An unusual presentation of a pediatric patient with mixed phenotypic acute leukemia with PICALM::MLLT10 gene rearrangement.

Mixed phenotype leukemia (MPAL) is a rare type of acute leukemia with blasts that co-express antigens of more than one lineage on the same cell or that have separate populations of blasts of different lineages. Here, we report a five-year-old male with inguinal lymphadenopathy diagnosed with MPAL-T/Myeloid MPAL-T/M. The clone demonstrated lineage and immunophenotypically distinct blast populations in the bone marrow and lymph nodes. Bone marrow cytogenetic studies confirmed a rare PICALM::MLLT10 gene fusion. Patients with this fusion gene have been found to have high risk features and poor survival rates in several small case series. Our case report highlights an unusual presentation in medullary and extramedullary sites, within a pediatric patient. At the time of submission of this case report, the patient has shown good response to chemotherapy and continues to be in remission.

Calretinin Staining in Anorectal Line Biopsies Accurately Distinguished Hirschsprung Disease in a Retrospective Study.

INTRODUCTION: The absence of submucosal ganglion cells does not reliably distinguish Hirschsprung disease from non Hirschsprung disease in anorectal line biopsies. Calretinin staining might be helpful in these biopsies. To determine its value, we analyzed calretinin positive mucosal neurites in anorectal line biopsies. METHODS: Two pediatric pathologists, without access to patient data, evaluated calretinin positive mucosal neurites in anorectal line junctional mucosa in archival rectal biopsies contributed by 17 institutions. A separate investigator compiled patient information and sent data for statistical analysis. RESULTS: Biopsies with anorectal junctional mucosa from 115 patients were evaluated for calretinin positive mucosal neurites. 20/20 Hirschsprung disease biopsies were negative. 87/88 non Hirschsprung disease biopsies and 7/7 post pullthrough Hirschsprung disease neorectal biopsies were positive. Statistical analysis of the 108 non pullthrough biopsies yielded an accuracy of 99.1% (sensitivity 100%, specificity 98.9%). Age range was preterm to 16 years. Biopsy size was less than 1 mm to over 1 cm. CONCLUSIONS: Absence of calretinin positive mucosal neurites at the anorectal line was highly accurate in distinguishing Hirschsprung disease from non Hirschsprung disease cases in this blinded retrospective study. Calretinin staining is useful for interpreting biopsies from the physiologic hypoganglionic zone up to the anorectal line.

Ambulation Recovery After Surgery for Metastases to the Femur.

BACKGROUND: Postoperative ambulation recovery after surgery for femur metastases has significant implications for not only the patient's quality of life but also administration of further cancer treatment. Thus, identification of preoperative predictors of ambulation recovery is necessary to set appropriate expectations and guide treatment. This study aimed to assess ambulation recovery rate and identify predictors of ambulation recovery in patients undergoing surgery for femur metastases. MATERIALS AND METHODS: A total of 244 patients who underwent surgery for femur metastases at our institution were reviewed. Patients were considered ambulatory if they were able to walk independently or walk with aids and nonambulatory if they were wheelchair bound or bedridden. The following potential clinicopathologic factors that might predict postoperative ambulation recovery were evaluated: premorbid general status, cancer burden, and local factors. RESULTS: A total of 165 patients (68%) regained ambulatory status postoperatively. A multivariate analysis revealed poor Eastern Cooperative Oncology Group (ECOG) performance status (odds ratio [OR], 5.327; p < .001) and nonambulatory premorbid ambulatory status (OR, 7.459; p < .001) as independent predictors of poor ambulation recovery after surgery for femur metastases. Postoperative ambulatory status was significantly associated with postoperative survival time (p < .001). CONCLUSION: Postoperative ambulation recovery rate in our cohort was 68%. Premorbid ambulatory status and ECOG performance status are predictors of ambulation recovery in patients undergoing surgery for femur metastases. IMPLICATIONS FOR PRACTICE: Postoperative ambulation recovery rate in this cohort was 68%. Premorbid ambulatory status and Eastern Cooperative Oncology Group performance status are predictors of ambulation recovery in patients undergoing surgery for femur metastases.

INSM1 Expression in Peripheral Neuroblastic Tumors and Other Embryonal Neoplasms.

