Second MAFA Variant Causing a Phosphorylation Defect in the Transactivation Domain and Familial Insulinomatosis.

Adult-onset familial insulinomatosis is a rare disorder with recurrent, severe hypoglycemia caused by multiple insulin-secreting pancreatic tumors. The etiology was unclear until the variant p.Ser64Phe in the transcription factor MAFA, a key coordinator of ß-cell insulin secretion, was defined as the cause in two families. We here describe detailed genetic, clinical, and family analyses of two sisters with insulinomatosis, aiming to identify further disease causes. Using exome sequencing, we detected a novel, heterozygous missense variant, p.Thr57Arg, in MAFA's highly conserved transactivation domain. The impact of the affected region is so crucial that in vitro expression studies replacing Thr57 have already been performed, demonstrating a phosphorylation defect with the impairment of transactivation activity and degradation. However, prior to our study, the link to human disease was missing. Furthermore, mild hyperglycemia was observed in six additional, heterozygote family members, indicating that not only insulinomatosis but also MODY-like symptoms co-segregate with p.Thr57Arg. The pre-described MAFA variant, p.Ser64Phe, is located in the same domain, impairs the same phosphorylation cascade, and results in the same symptoms. We confirm MAFA phosphorylation defects are important causes of a characteristic syndrome, thus complementing the pathophysiological and diagnostic disease concept. Additionally, we verify the high penetrance and autosomal dominant inheritance pattern.

Life-threatening disseminated enterovirus infection during combined rituximab and ibrutinib maintenance treatment for mantle cell lymphoma: a case report.

BACKGROUND: Rituximab is a well-established component of treatment regimens for B-cell non-Hodgkin lymphoma. Rituximab binds the CD20 antigen on the surface of B lymphocytes, causing an enhanced clearance of malignant and benign B cells. Thus, rituximab leads to depletion of normal B lymphocytes as well, which can cause substantial immunodeficiency. Ibrutinib inhibits the Bruton tyrosine kinase and thereby B-cell activity. It is used for the treatment of different B-lymphocyte malignancies, such as mantle cell lymphoma. Recently, the combination of both drugs has been tested in various clinical scenarios. CASE PRESENTATION: We present a case of disseminated enterovirus infection resulting from combined rituximab and ibrutinib maintenance treatment in a 57-year-old Caucasian patient. with mantle cell lymphoma. Initially presenting with myositis symptoms, further diagnostic investigation revealed myocarditis, enteritis, myeloencephalitis, and hepatitis. These organ manifestations led to potentially life-threatening complications such as rhabdomyolysis, delirium, and heart rhythm disturbances. After treatment with high-dose intravenous immunoglobulins, virus clearance was achieved and organ functions could be restored. CONCLUSIONS: This case emphasizes the risk of combined therapy with rituximab/ibrutinib for severe immune-related side effects with the necessity of continuous patient monitoring. High-dose intravenous therapy should be considered as treatment for severe enterovirus infection. In severe enterovirus infections, we recommend subtyping for the development of efficient preventive and therapeutic strategies.

Impact of combined FDG-PET/CT and MRI on the detection of local recurrence and nodal metastases in thyroid cancer.

