proposed superior results. Our study aims to evaluate the results among a population of active elderly patients with displaced fractures managed with either cast immobilization or internal fixation with volar locking plate. Seventy-five patients (35 cast immobilization and 40 internal fixation) with mean age of 74 ± 7.5 years with minimum of 12 months follow-up were studied. The radiological and clinical parameters were assessed at three, six, and 12 months. Functional outcomes (DASH, Green-O'Brien) were assessed at 12 months. Patients who underwent surgery regain wrist motion and grip strength earlier, but this was not statistically significant after six months.

Mechanical failure of the distal radius volar locking plate.

PURPOSE: To review 9 cases of mechanical failure of the volar locking plate for distal radial fractures. METHODS: Records of 374 consecutive patients who underwent volar locking plating for distal radial fractures were reviewed. Mechanical failures of the volar locking plate were defined as plate breakage or bending, screw breakage or loosening, or collapse of articular fragments resulting in intra-articular screw extrusion. RESULTS: Nine mechanical failures occurred between 2 weeks and 3 months in 8 (2.4%) of the patients aged 25 to 82 (median, 74) years with AO fracture types of A3 (n=4), C1 (n=1), C2 (n=1), and C3 (n=3). Mechanical failures included screw pullout (n=5), locking plate bending (n=2), locking screws breakage (n=1), and loosening of locked variable angle screws (n=1). One patient underwent revision of fixation and 2 underwent implant removal. The remainder were treated conservatively. All patients were followed up for a minimum of 12 months; their mean flexion arc was 87 degrees (standard deviation [SD], 17) and the mean rotation arc was 136 degrees (SD, 29 degrees). According to the Green and O'Brien score, their outcomes were good (n=1), fair (n=4), and poor (n=3). CONCLUSION: Although mechanical failure of volar locking plate is uncommon, some are potentially preventable.

Beware! The volar ulnar fragment in a comminuted Bartons fracture.

The purpose of this study is to highlight a cohort of patients with a comminuted volar shearing type of distal radius fractures (AO B3.3) with the volar ulnar fragment that is prone to re-displace, resulting in volar subluxation of the radiocarpal joint. We report our experience with two such patients with re-displacement of the fragment and joint requiring repeat surgery; one of whom required a third procedure to stabilize that fragment. Three subsequent patients were successfully treated with one surgery when particular attention was paid to stabilize the volar ulnar fragment. This highlights the importance of stabilizing this fragment at the primary procedure.

Use of the fix and flap approach to complex open elbow injury: the role of the free anterolateral thigh flap.

BACKGROUND: Complex elbow injuries with associated nerve, muscle, or joint injury commonly develop post-inury stiffness. In order to preserve function, joint congruency, elbow stability and durable wound coverage must be achieved in a timely manner. METHODS: A retrospective review of patients who underwent orthopaedic fixation followed by free anterolateral thigh (ALT) flap soft tissue coverage was performed. Five patients were identified and included in this study. RESULTS: We present a series of 5 cases managed with this principle. Soft tissue defects ranged in size from 4×9 cm (36 cm(2)) to 15×30 cm (450 cm(2)) and were located either posteriorly (n=4) or anteriorly (n=1). Associated injuries included open fractures (n=3) and motor nerve transection (n=2). Wound coverage was achieved in a mean duration of 18.8 days (range, 11 to 42 day). There were no flap failures and no major complications. The mean postoperative active elbow motion was 102° (range, 45° to 140°). CONCLUSIONS: In our small series we have highlighted the safety and utility of using the free ALT flap in complex elbow injuries. The ALT flap has many advantages which include abundant skin and subcutaneous tissue; vascularised vastus lateralis muscle that was used in our series to obliterate dead space, provide a vascular bed for nerve grafts and combat infection; and, access to fascia lata grafts for reconstruction of the triceps tendon.

Safe and easy method to preserve fingertip contour in VY-plasty.

VY-plasty is a well-known technique to reconstruct fingertip defects. A simplified method combining pinning of flap and healing of donor site by secondary intention is described. These steps preserve the rounded appearance of the fingertip and restore the convexity of the hyponychium. Flap ischemia due to suture-line tension is also averted.

Volar plating for unstable proximal interphalangeal joint dorsal fracture-dislocations.

