Expanding the understanding of telomere biology disorder with reports from two families harboring variants in ZCCHC8 and TERC.

Telomere biology disorder (TBD) can present within a wide spectrum of symptoms ranging from severe congenital malformations to isolated organ dysfunction in adulthood. Diagnosing TBD can be challenging given the substantial variation in symptoms and age of onset across generations. In this report, we present two families, one with a pathogenic variant in ZCCHC8 and another with a novel variant in TERC. In the literature, only one family has previously been reported with a ZCCHC8 variant and TBD symptoms. This family had multiple occurrences of pulmonary fibrosis and one case of bone marrow failure. In this paper, we present a second family with the same ZCCHC8 variant (p.Pro186Leu) and symptoms of TBD including pulmonary fibrosis, hematological disease, and elevated liver enzymes. The suspicion of TBD was confirmed with the measurement of short telomeres in the proband. In another family, we report a novel likely pathogenic variant in TERC. Our comprehensive description encompasses hematological manifestations, as well as pulmonary and hepatic fibrosis. Notably, there are no other reports which associate this variant to disease. The families expand our understanding of the clinical implications and genetic causes of TBD.

Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab.

BACKGROUND AIM: Indoleamine 2,3-dioxygenase (IDO) is an emerging new target in cancer therapy that can be targeted with active immunotherapy (e.g. through peptide vaccination). Furthermore, IDO has been identified as a key mechanism underlying resistance to treatment with the checkpoint blocking antibody ipilimumab (ipi). METHODS: Ten patients with metastatic melanoma participated in a phase I first-in-human clinical study assessing safety of combining ipi with a 21-mer synthetic peptide vaccine from IDO denoted IDOlong. Secondary and tertiary end points included vaccine and clinical response. RESULTS: Treatment was generally safe and well tolerated. Vaccine related adverse reactions included grade I and II erythema, oedema and pruritus at the vaccination site, which were manageable with mild topical corticosteroids. One patient developed presumed ipi-induced colitis. It initially responded to high-dose parenteral corticosteroids but later relapsed while the patient was admitted to a local hospital, where he died after receiving suboptimal therapy. Vaccine-specific T-cell responses were detectable ex vivo in three patients. At first evaluation, five of the 10 treated patients were in stable disease, one of whom had an unconfirmed partial response. CONCLUSIONS: Treatment with IDOlong synthetic peptide vaccine in combination with ipi was generally safe and without augmented toxicity. The vaccine induced readily detectable T-cell responses in a subset of patients. Treatment showed signs of clinical activity, although not exceeding efficacy of ipi alone. Results should be confirmed in a larger study.

Risk of cancer in relatives of patients with myelodysplastic neoplasia and acute leukemias.

BACKGROUND: The risk of cancer among relatives of patients with either myelodysplastic neoplasia (MDS), acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) has not been thoroughly examined. METHODS: We linked the Danish Civil Registration System with the Danish Cancer Registry, the Danish National Acute Leukemia Registry, and the Danish Myelodysplastic Syndrome Database to estimate the relative risk of cancer among relatives of patients with MDS/AML/ALL. We used standardized incidence ratios (SIRs), i.e., the ratio of observed to expected number of cancers among the relatives as a measure of relative risk. RESULTS: We identified 13010 first-degree (FDR) and 22051 second-degree (SDR) relatives of 8386 patients with MDS/ALL/AML. Disregarding basal cell carcinoma (BCC), the relative risk for cancer overall was increased in both FDR (SIR=1.3; 95% confidence interval (CI) 1.1-1.4) and SDR (SIR=1.5; 95% CI 1.2-1.8). SIRs among FDRs were statistically significantly increased for malignant melanoma, BCC and for the combined groups of cancers of the male genital organs, urinary tract, and MDS/AML/ALL. Among SDRs, SIRs were statistically significantly increased for malignant melanoma, BCC, and cancers in the digestive organs and peritoneum. CONCLUSIONS: We observed an increased risk of cancer among FDR and SDR of patients with MDS/AML/ALL.

[Germ line predisposition for myeloid neoplasia in adults].

Myeloid neoplasms with germ line predisposition (hMN) are likely underdiagnosed and are estimated to constitute a substantial fraction of patients with myelodysplastic syndrome and acute myeloid leukaemia. Correct diagnosis of hMN is vital, as it can influence treatment decisions, facilitate genetic counselling and help identify family members at risk. In this review, we describe the symptoms associated with hMN and present an example of the underlying molecular mechanism. Furthermore, we summarise the current knowledge and recommendations for diagnosis, surveillance and treatment of hMN.

Indoleamine 2,3-dioxygenase and survivin peptide vaccine combined with temozolomide in metastatic melanoma.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) and survivin have been identified as potential targets for cancer vaccination. In this phase II study a vaccine using the peptides Sur1M2 and IDO5 was combined with the chemotherapy temozolomide (TMZ) for treatment of metastatic melanoma patients. The aim was to simultaneously target several immune inhibiting mechanisms and the highly malignant cells expressing survivin. METHODS: HLA-A2 positive patients with advanced malignant melanoma were treated biweekly with 150 mg/m2 TMZ daily for 7 days followed by subcutaneous vaccination with 250 µg of each peptide in 500 µL Montanide solution at day 8. Granulocyte-macrophage colony-stimulating factor was used as an adjuvant and topical imiquimod was applied prior to vaccination. Treatment was continued until disease progression. Clinical response was evaluated by PET-CT and immunological outcome was assessed by ELISPOT and flow cytometry. RESULTS: In total, 17 patients were treated with a clinical benefit rate of 18% including one patient with partial tumor regression. Immune analyses revealed a vaccine specific response in 8 (67%) of 12 patients tested, a significant decrease in the frequency of CD4+ T-cells during treatment, a tendency towards decreasing frequencies of naïve CD4+ and CD8+ T-cells, and increasing frequencies of memory CD4+ and CD8+ T-cells. CONCLUSIONS: These results demonstrate that vaccine-induced immunity towards survivin and IDO-derived peptides can be achieved in combination with TMZ in patients mainly suffering from grade M1c melanoma including patients with brain metastases. A significant clinical activity could not be proven in this small study and a larger setup is needed to properly assess clinical efficacy.