BACKGROUND: Suspected recurrence of thyroid carcinoma is a diagnostic challenge when findings of both a radio iodine whole body scan and ultrasound are negative. PET/CT and MRI have shown to be feasible for detection of recurrent disease. However, the added value of a consensus reading by the radiologist and the nuclear medicine physician, which has been deemed to be helpful in clinical routines, has not been investigated. This study aimed to investigate the impact of combined FDG-PET/ldCT and MRI on detection of locally recurrent TC and nodal metastases in high-risk patients with special focus on the value of the multidisciplinary consensus reading. MATERIALS AND METHODS: Forty-six patients with suspected locally recurrent thyroid cancer or nodal metastases after thyroidectomy and radio-iodine therapy were retrospectively selected for analysis. Inclusion criteria comprised elevated thyroglobulin blood levels, a negative ultrasound, negative iodine whole body scan, as well as combined FDG-PET/ldCT and MRI examinations. Neck compartments in FDG-PET/ldCT and MRI examinations were independently analyzed by two blinded observers for local recurrence and nodal metastases of thyroid cancer. Consecutively, the scans were read in consensus. To explore a possible synergistic effect, FDG-PET/ldCT and MRI results were combined. Histopathology or long-term follow-up served as a gold standard. For method comparison, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were calculated. RESULTS: FDG-PET/ldCT was substantially more sensitive and more specific than MRI in detection of both local recurrence and nodal metastases. Inter-observer agreement was substantial both for local recurrence (κ = 0.71) and nodal metastasis (κ = 0.63) detection in FDG-PET/ldCT. For MRI, inter-observer agreement was substantial for local recurrence (κ = 0.69) and moderate for nodal metastasis (κ = 0.55) detection. In contrast, FDG-PET/ldCT and MRI showed only slight agreement (κ = 0.21). However, both imaging modalities identified different true positive results. Thus, the combination created a synergistic effect. The multidisciplinary consensus reading further increased sensitivity, specificity, and diagnostic accuracy. CONCLUSIONS: FDG-PET/ldCT and MRI are complementary imaging modalities and should be combined to improve detection of local recurrence and nodal metastases of thyroid cancer in high-risk patients. The multidisciplinary consensus reading is a key element in the diagnostic approach.

Serum S100B levels correlate with clinical benefit in a metastatic melanoma patient treated by CTLA-4 blockade: a case report.

BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immunoregulatory molecule expressed by activated T cells. In patients with metastatic melanoma, anti-CTLA-4 antibody therapy with ipilimumab achieves durable cancer regression in approximately 10-15% of patients. In the face of complex and sometimes delayed tumor response patterns, prognostic and predictive biomarkers are needed to monitor therapy outcomes and to identify early potential long-term survivors who might also benefit from therapy re-induction. CASE REPORT: The clinical case of a 49-year-old male patient with metastatic melanoma and unfavorable prognostic factors is presented. The time course of the serum biomarker S100B during initial anti-CTLA-4 therapy correlated very well with the clinical situation and, in the present case, proved its potential value as an early biomarker of a subsequently observed radiological response in this stage IV melanoma patient. The observed clinical response lasted for more than 24 months. CONCLUSIONS: Further efforts are required to better understand the patterns of response and the immunological tumor response in patients undergoing CTLA-4 blockade. A validation of S100B as a marker to identify early long-term responders among patients treated with ipilimumab is warranted.

AFP measurement in monitoring treatment response of advanced hepatocellular carcinoma to sorafenib: case report and review of the literature.

BACKGROUND: The multi-targeted tyrosine kinase inhibitor sorafenib was the first agent to demonstrate a significant improvement in overall survival in patients with advanced hepatocellular carcinoma (HCC). However, survival under sorafenib treatment is still lower than 1 year in most patients in clinical practice. Sorafenib rarely produces radiological tumor regression, pointing out limitations in using conventional radiological assessment of response to targeted therapy. Serial alpha-fetoprotein (AFP) measurement may be useful in monitoring treatment response in patients with advanced HCC undergoing systemic therapy; however, this approach is poorly defined for the case of sorafenib. CASE REPORT: We herein report the case of a 48-year-old patient with advanced HCC presenting with normalization of highly elevated AFP levels after 5 months of reduced-dose sorafenib treatment, resulting in a sustained radiological and clinical response. CONCLUSIONS: Complete response to sorafenib may be possible in a small subgroup of patients with advanced HCC, strongly depending on one or more of the targets inhibited by sorafenib. Serial AFP measurement may provide additional information in monitoring treatment response to sorafenib and should be evaluated in future clinical trials in advanced HCC.

Diagnosis and treatment of pancreatic metastases of a papillary thyroid carcinoma.