PURPOSE: To report our results of open reduction internal fixation with volar mini plate and screw fixation for unstable dorsal fracture dislocations (DFDs) of the proximal interphalangeal (PIP) joint. METHODS: We performed a retrospective review of 13 consecutive DFDs of the PIP joint treated with volar mini plate and screw fixation, measuring both clinical and radiological outcomes. RESULTS: The age range of our patients was 15 to 56 years (average, 33 y). Six injuries were related to work, 5 to sports, and 2 to motor vehicle accidents. Of the 13 DFDs, 6 were comminuted. Articular involvement ranged from 30% to 70% (average, 44%). The average time to surgery was 7 days (range, 0-23 d). Patients had follow-up of 12 to 60 months (average, 25 mo). Four patients had a postoperative course complicated by plate and screw removal at an average of 4 months later, either as part of a secondary procedure to improve range of motion or owing to patient request. All patients returned to their original occupation. Of the 13 patients, 11 were satisfied with the result, and 12 of 13 had either no or mild pain. All 13 DFDs united in good alignment but 3 showed degenerative changes. Average grip strength was 85% of the unaffected side, and average active PIP joint and distal interphalangeal joint motion arcs were 75° and 65°, respectively. Average Quick Disabilities of Arm, Shoulder, and Hand score was 4 (range, 0-9). All patients had non-tender swelling of the proximal interphalangeal joints but no signs of flexor tenosynovitis or infection. CONCLUSIONS: Fixation of unstable PIP joint DFDs via a volar approach is technically feasible with mini plates and screws. This treatment allows early active range of motion and provides good objective and subjective outcomes; however, noteworthy complications occurred in 39% of patients. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Serratus anterior venous tributary as a second outflow vein in latissimus dorsi free flaps.

The latissimus dorsi (LD) flap is a large and reliable myocutaneous flap with a consistently long vascular pedicle. However, the limitation of the thoracodorsal pedicle is that it has only one draining vein for anastomosis. We describe a simple technique of recruiting the tributary vein to the serratus anterior and using it as a second draining vein to alleviate congestion in lower limb reconstruction. The serratus anterior venous tributary segment is cut back to an avalvular segment which averages 5 mm in length. Provision of an additional venous outflow to the flap enabled a second venous anastomosis to the short saphenous vein (N = 1), the long saphenous vein (N = 2), a deep vein (N= 1), and to a deep vein via a vein graft (N = 1), respectively. Five patients with degloving injury of the lower extremity of sizes 150 cm(2) (10 × 15 cm) to 260 cm(2) (10 × 26 cm) underwent successful reconstruction using the LD muscle flap with the serratus anterior tributary vein as a second outflow vein. This serratus anterior venous tributary serves as a useful second outflow channel for alleviating venous congestion during lower limb reconstructive surgery and should be routinely preserved as a lifeboat.

Improving the reliability of the distally based posterior tibial artery adipofascial flap with the great saphenous venoneural network.

The distally based posterior tibial adipofascial flap is a useful option for distal leg and ankle coverage. Traditionally, its dimension is constrained by a length-to-width ratio of 2:1. We have increased this ratio to 4:1 by including the great saphenous vein and saphenous nerve with the flap. These structures with their venoneural network, and their connections with posterior tibial artery perforators, form the vascular axis of the flap. In our series of 21 flaps, 70% (n = 15) had ratios of 3:1 or higher. In remaining 30% (n = 6), the ratio was 2:1, as the defects were more proximal. Complications include one complete flap loss due to compression from tunneling and one superficial tip necrosis. Postoperatively, we performed wet-to-wet dressings, phlebotomy, and delayed skin grafting to optimize flap survival. Of 21 flaps, 20 were healthy after an average follow-up of 24 months.

Articularly placed interfragmentary screw fixation of difficult condylar fractures of the hand.

PURPOSE: To retrospectively review the outcomes of intra-articularly placed interfragmentary screws for fixation of difficult condylar fractures of the metacarpal and proximal phalangeal heads. METHODS: We placed interfragmentary screws intra-articularly in 10 patients with 11 fractures to achieve a rigid fixation construct in which the non-articular portion of the bone fragment is too small to allow a stable fixation, or where the bone fragment is entirely osteochondral. RESULTS: The mean duration of follow-up was 15.9 months (range, 6-45 mo). All fractures united within 16 weeks (average, 8.1 wk). We observed subsidence in 1 case; another patient had screw protrusion that required removal. The range of motion of the involved metacarpophalangeal joints for the metacarpal head fractures was 79° (range, 60° to 90°). The range of motion of the involved proximal interphalangeal joints for the proximal phalangeal head fractures was 86° (range, 80° to 90°). CONCLUSIONS: Intra-articularly placed interfragmentary screw fixation is a good technique for treating difficult condylar fractures of the hand.

Volar plate and screw fixation for dorsal fracture-dislocation of the proximal interphalangeal joint: case report.

We present a case of a man who sustained a closed dorsal fracture-dislocation of his left ring finger proximal interphalangeal joint in a fall. The patient was treated surgically with plate and screw fixation via a volar approach. This method theoretically provides more secure fixation than internal fixation with screws alone, allowing early rehabilitation with active range of motion and potentially better functional outcome.