Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients.

BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.

Access to innovative medicines for metastatic melanoma worldwide: Melanoma World Society and European Association of Dermato-oncology survey in 34 countries.

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found.

Prognosticating metastatic osteosarcoma treated with uniform chemotherapy protocol without high dose methotrexate and delayed metastasectomy: a single center experience of 102 patients.

PURPOSE: Data on prognostic factors in patients with metastatic osteosarcoma treated with uniform chemotherapy protocol are lacking. The objective of this study was to analyze demographic data, treatment outcome and prognostic factors for patients with metastatic osteosarcoma at our center treated with a uniform chemotherapy protocol without high dose methotrexate. METHODS: This is a single-institutional data review of patients treated between June 2003 and December 2012 with neoadjuvant chemotherapy, local site surgery followed by adjuvant chemotherapy and metastasectomy at completion of adjuvant chemotherapy. RESULTS: 102 patients of metastatic osteosarcoma were treated with a median age of 18 years (range 8-48 years), male to female ratio of 3.3:1 and median symptom duration of 4 months. EFS and OS at 5 years were 12.7 ± 0.1 and 28.1 ± 0.1 %, respectively. On multivariate analysis, elevated serum alkaline phosphatase (p < 0.001) and number of metastasis >3 (p = 0.04) were predictive of lower EFS, whereas elevated serum alkaline phosphatase (p = 0.01), number of metastasis >3 (p = 0.05), and margin positivity (p < 0.001) were predictive of lower OS. CONCLUSIONS: This is the largest data on metastatic osteosarcoma treated with a uniform chemotherapy protocol without high dose methotrexate. The data showed prognostic factors similar to what have been observed previously such as elevated serum alkaline phosphatase and >3 metastatic lesions in lung predicting inferior outcome. Notably our survival was comparable to data from other studies despite our practice of delaying metastasectomy to completion of chemotherapy rather than performing the same along with local site surgery.

Prognostic factors affecting survival in metastatic soft tissue sarcoma: an analysis of 110 patients.

BACKGROUND: Data on treatment outcome and prognostic factors in patients with metastatic soft tissue sarcoma (STS) are limited in the literature. METHODS: A total of 119 patients with metastatic STS treated between June 2003 and December 2012 were analyzed for treatment outcome and prognostic factors. RESULTS: Median age was 37 years (range 2-72 years) with a male to female ratio of 1.5:1. Most common histologic subtypes were synovial sarcoma (36 %) and leiomyosarcoma (16 %). Median tumor size was 12 cm (range 1.6-30 cm). Twenty-four (20 %) patients were treated with multimodality therapy and 80 % patients received systemic chemotherapy alone. At a median follow-up of 10 months (range 1-66 months), the 2-year EFS and OS were 10 and 19 %, respectively, with a median EFS and OS of 6 and 10 months, respectively. Univariate analysis identified albumin ≤4 g/dl (p = 0.001), histologic subtypes other than synovial sarcoma (p = 0.02), non-extremity tumors (p = 0.03) and single modality treatment (p = 0.03) as factors predicting poor EFS; however, for OS, hemoglobin ≤10 g/dl (p = 0.02), tumor size >10 cm (p = 0.01) and single modality treatment (p = 0.04) were identified as poor prognostic factors. Multivariate analysis identified only serum albumin ≤4 g/dl (p = 0.002, HR 0.47, 95 % CI 0.29-0.75) associated with poor EFS; however, for OS, hemoglobin ≤10 g/dl (p = 0.009, HR 0.49, 95 % CI 0.29-0.83), tumor size >10 cm (p = 0.003, HR 2.11, 95 % CI 1.28-3.47) and single modality treatment (p = 0.01, HR 0.47, 95 % CI 0.25-0.86) emerged as poor prognostic factors. CONCLUSIONS: Serum albumin, tumor size, hemoglobin and treatment modality affect survival in metastatic STS.