BACKGROUND: Apart from regional lymph node metastases, systemic metastases occur sporadically in papillary thyroid carcinomas (PTC). The lung and bones are the most frequent localizations. Additionally known but extremely rare locations are metastases of the skeletal muscles, ovaries, submandibular gland, sphenoidal sinus, brain, adrenals, and, as shown in only two previously published cases to date, the pancreas. SUMMARY: In this article we report about two additional patients with pancreatic metastases from PTC. There is almost no prior experience about therapeutic approaches to this type of metastases. In both patients distant metastases within the pancreas were successfully removed. Postoperative histology confirmed the diagnoses. Supplemental genetic analysis did not demonstrate a BRAF V600E mutation or expression of a RET/PTC1 rearrangement in one case, but revealed a BRAF V600E mutation in the second case. Surgery avoided impending complications maintaining quality of life. One patient had a tumor-specific survival of 42 months. The other patient has occult disease. CONCLUSIONS: Our two patients benefited of a calculated aggressive surgical action. Thus, if low perioperative mortality and morbidity can be warranted, surgical measures are justifiable in selected cases.

Successful treatment of adult multisystemic Langerhans cell histiocytosis with psoralen-UV-A, prednisolone, mercaptopurine, and vinblastine.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease with a peak incidence in childhood. There is limited experience with treatment options for adult patients having multisystemic LCH involvement. We report successful treatment of a 70-year-old woman with adult onset of LCH and multisystem disease (diabetes insipidus centralis, bone marrow infiltration, and lung and skin involvement). OBSERVATIONS: A 70-year-old woman with erythematous plaques and papules of the submammary and inguinal skin attended our outpatient clinic and was diagnosed as having LCH. Organ involvement was found in the infundibulum of the pituitary gland, associated with diabetes insipidus centralis, bone marrow infiltration, and several micronodules of the thoracic and lumbar spine and lungs. Based on the Histiocyte Society's LCH-A1 study in adults, the patient was treated for 12 months with a combination of corticosteroids, vinblastine, and mercaptopurine. No major adverse effects were observed. The skin was also treated with a combination of psoralen-UV-A and local corticosteroids. Restaging revealed regression of all clinical symptoms (skin involvement and diabetes insipidus centralis) and regression of organ infiltration (pituitary gland, bone marrow, and lungs). CONCLUSION: Effective treatment of adult multisystemic LCH disease was achieved using prednisolone, vinblastine, and mercaptopurine, which was well tolerated.

Gemcitabine in combination with EGF-Receptor antibody (Cetuximab) as a treatment of cholangiocarcinoma: a case report.

BACKGROUND: Extensive disease of cholangiocarcinoma (CC) determines the overall outcome and limits curative resection. Despite chemotherapy, which has been introduced to improve the outcome of biliary tract malignancies, the benefit in survival is still marginal. CASE PRESENTATION: We report a 69-year-old patient with non-resectable CC showing hepatic metastasis and peritoneal carcinomatosis. Diagnosis was based on computed tomography, mini-laparoscopy and bioptic specimens. Histology revealed an adenocarcinoma of the biliary tract with expression of epithelial growth factor receptor. After informed consent the patient received experimental gemcitabine (1000 mg/m2) every other week and cetuximab (250 mg/m2) weekly for palliative chemotherapy. During the reported follow up (since time of first presentation) 20 cycles of chemotherapy were administered. Relevant chemotherapy-related toxicity was limited on gemcitabine-associated side effects. Predominantly, haematological toxicity (CTC, grade 3) and neutropenic fever (CTC, grade 3) promoted by catheter-related sepsis were observed. Cetuximab caused only mild skin toxicity (CTC, grade 1). Chemotherapy led to a partial response (> 30% reduction, according to RECIST) of the target lesions and disappearance of the peritoneal carcinomatosis as shown by computed tomography. Partial response occurred after 17 weeks of treatment and remained stable during the entire course of chemotherapy for 9.7 months. In parallel, Ca 19-9 serum levels, which were elevated 5-fold at time of diagnosis, returned to normal after 16 weeks of treatment. The performance status stabilized and intravenous alimentation could be discontinued. CONCLUSION: Our experience from one patient with CC suggests, that a combination of cytotoxic chemotherapy together with cetuximab may show promising efficacy in respect to survival and quality of life. Therefore cetuximab, as a component of palliative chemotherapy in biliary tract cancer, needs further evaluation in prospective randomized trials.