Insulinoma-associated protein 1 (INSM1) is a transcription factor that functions in neuroepithelial tissue development and shows expression in neuroendocrine neoplasms. Given the role of INSM1 in controlling differentiation of the sympatho-adrenal lineage, we hypothesized that INSM1 expression would define a subset of neuroblastic tumors. This study aimed to characterize the immunohistochemical profile of INSM1 in a cohort of peripheral neuroblastic tumors and compare INSM1 expression in these tumors to that seen in other embryonal neoplasms, using both tissue microarrays and whole-slide histologic sections. INSM1 showed nuclear expression in 39/50 (78%) peripheral neuroblastic tumors, including 27/32 (84%) neuroblastomas, 9/9 (100%) ganglioneuroblastomas, and 3/9 (33%) ganglioneuromas. Altogether, 70% of peripheral neuroblastic tumors showed anti-INSM1 immunoreactivity in more than 20% of tumor nuclei. Although no non-neuroblastic tumors in this study exhibited INSM1 expression in more than 20% of nuclei, focal or patchy staining was identified in 7/14 (50%) rhabdomyosarcomas, 7/22 (32%) nephroblastomas, and 4/20 (20%) Ewing sarcomas. The absence of INSM1 expression in peripheral neuroblastic tumors was restricted to undifferentiated and poorly differentiated neuroblastomas, as well as mature ganglioneuromas, mimicking the transient INSM1 expression seen in sympatho-adrenal differentiation during normal development. No significant association between MYCN amplification status and INSM1 expression was observed. We found that all 3 INSM1-negative neuroblastoma patients with available follow-up were alive at a median of 15 years, in comparison to 9 of 13 INSM1-positive neuroblastoma patients living at a median of 5 years. Additional studies are needed to determine whether INSM1 expression is indicative of a clinically significant differentiation state in neuroblastoma.

Factors associated with local recurrence after surgery for bone metastasis to the extremities.

BACKGROUND AND OBJECTIVES: With increasing life expectancy of patients with bone metastasis, durable surgical stabilization of bone metastasis is necessary. Local recurrence (LR) can compromise surgical stabilization and necessitate retreatment. We analyzed LR rate and factors associated with LR in patients undergoing surgery for bone metastasis. METHODS: Patients (n = 301) who underwent surgery for bone metastasis to the extremities were reviewed. Possible factors that might be associated with LR were investigated. RESULTS: LR rate was 16% (49/301). Surgical margin was associated with LR, as patients with en-bloc resection had significantly less LR than patients who underwent curettage (5/66 vs 44/235, P = 0.03). Prostate cancer had lowest rate (0%) of LR and colon cancer had highest rate (31%). Interval from surgery to LR differed among primary cancer types (4.5 ± 3.9 months [lung cancer], vs 12.3 ± 12.9 months [other cancers], P = 0.041). In multivariate analysis, en-bloc surgical margins (HR = 0.372, P = 0.036) and primary cancers of breast or prostate (HR = 0.391, P = 0.049) were independent factors associated with longer LR-free survival. CONCLUSIONS: LR after surgery for bone metastasis to extremities is affected by surgical margin and primary cancer type. These factors, along with expected patient survival, need to be considered when planning surgery for bone metastasis to extremities.

Single-Stage Free Flap Reconstruction Following Extremity Sarcoma Resection: a Regional Cancer Center Experience.

Surgery remains mainstay modality of treatment of STS of extremity. In majority of patients, primary closure is possible following surgical resection of the tumor. Primary closure of wound may not be feasible in tumors with large area of skin involvement and sometimes following a whoops procedure. We analyzed postoperative complications and oncological outcomes in patients who underwent free flap reconstruction. Thirty-seven patients who required a free flap for reconstruction of the defect following resection of the STS were included in the study. There were 26 men and 11 women with a mean age of 40 years. Seventy-three percent tumors were in lower limb; 62% patients had undergone a whoops procedure elsewhere. Flaps were fasciocutaneous in 19, myocutaneous in 15, and free muscle transfers in 3 patients. Seventeen patients had early surgical site complications. Nine patients had early flap failures. Of the 9, 6 patients had total loss of flap and in 3 the flaps were salvaged. Two patients had partial loss (< 50% of total area) of flap. Four patients had edge necrosis and two had suture diastasis. Nine patients had late surgical site complications. Four had post-radiotherapy wound dehiscence. Late SSI was noted in two. Late joint contracture and chronic lymphedema was seen in one patient each. One died due to sepsis. Statistically significant association was not found between patient, tumor or treatment-related factors and complications or flap failures. Mean duration of surgery was 7.73 h. Twenty-three patients required multiple surgeries due to complications. Mean time to initiate adjuvant therapy from the date of surgery was 47 days. Mean OS of the group was 67 ± 7.3 months. Mean RFS was 58 ± 7.8 months. Single-stage free flap reconstruction following surgical resection of extremity sarcoma is a viable option of reconstruction while salvaging the limb. Though associated with high rate of early surgical site complications, they are manageable.