A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma.

BACKGROUND: The efficacy and safety of nab-paclitaxel versus dacarbazine in patients with metastatic melanoma was evaluated in a phase III randomized, controlled trial. PATIENTS AND METHODS: Chemotherapy-naïve patients with stage IV melanoma received nab-paclitaxel 150 mg/m(2) on days 1, 8, and 15 every 4 weeks or dacarbazine 1000 mg/m(2) every 3 weeks. The primary end point was progression-free survival (PFS) by independent radiologic review; the secondary end point was overall survival (OS). RESULTS: A total of 529 patients were randomized to nab-paclitaxel (n = 264) or dacarbazine (n = 265). Baseline characteristics were well balanced. The majority of patients were men (66%), had an Eastern Cooperative Oncology Group status of 0 (71%), and had M1c stage disease (65%). The median PFS (primary end point) was 4.8 months with nab-paclitaxel and 2.5 months with dacarbazine [hazard ratio (HR), 0.792; 95.1% confidence interval (CI) 0.631-0.992; P = 0.044]. The median OS was 12.6 months with nab-paclitaxel and 10.5 months with dacarbazine (HR, 0.897; 95.1% CI 0.738-1.089; P = 0.271). Independently assessed overall response rate was 15% versus 11% (P = 0.239), and disease control rate (DCR) was 39% versus 27% (P = 0.004) for nab-paclitaxel versus dacarbazine, respectively. The most common grade ≥3 treatment-related adverse events were neuropathy (nab-paclitaxel, 25% versus dacarbazine, 0%; P < 0.001), and neutropenia (nab-paclitaxel, 20% versus dacarbazine, 10%; P = 0.004). There was no correlation between secreted protein acidic and rich in cysteine (SPARC) status and PFS in either treatment arm. CONCLUSIONS: nab-Paclitaxel significantly improved PFS and DCR compared with dacarbazine, with a manageable safety profile.

RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: The open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/BEV) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Previously untreated patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with either everolimus 10 mg/day (EVE/BEV) or interferon (9 MIU 3 times/week, if tolerated) (IFN/BEV). Tumor assessments occurred every 12 weeks. The primary objective was the assessment of treatment effect on progression-free survival (PFS), based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). RESULTS: Baseline characteristics were balanced between the EVE/BEV (n = 182) and IFN/BEV (n = 183) arms. The median PFS was 9.3 and 10.0 months in the EVE/BEV and IFN/BEV arms, respectively (P = 0.485). The predicted probability of phase III success was 5.05% (hazard ratio = 0.91; 95% confidence interval 0.69-1.19). The median duration of exposure was 8.5 and 8.3 months for EVE/BEV and IFN/BEV, respectively. The percentage of patients discontinuing because of adverse events (AEs) was 23.4% for EVE/BEV and 26.9% for IFN/BEV. Common grade 3/4 AEs included proteinuria (24.4%), stomatitis (10.6%), and anemia (10.6%) for EVE/BEV and fatigue (17.1%), asthenia (14.4%), and proteinuria (10.5%) for IFN/BEV. The median overall survival was 27.1 months in both arms. CONCLUSIONS: The efficacy of EVE/BEV and IFN/BEV appears similar. No new or unexpected safety findings were identified and, with the exception of proteinuria in about one-fourth of the population, EVE/BEV was generally well tolerated. CLINICAL TRIAL REGISTRY AND TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00719264.

Developing a prognostic model for localized Ewing sarcoma family of tumors: A single institutional experience of 224 cases treated with uniform chemotherapy protocol.

