Ensuring no patient is lost along the way - a single-centre experience of the clinical genetics referral pathways for Lynch syndrome.

Lynch syndrome (LS), caused by heterozygous germline mutation in one of the key mismatch repair (MMR) genes, is the primary cause of inherited colorectal cancer (CRC). LS also increases susceptibility to several other cancers. It is estimated that just 5% of patients with LS are aware of their diagnosis. Therefore, in an attempt to increase the identification of cases within the UK population, the 2017 NICE guidelines recommend offering immunohistochemistry for MMR proteins or microsatellite instability (MSI) testing to all people with CRC when first diagnosed. Following identification of MMR deficiency, eligible patients should be assessed for underlying causes, including potential referral to the genetics service and/or germline LS testing (if appropriate). In our regional centre for CRC, we audited local pathways to identify what proportion of patients are being correctly referred, in line with national guidelines. Reflecting on these results, we highlight our practical concerns by identifying the pitfalls and issues faced with the recommended referral pathway. We also propose possible solutions to improve the efficacy of the system for both referrers and patients. Finally, we discuss the ongoing interventions that national bodies and regional centres are implementing to improve and further streamline this process.

Prospective molecular and morphological assessment of testicular prepubertal-type teratomas in postpubertal men.

In 2016, the World Health Organization classification system of testicular tumors included the new entity prepubertal-type teratoma based on its morphological and molecular profile, and the realization that these tumors may occur in postpubertal men. For treatment and prognostic purposes, it is important to distinguish prepubertal-type teratoma from the usual postpubertal-type teratoma, because the former is benign unlike the latter. The distinction may be challenging. In this study, we investigated clinical, morphological, and molecular criteria for distinguishing prepubertal-type teratoma from postpubertal-type teratoma in a prospective series of pure testicular teratomas. All cases of pure teratoma in postpubertal men assessed at Barts Health NHS Trust or in consultation since the introduction of routine investigation of chromosome 12p status in 2010 were reviewed. Morphological features suggestive of prepubertal-type teratoma were observed in 14 out of 35 cases. All underwent molecular testing and none displayed 12p amplification. Mean tumor size was 16 mm (range 7-28 mm). None had associated germ cell neoplasia in situ or significant atrophy. Four incorporated a well-differentiated neuroendocrine tumor, 1-2 mm in size. Of the ten patients with follow-up information, none have recurred or metastasized. Twenty-one of the 35 cases were diagnosed as postpubertal-type teratoma, mean tumor size 40 mm (range 6-90 mm). One case underwent molecular testing: a tumor of pure skeletal muscle differentiation and possessed 12p amplification. Three cases presented with clinical metastases. Eight cases contained immature areas, ten cases had associated germ cell neoplasia in situ, and 17 cases had severe atrophy of the parenchyma. One case with neither germ cell neoplasia in situ nor atrophy showed necrosis. We conclude that both morphological and molecular features are of help in differentiating prepubertal-type teratoma from postpubertal-type teratoma. In nearly all postpubertal-type teratomas, molecular testing was unnecessary, and merely confirmed the morphological impression in the prepubertal-type teratomas. Our study confirmed the high incidence of well-differentiated neuroendocrine tumors in the prepubertal-type.

Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo.

The strategy of enzymatic degradation of amino acids to deprive malignant cells of important nutrients is an established component of induction therapy of acute lymphoblastic leukemia. Here we show that acute myeloid leukemia (AML) cells from most patients with AML are deficient in a critical enzyme required for arginine synthesis, argininosuccinate synthetase-1 (ASS1). Thus, these ASS1-deficient AML cells are dependent on importing extracellular arginine. We therefore investigated the effect of plasma arginine deprivation using pegylated arginine deiminase (ADI-PEG 20) against primary AMLs in a xenograft model and in vitro. ADI-PEG 20 alone induced responses in 19 of 38 AMLs in vitro and 3 of 6 AMLs in vivo, leading to caspase activation in sensitive AMLs. ADI-PEG 20-resistant AMLs showed higher relative expression of ASS1 than sensitive AMLs. This suggests that the resistant AMLs survive by producing arginine through this metabolic pathway and ASS1 expression could be used as a biomarker for response. Sensitive AMLs showed more avid uptake of arginine from the extracellular environment consistent with their auxotrophy for arginine. The combination of ADI-PEG 20 and cytarabine chemotherapy was more effective than either treatment alone resulting in responses in 6 of 6 AMLs tested in vivo. Our data show that arginine deprivation is a reasonable strategy in AML that paves the way for clinical trials.

Phase 1, pharmacogenomic, dose-expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1-deficient non-squamous non-small cell lung cancer.