Single-Stage Combined Approach Sagittal En Bloc Spondylectomy for L3 Vertebral Chondrosarcoma: A Technical Note.

BACKGROUND: Primary malignant tumors of the spine are rare and most commonly occur in lumbar and thoracic vertebrae. We report a rare case of retroperitoneal chondrosarcoma of L3 that was managed with sagittal en bloc spondylectomy following chemoradiation. CASE DESCRIPTION: A 26-year-old woman was evaluated for abdominal pain with contrast-enhanced computed tomography of the abdomen and pelvis, which revealed a soft tissue retroperitoneal mass arising from L3. She underwent laparotomy and biopsy, which revealed chondrosarcoma, and she received chemoradiation over a period of 28 weeks 6 days. After repeat imaging, she underwent single-stage combined approach sagittal en bloc spondylectomy of retroperitoneal chondrosarcoma of L3 with right nephrectomy and spine reconstruction. At 3-year follow-up, there was no evidence of recurrence on contrast-enhanced computed tomography of the abdomen and pelvis. She demonstrated no gait abnormality or spinal deformity. CONCLUSIONS: Sagittal en bloc spondylectomy is a preferred surgical approach for eccentrically placed spinal tumors that offers better oncological and functional outcomes.

Factors that Impact the Outcomes in Ewing's Sarcoma: Experience from a Regional Cancer Center in Southern India.

Ewing's sarcoma family of tumors (EWSFT) is common in the second decade of life. Achieving good outcomes in EWSFT requires a multimodality approach. We report the clinico-pathological features, treatment, and survival outcomes of patients with EWSFT treated at our center. Patients diagnosed and treated for EWSFT at our center from 2009-2017 were included in this study. Data was collected from the patient's case records. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The study included 173 patients among whom 44 (25%) patients were metastatic at diagnosis. The median age of patients was 16 years. The most common site of the primary tumor was the pelvis (16.1%), followed by long bones. The median follow-up was 75 months and the 5-year EFS and OS were 43.7% and 45.1% respectively for the overall cohort whereas for the localized disease were 56.6% and 57.2% respectively. Metastatic disease, tumor volume > 200 ml, tumor diameter > 8 cm, pelvic site, hemoglobin < 10 gms%, elevated lactate dehydrogenase, positive margin, and necrosis less than 90% were significantly associated with inferior OS on univariate analysis. On multivariate analysis, metastasis disease, tumor diameter > 8 cm, and necrosis < 90% were significantly associated with inferior OS. Large tumors, advanced disease, and poor response to chemotherapy are associated with poor outcomes in EWSFT. Whether the use of dose-dense chemotherapy and/or autologous stem cell transplant would improve outcomes without increased toxicity in resource-limited settings needs to be explored. Supplementary Information: The online version contains supplementary material available at 10.1007/s13193-023-01817-6.

Distally Based Pedicled Fibula Flap for Reconstruction of Distal Tibia After Oncological Resection: A Case Series and Review of Literature.

Reconstruction of distal tibial defects pose a difficult challenge because the bone is subcutaneous and close to the tendons and neurovascular bundles. Distally based pedicled fibula with retrograde flow can be used for the reconstruction of distal tibial defects. This is based on the communicating branch of the peroneal artery to the posterior tibial artery. We present three cases of distal tibia primary tumours which were resected and reconstructed using recycled autograft plus distally based pedicled fibula and ankle arthrodesis. This pedicled retrograde fibula flap is a novel technique for the reconstruction of distal tibial defects after oncological resections. It provides a vascularized graft without the need for microvascular surgery and without violating the normal limb. Meticulous dissection of and preservation of the communicating branches between the peroneal artery and the posterior tibial artery with confirmation of retrograde flow before dividing the proximal peroneal pedicle is sine quo non for the success of this graft. This flap overcomes the drawback of the limited arc of rotation and limited reach of proximal pedicle-based flap for distal tibial reconstruction. Long-term functional outcomes, limb shortening associated with this flap, and its effect on functional outcomes remain to be ascertained.

Limb Salvage Surgery in a Rare Case of Recurrent Parosteal Osteosarcoma with Vascular Graft Thrombosis.