BACKGROUND: Data on patients with localized Ewing sarcoma family of tumors (ESFT) who have received a uniform chemotherapy protocol are minimal. METHODS: This is a single institutional review of patients with ESFT treated between June 2003 and November 2011. RESULTS: 224/374 (60%) patients with ESFT presented with localized disease; median age was 15 years (range: 0.1-55). Ninety-nine patients underwent surgery of which 50 received adjuvant radiotherapy; 80 patients received radical radiotherapy following neoadjuvant chemotherapy. At median follow-up of 40.2 months (range: 1.3-129), 5-year EFS, OS, and local-control-rate, were 36.8 ± 3.6%, 52.4 ± 4.3%, and 63 ± 4.3%, respectively. In multivariate analysis, tumor diameter > 8 cm (P = 0.03), symptom duration > 4 months (P = 0.04), and WBC > 11 × 10(9) /L (P = 0.003) predicted inferior EFS; spine/abdomino-pelvic primary (P = 0.009) and WBC > 11 × 10(9) /L (P = 0.003) predicted inferior OS. Tumor size > 8 cm (P = 0.03) and radical radiotherapy as local treatment (P = 0.01) predicted inferior local-control-rate. CONCLUSION: Prognostic hazard models for EFS and OS based on significant prognostic factors suggested that patients with combination of ESFT of spine/abdomino-pelvic region and baseline WBC > 11 × 10(9) /L had inferior OS (hazard ratio 4.44, P < 0.001) while patients with combination of ESFT with symptom duration > 4 months, tumor diameter > 8 m and baseline WBC > 11 × 10(9) /L had inferior EFS (hazard ratio 3.89, P = 0.002).

Hypoalbuminaemia is an independent predictor of poor outcome in metastatic Ewing's sarcoma family of tumours: a single institutional experience of 150 cases treated with uniform chemotherapy protocol.

AIMS: Data on metastatic Ewing's sarcoma family of tumours (ESFT) with uniform chemotherapy protocol are minimal. MATERIALS AND METHODS: This was a single institutional patient review of patients treated between June 2003 and November 2011 and evaluated on an intent-to-treat analysis. All patients received uniform chemotherapy: neoadjuvant chemotherapy (NACT), surgery and/or radiotherapy as local treatment followed by adjuvant chemotherapy. Local treatment was offered if the patient achieved a complete response and/or a partial response at both the primary and the metastatic site. RESULTS: In total, 150/374 (40%) ESFT patients were metastatic, with a median age of 15 years (range: 2-50); a tumour diameter of 10 cm (range: 1.8-26). Most common metastatic sites were lung only (53; 35%), bone only (35; 23%) and combined bone/lung (25; 17%). Twenty patients underwent surgery; 55 patients received radical radiotherapy after NACT. After a median follow-up of 26.1 months (range: 1.6-101.6), 5 year event-free survival (EFS), overall survival and local control rate (LCR) were 9.1 ± 3.3%, 16.9 ± 5.2% and 31.8 ± 7.9%, respectively. Univariate analysis showed serum albumin ≤3.4 g/dl (P < 0.001) to predict inferior EFS. Tumour size >8 cm (P = 0.05), haemoglobin ≤10 g/dl (P = 0.04), hypoalbuminaemia (P = 0.003) and radical radiotherapy as local treatment (P = 0.03) predicted inferior overall survival. No factor significantly predicted LCR, although age ≤15 years (P = 0.08) and radical radiotherapy as local treatment (P = 0.09) had a trend towards inferior LCR. Hypoalbuminaemia was the only prognostic factor to predict EFS on multivariate analysis. CONCLUSION: This was the largest study of metastatic ESFT from Asia and identified a unique prognostic factor. In view of dismal prognosis with conventional chemotherapy in metastatic ESFT with hypoalbuminaemia, palliative intent therapy may be a potential therapeutic alternative for this subgroup of patients, especially in resource-challenged situations.

Liver histology in choledochal cyst- pathological changes and response to surgery: the overlooked aspect?