INTRODUCTION: We evaluated the arginine-depleting enzyme pegargiminase (ADI-PEG20; ADI) with pemetrexed (Pem) and cisplatin (Cis) (ADIPemCis) in ASS1-deficient non-squamous non-small cell lung cancer (NSCLC) via a phase 1 dose-expansion trial with exploratory biomarker analysis. METHODS: Sixty-seven chemonaïve patients with advanced non-squamous NSCLC were screened, enrolling 21 ASS1-deficient subjects from March 2015 to July 2017 onto weekly pegargiminase (36 mg/m2 ) with Pem (500 mg/m2 ) and Cis (75 mg/m2 ), every 3 weeks (four cycles maximum), with maintenance Pem or pegargiminase. Safety, pharmacodynamics, immunogenicity, and efficacy were determined; molecular biomarkers were annotated by next-generation sequencing and PD-L1 immunohistochemistry. RESULTS: ADIPemCis was well-tolerated. Plasma arginine and citrulline were differentially modulated; pegargiminase antibodies plateaued by week 10. The disease control rate was 85.7% (n = 18/21; 95% CI 63.7%-97%), with a partial response rate of 47.6% (n = 10/21; 95% CI 25.7%-70.2%). The median progression-free and overall survivals were 4.2 (95% CI 2.9-4.8) and 7.2 (95% CI 5.1-18.4) months, respectively. Two PD-L1-expressing (≥1%) patients are alive following subsequent pembrolizumab immunotherapy (9.5%). Tumoral ASS1 deficiency enriched for p53 (64.7%) mutations, and numerically worse median overall survival as compared to ASS1-proficient disease (10.2 months; n = 29). There was no apparent increase in KRAS mutations (35.3%) and PD-L1 (<1%) expression (55.6%). Re-expression of tumoral ASS1 was detected in one patient at progression (n = 1/3). CONCLUSIONS: ADIPemCis was safe and highly active in patients with ASS1-deficient non-squamous NSCLC, however, survival was poor overall. ASS1 loss was co-associated with p53 mutations. Therapies incorporating pegargiminase merit further evaluation in ASS1-deficient and treatment-refractory NSCLC.

Nonteratoid Medulloepithelioma Presenting in a 78-Year-Old Male.

BACKGROUND: Medulloepithelioma is a rare congenital neoplasm derived from precursors of the nonpigmented ciliary epithelium of the ciliary body. The average patient age at clinical presentation is 3.8 years. CASE PRESENTATION: We present the case of a 78-year-old male with progressive lens subluxation and ocular hypertension who was found to have a ciliary body mass. After enucleation for presumed ciliary body melanoma, histopathology showed a nonteratoid medulloepithelioma. Cytogenetic analysis revealed abnormalities in chromosomes 3 and 8. CONCLUSION: Medulloepithelioma is often initially misdiagnosed. Though congenital in nature, it can exhibit rapid growth, have chromosomal abnormalities, and must be considered in all age groups.

Metabolic activity of primary uveal melanoma on PET/CT scan and its relationship with monosomy 3 and other prognostic factors.

PURPOSE: To correlate the metabolic activity of primary uveal melanoma on positron emission tomography (PET)/CT scan with known clinical and pathological prognostic factors. METHODS: A retrospective cohort analysis of eyes enucleated for uveal melanoma that underwent preoperative imaging with a PET/CT scan was performed. Tumour dimensions were recorded and classified using Collaborative Ocular Melanoma Study (COMS) and American Joint Committee on Cancer (AJCC) Tumour - Nodes - Metastases (TNM) criteria. Metabolic activity was determined by measurement of the maximal standardised uptake value (SUVmax) on PET/CT scans. SUVmax of >2.5 and >4 was also used as cut-off value for metabolic positivity. Chromosome 3 and 8 status was determined using fluorescence in situ hybridisation analysis. Pearson correlation, χ(2) test and non-parametric tests were used. p<0.05 was considered statistically significant. RESULTS: Seventy-six uveal melanomas were imaged preoperatively with a PET/CT scan. Overall 92% of tumours had a SUVmax >2.5 and 67% had a SUVmax >4. Monosomy 3 was found in 35 melanomas, of which 94% had an SUVmax >2.5 and 80% had an SUVmax >4. Only 57% of disomy 3 melanomas had an SUVmax >4. SUVmax was significantly increased in tumours with monosomy 3 (p=0.043) but not in tumours with chromosome 8 gain (p=0.49). SUVmax and increasing tumour size were positively correlated (p<0.05). Using the AJCC criteria, there was a significant difference in SUVmax among prognostic groups (p=0.024). There was no correlation with histopathological cell type (p=0.923). CONCLUSIONS: Metabolic activity of uveal melanoma on PET/CT scan is positively correlated with monosomy 3, increasing tumour size and TNM prognostic groups. No association with chromosome 8 gain or histopathology cell type was noted. SUVmax >4 is a relative but not an absolute indicator of monosomy 3 status.