Recurrent parosteal sarcomas with vascular involvement are rare and present unique challenges in their diagnosis and management. We report the case of a 21-year-old woman with parosteal osteosarcoma of the left distal femur, encasing the popliteal vessels. En bloc transarticular resection of the distal femur and popliteal vessels was performed, followed by reconstruction using a modular prosthesis and a saphenous vein autograft for both the artery and vein. On the 1st postoperative day, the patient developed an arterial thrombus requiring reintervention with a jump polytetrafluoroethylene (PTFE) graft. Histopathology confirmed parosteal osteosarcoma. After a disease-free survival of 41 months, the patient experienced local recurrence involving the PTFE graft, leading to graft compression, erosion, and subsequent thrombosis. Despite these complications, limb salvage was possible due to adequate collateral blood supply. This case highlights the feasibility of limb salvage surgery in select cases of parosteal osteosarcoma with vascular involvement.

Neoadjuvant Chemotherapy with Laser Interstitial Thermal Therapy in Central Nervous System Neuroblastoma: Illustrative Case and Literature Review.

Primitive neuroectodermal tumors of the central nervous system, or CNS neuroblastoma, are rare neoplasms in children. Recently, methylation profiling enabled the discovery of four distinct entities of these tumors. The current treatment paradigm involves surgical resection followed by chemotherapy and radiation. However, upfront surgical resection carries high surgical morbidity in this patient population due to their young age, tumor vascularity, and often deep location in the brain. We report a case of CNS neuroblastoma that can be successfully treated with neoadjuvant chemotherapy followed by minimally invasive laser interstitial thermal therapy and radiation. The patient has complete treatment with no evidence of recurrence at one year follow-up. This case illustrates a potential paradigm shift in the treatment of these rare tumors can be treated using minimally invasive surgical approach to achieve a favorable outcome.

Study on prediction of arterio-venous fistula maturation by flow mediated dilatation and AVF blood flow.

BACKGROUND: The physiology and pathology of AVF maturation depends on the vessels characteristics and its ability to remodel. Outcome of AVF using flow mediated dilatation (FMD), AVF blood flow and diameter has been studied. METHODOLOGY: Present observational study included single stage AVF (both Radiocephalic and Brachiocephalic) in consecutive CKD five patients (n = 158) prospectively over 1 year. Demographic and Doppler ultrasound parameters of upper limb (for vessel diameter and FMD) at baseline were recorded. Blood flow, diameter and depth of AVF were studied at 2, 6 and 12 weeks and their association with clinical maturation (usage of fistula with two needles for 75% of dialysis sessions during 15 day period) was studied (n = 129, after excluding lost to followup and expired patients; accordingly cohort was divided in matured (M) or non-matured (NM) groups. Clinical and radiological parameters between both groups were compared; receiver operator curve (ROC) and correlation of Doppler parameters were analysed. RESULTS: Of 129 AVF, 67.4% were matured and 32.5% non-matured. Mean age was 40 years with male predominance75% in both the groups. The mean arterial diameter for distal (NM = 1.96 ± 0.58 and M = 2.02 ± 0.41) and proximal AVF (NM = 3.37 ± 0.82 and M = 3.36 ± 0.75) was not statistically different in both the groups. The matured fistula group had a mean FMD of 11.67 ± 4.09 as against FMD value of 9.365 ± 3.55 in the failed fistula group (p value 0.01). For maturation prediction, sensitivity and specificity of blood flow at 2 weeks were 86.2% and 59.5% and at 6 weeks 96.6% and 64.3%, respectively. In multivariate analysis predictors for AVF maturation were FMD (adjusted odds ratio (AOR) = 1.15) and blood flow (AOR = 1.67). CONCLUSION: Second and Sixth week AVF blood flow was found to be predicting AVF maturation. Higher baseline FMD correlated with the AVF maturation, but not with vessel diameter.

Stability analysis of vascular endothelial growth factor in cerebrospinal fluid.

Vascular endothelial growth factor (VEGF) is a promising biological marker and prognostic indicator in many neurological diseases. Although VEGF concentrations in plasma and cerebrospinal fluid (CSF) are increasingly reported, CSF-VEGF stability pre- and during-assay procedures is seldom evaluated. In the current study, we investigated VEGF variability and stability in CSF related to sample preparation, storage, and routine experimental procedures. Results showed that contaminant cell breakdown or aggregation can occur gradually before sample processing. However, after the removal of contaminant cell components, CSF-VEGF levels did not show significant changes in samples incubated at room temperature for 5 h, thawed/refrozen for 6 cycles. Samples preserved at -80 °C for up to 7 years continued to show measurable levels. Since some cellular components such as platelets contain a large amount of releasable VEGF, we conclude that CSF samples should be processed as soon as possible to carefully remove all cellular components and prevent possible consequent release of VEGF into CSF. After centrifugation to remove cellular contents, VEGF in CSF was relatively stable during routine experimental procedures and storage.

Clinical presentation and urachal remnant pathology: implications for treatment.