BACKGROUND: Histological changes in the liver in cases of choledochal cyst are seldom reported. The severity of liver pathology has an impact on the presentation, course and prognosis of hepatobiliary lesions. This study aims to record the histological changes in the liver and response to surgery in patients with choledochal cyst and to correlate these with the clinical symptoms and recovery. MATERIALS AND METHODS: All children <12 years diagnosed with choledochal cyst were evaluated clinically, radiologically and biochemically at presentation. Excision of the cyst with intra-operative liver biopsy was done. Liver biopsy was repeated after 6 months of surgery. Both the liver biopsies were compared objectively in terms of hepatocellular damage, cholestasis, parenchymal inflammation, bile duct inflammation, bile duct proliferation, portal fibrosis and central venous distension with appropriate statistical tests. Clinical presentation and recovery were correlated with grades of liver pathology. RESULTS: Forty-six patients were included. Pathological damage was observed in all the livers preoperatively. Post-operatively, significant resolution of histological changes was seen in hepatocellular damage (p < 0.0001), parenchymal inflammation (p = 0.0001), cholestasis (p = 0.0003) and bile duct proliferation (p = 0.0001). Portal fibrosis did not resolve. Central venous distension worsened. Severity of damage correlated significantly with younger age, symptom severity, anomalous pancreatico-biliary junction (APBJ) and obstructive biliary clearance on Tc-99 HIDA scan. Post-operative bile duct proliferation, bile duct inflammation and portal fibrosis were associated with cholangitis, re-do surgery and obstructive Tc-99 HIDA scan clearance in the post-operative period. CONCLUSIONS: All patients with choledochal cyst show pathological changes in liver of varying severity. More severe symptoms, younger age and APBJ are associated with higher degree of liver damage. Except portal fibrosis and central venous distension, all other pathological changes regress after surgery. Regression can be hindered by post-op cholangitis, obstructive biliary clearance and post-op IHBR dilatation.

Effect of stem cells on renal recovery in rat model of partial unilateral upper ureteric obstruction.

BACKGROUND: Untreated obstructive uropathy produces irreversible renal damage and is an important cause of pediatric renal insufficiency. This study was designed to evaluate the effects of stem cell injection on morphological and pathological changes in the rat kidneys with partial unilateral upper ureteric obstruction (PUUUO). METHODS: Wistar rats (n = 30) were operated upon to create a PUUUO by the psoas hitch method and were randomized into Group I (control, n = 15) and Group II (stem cell, n = 15); at day 5, 10 and 15, a subgroup of rats (n = 5) from each group was killed and the kidneys harvested. Pathological and morphological changes in the harvested kidneys were studied and compared between the two groups. RESULTS: Morphologically, at day 15, Group II had significantly (p = 0.04) greater cortical thickness (0.48 ± 0.17 vs. 0.38 ± 0.09 mm). Histologically, at day 5, Group II had significantly (p = 0.032) lower peri-pelvic fibrosis. Group II group showed greater peri-pelvic inflammation as compared to Group I (p = 0.05). At day 10, lower grades of peri-pelvic fibrosis (p = 0.08), interstitial fibrosis (p = 0.037) and tubular atrophy (p = 0.05) were seen in the Group II. At day 15, Group II demonstrated significantly lower parenchymal loss (p = 0.037), glomerulosclerosis (p = 0.08), interstitial fibrosis (p = 0.08), tubular atrophy (p = 0.08) and peri-pelvic fibrosis (p = 0.08). CONCLUSIONS: In a rat model of PUUUO, stem cell injection prevented detrimental changes in renal pathology and preserved renal parenchymal mass.

An unusual cause of reversible axonal neuropathy and hypertension in a 10-year-old girl.

A 10-year-old girl, who was referred with refractory epilepsy, had 1.5 years of episodic abnormal behavior. On examination, she also had hypertension and peripheral neuropathy. Hypoglycemia with correspondingly high insulin levels was documented during a confusional episode. MRI of the abdomen revealed an islet cell tumor in the body of the pancreas. One year after tumor excision, both the neuropathy and hypertension showed remarkable improvement. A final diagnosis of insulinoma with hypoglycemic axonal neuropathy and hypertension (reversed with tumor excision) was made. Insulinoma is the commonest cause of hyperinsulinemic hypoglycemia in adults, but is rare in childhood. To our knowledge, distal symmetrical motor-sensory axonal neuropathy has been described in only 40 patients, and hypertension has not been reported with insulinoma.

Loss of heterozygosity on chromosome 11p15.5 and relapse in hepatoblastomas.

BACKGROUND: IGF2 is a tumor suppressor gene at locus 11p15. Many hepatoblastomas have loss of heterozygosity (LOH) at this locus. Earlier studies have not demonstrated any association between LOH and prognosis. Aim of the study was to evaluate the prognostic significance of LOH at 11p15.5 in hepatoblastomas. METHODS: DNA was isolated from normal liver and tumor tissue in 20 patients with hepatoblastoma. PCR was performed and cases were classified as LOH present, absent or non-informative. Patients' follow-up data was analyzed using Fischer's exact test and Kaplan-Meier survival analysis for relapse-free survival (RFS) in relation to LOH. Ethical clearance was obtained from the institutional ethics board. RESULTS: All cases were informative for at least one microsatellite marker used. 4 of the 20 cases (20%) had LOH at 11p15.5. One patient died in the immediate postoperative period. 5 of 19 patients relapsed (26%). Of 4 patients who had LOH, 3 (75%) relapsed, the time to relapse being 7, 7 and 9 months, respectively. Of the 15 cases without LOH, 2 (13.3%) relapsed. 4 patients had mixed epithelial and mesenchymal histology; 3 of them had LOH. The 2 groups with and without LOH were well matched. The RFS for patients with LOH (n=4) was 13% (mean survival time [MST]: 8.7 months; 95CI 6.7-10.7), while the RFS for cases without LOH (n=15) was 75% (MST: 100.7 months; 95CI 74.5-126.8). CONCLUSION: Mixed epithelial and mesenchymal histology is more frequently associated with LOH on chromosome 11p15.5 than pure epithelial histology. LOH on chromosome 11p15.5 is associated with a significantly increased incidence of relapse and a significantly shorter relapse-free survival in patients with hepatoblastoma. The risk of relapse is higher and the RFS lower both in standard-risk and high-risk patients with hepatoblastoma if they demonstrate the presence of LOH at 11p15.5.

Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma.

BACKGROUND: Docosahexaenoic acid-paclitaxel (DHA-paclitaxel, Taxoprexin(®)) is made by covalently conjugating the essential fatty acid DHA to the paclitaxel molecule. Preclinical studies of DHA-paclitaxel have demonstrated increased activity relative to paclitaxel and the potential for an improved therapeutic ratio. In the present study, the efficacy and toxicity profiles of DHA-paclitaxel were compared with those of dacarbazine. METHODS: In this study, 393 chemonaive patients with metastatic melanoma were randomly assigned to receive either DHA-paclitaxel at a starting dose of 900 mg/m(2) IV on day 1 every 3 weeks or dacarbazine at a starting dose of 1000 mg/m(2) IV on day 1 every 3 weeks. The primary end point of the study was the comparison of overall survival (OS). RESULTS: No significant difference in OS was noted between patients in the DHA-paclitaxel and dacarbazine arms. Similarly, there were no significant differences in response rate, duration of response, time to progression, and time to treatment failure between the two drugs. Safety results of the two drugs were as predicted from prior studies. Myelosuppression was more common with DHA-paclitaxel. CONCLUSIONS: DHA-paclitaxel was not superior to dacarbazine. We conclude that further studies with the drug on an every 3-week schedule in melanoma are not warranted.

The cytomorphologic spectrum of Wilms tumour on fine needle aspiration: a single institutional experience of 110 cases.