PURPOSE: Symptomatic pediatric urachal remnants are frequently excised but to our knowledge it is unknown whether incidentally identified urachal remnants require removal. Urachal remnant excision in childhood is advocated to avoid future malignancy. Urachal anomalies that contain fibrostromal tissue without epithelium may have lower malignant potential and not require excision. In contrast, lesions with epithelium may have increased potential to undergo malignant transformation. We examined whether incidentally identified urachal remnants would be less likely to contain epithelial elements and not require removal. MATERIALS AND METHODS: At our institution 29 patients underwent surgical excision of a urachal anomaly from 1999 to 2008. We retrospectively investigated the presentation mode, radiographic findings, associated genitourinary abnormalities, operative approach, tissue pathology, complications and followup in each patient. RESULTS: The male-to-female ratio was 1.2:1. Patient presentation was incidental (5) or symptomatic (24). Symptomatic presentations included umbilical discharge without omphalitis in 13 cases, umbilical discharge with omphalitis in 7, omphalitis without umbilical discharge in 3 and urinary tract infection in 1. The epithelial types identified were transitional, gastrointestinal, squamous, metaplastic and mixed. Epithelium was present on pathological analysis in 3 of 5 patients who presented incidentally and in 17 of 24 who presented symptomatically. Statistical analysis showed no association between presentation mode and pathology (p = 0.63). Five patients 4 weeks to 2.5 months old had vesicoureteral reflux on voiding cystourethrogram for urachal remnant evaluation. CONCLUSIONS: Analysis of 29 patients with urachal anomalies showed no association between incidental presentation and fibrostromal pathology. Patients presenting without symptoms were as likely to have epithelial elements in the urachal remnant as those presenting with symptoms. We could not define treatment recommendations for incidentally identified urachal remnants based on predicting the histopathological composition.

Guidelines for synoptic reporting of surgery and pathology in Hirschsprung disease.

BACKGROUND/PURPOSE: Synoptic, or standardized, reporting of surgery and pathology reports has been widely adopted in surgical oncology. Patients with Hirschsprung disease may experience morbidity related to surgical factors or underlying pathology and often undergo multiple operations. Our aim is to improve the postoperative outcome and care of patients with Hirschsprung disease by proposing a standardized set of data that should be included in every surgery and pathology report. METHODS: Members of the American Pediatric Surgical Association Hirschsprung Disease Interest Group and experts in pediatric pathology of Hirschsprung disease participated in group discussions, performed literature review and arrived at expert consensus guidelines for surgery and pathology reporting. RESULTS: The importance of accurate operative and pathologic reports and the implications of inadequate documentation in patients with Hirschsprung disease are discussed and guidelines for standardizing these reports are provided. CONCLUSIONS: Adherence to the principles of reporting for operations and surgical pathology may improve outcomes for Hirschsprung disease patients and will facilitate identification of correlations among morphology, function, genetics and outcomes, which are required to improve the overall management of these patients. LEVEL OF EVIDENCE: V.

Desmoplastic Infantile Ganglioglioma: A MAPK Pathway-Driven and Microglia/Macrophage-Rich Neuroepithelial Tumor.

MAPK pathway activation has been recurrently observed in desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) with reported disproportionally low mutation allele frequencies relative to the apparent high tumor content, suggesting that MAPK pathway alterations may be subclonal. We sought to expand the number of molecularly profiled cases and investigate if tumor cell composition could account for the observed low mutation allele frequencies. Molecular (targeted neuro-oncology next-generation sequencing/RNA sequencing and OncoScan microarray) and immunohistochemical (CD68-PGM1/CD163/CD14/CD11c/lysozyme/CD3/CD20/CD34/PD-L1) studies were performed in 7 DIG. Activating MAPK pathway alterations were identified in 4 (57%) cases: 3 had a BRAF mutation (V600E/V600D/V600_W604delinsDQTDG, at 8%-27% variant allele frequency) and 1 showed a TPM3-NRTK1 fusion. Copy number changes were infrequent and nonrecurrent. All tumors had at least 30% of cells morphologically and immunophenotypically consistent with microglial/macrophage lineage. Two subtotally resected tumors regrew; 1 was re-excised and received adjuvant treatment (chemotherapy/targeted therapy), with clinical response to targeted therapy only. Even with residual tumor, all patients are alive (median follow-up, 83 months; 19-139). This study further supports DIG as another MAPK pathway-driven neuroepithelial tumor, thus expanding potential treatment options for tumors not amenable to surgical cure, and suggests that DIG is a microglia/macrophage-rich neuroepithelial tumor with frequent low driver mutation allele frequencies.