OBJECTIVE: To analyse the cytomorphologic spectrum of Wilms tumour (WT) on aspirates, the largest series reported to date. STUDY DESIGN: Adequate aspirates from paediatric renal tumours over a period of 17 years were reviewed and selected if subsequent excision showed WT or aspirates were diagnostic for WT and clinical/radiological evidence consistent with that diagnosis. Smears were re-examined for the proportion of components, degree of pleomorphism and mitosis. RESULTS: Of 110 aspirates, smears were triphasic in 44 (40.0%), biphasic (blastema and tubules) in 36 (32.7%) and monophasic (blastema alone) in 30 (27.3%). Stromal predominance was seen in 11 aspirates (10.0%) and five showed rhabdomyoblastic differentiation; all 11 were triphasic. Mean mitotic rate was 9.3/5000 cells (range 4-39/5000). Nuclear atypia not amounting to anaplasia and without atypical mitoses was seen in 15 (13.6%); these presented diagnostic problems. Two aspirates (1.8%) were considered anaplastic (unfavourable), both having atypical mitoses. Criteria similar to histology (i.e. 3-fold or more variation in nuclear size, marked hyperchromasia with bizarre nuclei and atypical mitoses in a biphasic or triphasic aspirate) helped in distinguishing anaplastic WT. Histopathological correlation in 67 cases showed good correlation of blastemal predominance, stromal predominance and anaplastic histology with the corresponding cytology. However, 9/27 (33.3%) triphasic tumours had only blastemal cells on corresponding aspiration because of sampling error. Cytokeratin was positive in 4 of 20 aspirates with blastema alone. CONCLUSIONS: Aspirates from WT were triphasic or biphasic in the majority (72.7%), permitting cytological diagnosis, which was improved by cytokeratin immunocytochemistry. Blastemal and stromal predominance on histology correlated well with cytology, but many triphasic tumours showed only blastema on aspiration. Anaplastic WT can be detected on aspirates using criteria similar to histology.

Recent advances in the management of congenital diaphragmatic hernia.

The management of congenital diaphragmatic hernia (CDH) is undergoing continual change and refinement, fuelled by recent advances in this field. Although many studies have documented the benefits of these recent advances but definite recommendations are lacking. Also, injudicious use of some of these strategies may be counterproductive, underscoring the importance of evidence based treatment strategy. This article discusses the utility of the recent advances in the management of CDH.

Fine needle aspiration cytology of infantile haemangioendothelioma of the liver: a report of two cases.

BACKGROUND: Fine needle aspiration cytology (FNAC) of infantile haemangioendothelioma of the liver (IHL) has not previously been described because routine use of FNAC is contraindicated due to the risk of bleeding. METHODS AND MATERIALS: Two patients presented with progressively increasing right upper quadrant abdominal mass. The index case was a girl aged two and a half years with a large single mass in the right lobe of the liver. The second was a 3-month-old girl in whom ultrasonography revealed multiple hypoechoic lesions in the liver. Ultrasound-guided fine needle aspiration had been performed on both patients. May-Grünwald-Giemsa stained smears from these two patients were reviewed and correlated with histopathology. RESULTS: Both aspirates showed predominantly normal hepatocytes and bile ductules amongst which tumour cells were admixed. The latter were oval to spindle-shaped with scant cytoplasm and wavy, kinked and indented nuclear outlines. The non-epithelial character of the tumour cells was apparent and helped to rule out hepatoblastoma. One case showed extramedullary haemopoiesis. The diagnosis of IHL was established on subsequent excision in the first case and a wedge biopsy in the second case. CD34 and factor VIII R antigen were positive in the tumour cells. CONCLUSION: Radiological diagnosis of IHL is possible in a majority of cases, but sometimes features may overlap with hepatoblastoma and fine needle aspiration may be performed inadvertently. Characteristic kinked nuclei and intermixed normal liver tissue might suggest IHL in the differential diagnosis of a spindle cell vasoformative tumour.