Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion.

BACKGROUND: The ETV6-NTRK3 gene fusion is present in the majority of cases of infantile fibrosarcoma (IFS) and acts as a potent oncogenic driver. We report the very rapid, complete, and sustained response of an advanced, chemotherapy-refractory, recurrent IFS to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib. PATIENT AND METHODS: A male infant born with a large congenital IFS of the tongue had the tumour surgically resected at age 4 days. Within 2 months, he developed extensive lymph node recurrence that progressed during two cycles of vincristine-doxorubicin-cyclophosphamide chemotherapy. At screening, a large right cervical mass was clinically visible. Magnetic resonance imaging (MRI) revealed bilateral cervical and axillary lymph node involvement as well as infiltration of the floor of the mouth. The largest lesion measured 5.5×4.5×4.4 cm (ca. 55 cm3). The patient started outpatient oral larotrectinib at 20 mg/kg twice daily at age 3.5 months. RESULTS: After 4 days on treatment, the parents noted that the index tumour was visibly smaller and softer. The rapid tumour regression continued over the following weeks. On day 56 of treatment, the first scheduled control MRI showed the target lesion had shrunk to 1.2×1.2×0.8 cm (ca. 0.6 cm3), corresponding to a complete response according to the Response Evaluation Criteria In Solid Tumors version 1.1. This response was maintained over subsequent follow-up visits, and on day 112 at the second control MRI the target lymph node was completely normal. At last follow-up, the disease remained in complete remission after 16 months on larotrectinib, with negligible toxicity and no safety concerns. CONCLUSION(S): Selective TRK inhibition by larotrectinib offers a novel, highly specific and highly effective therapeutic option for IFS carrying the characteristic ETV6-NTRK3 gene fusion. Its use should be considered when surgery is not feasible. (NCT02637687).

Rapid, complete and sustained tumour response to the TRK inhibitor larotrectinib in an infant with recurrent, chemotherapy-refractory infantile fibrosarcoma carrying the characteristic ETV6-NTRK3 gene fusion.

BACKGROUND: The ETV6-NTRK3 gene fusion is present in the majority of cases of infantile fibrosarcoma (IFS) and acts as a potent oncogenic driver. We report the very rapid, complete, and sustained response of an advanced, chemotherapy-refractory, recurrent IFS to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib. PATIENT AND METHODS: A male infant born with a large congenital IFS of the tongue had the tumour surgically resected at age 4 days. Within 2 months, he developed extensive lymph node recurrence that progressed during two cycles of vincristine-doxorubicin-cyclophosphamide chemotherapy. At screening, a large right cervical mass was clinically visible. Magnetic resonance imaging (MRI) revealed bilateral cervical and axillary lymph node involvement as well as infiltration of the floor of the mouth. The largest lesion measured 5.5×4.5×4.4 cm (ca. 55 cm3). The patient started outpatient oral larotrectinib at 20 mg/kg twice daily at age 3.5 months. RESULTS: After 4 days on treatment, the parents noted that the index tumour was visibly smaller and softer. The rapid tumour regression continued over the following weeks. On day 56 of treatment, the first scheduled control MRI showed the target lesion had shrunk to 1.2×1.2×0.8 cm (ca. 0.6 cm3), corresponding to a complete response according to the Response Evaluation Criteria In Solid Tumors version 1.1. This response was maintained over subsequent follow-up visits, and on day 112 at the second control MRI the target lymph node was completely normal. At last follow-up, the disease remained in complete remission after 16 months on larotrectinib, with negligible toxicity and no safety concerns. CONCLUSION(S): Selective TRK inhibition by larotrectinib offers a novel, highly specific and highly effective therapeutic option for IFS carrying the characteristic ETV6-NTRK3 gene fusion. Its use should be considered when surgery is not feasible. (NCT02637687).

[Regression of germ cell tumors after chemotherapy]. / Regression von Keimzelltumoren nach Chemotherapie.

Today the treatment of gonadal germ cell tumors is standardized. The cisplatin containing chemotherapy and the multi-modal therapy strategies have increased the rate of successful treatment enormously. Germ cell tumors are almost always treated surgically. Following the rare, primary chemotherapy, the residual tumor must be classified according to the WHO as accurately as possible. A binding system for the documentation of tumor regression does not exist. The diagnostic retroperitoneal lymphadenectomy is also rare. Here as well, the classification is performed according to the WHO and the TNM classification. The examination of the tissue samples from a retroperitoneal lymphadenectomy after chemotherapy is problematic. The morphology is often bizarre, preparatory and terminological standards do not exist. Is there still vital tumor present then it can most often be diagnosed as a teratoma. In that case a classification takes place as to whether it is "mature" or "immature". If a tissue sample contains other differentiations, the classification is performed in detail according to the WHO classification of germ cell tumors. Sarcomas or carcinomas must be reliably distinguished and classified, as they lead to different therapeutic consequences. The terminology must be defined in a binding manner between both the pathology and the clinic, due to the lack of global definitions.

[Intratesticular cysts in infancy - case report and review of the literature]. / Intratestikuläre Zysten im Säuglingsalter - Fallbericht und Literaturübersicht.

INTRODUCTION: Intratesticular cysts in neonates and infants are rare findings compared to other cystic lesions of the testes and can be diagnosed by high-power ultrasonography. In contrast to simple epithelial cysts seen in adults, which are usually small and incidental findings, intratesticular cysts in infants are often diagnosed because of an increase in scrotal size. CASE REPORT: We report the case of a 6-month-old child with painless swelling of the right scrotum and the ultrasonographic finding of an intratesticular cyst. Together with surgical enucleation of the cyst, biopsy of the macroscopically normal testicular parenchyma was performed and showed tubular atrophy in the vicinity of the cyst. CONCLUSIONS: In view of possible increase in size with resulting atrophy of testicular parenchyma, intratesticular cysts in neonates and infants should be treated surgically by simple cyst resection.

Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter.

Transport of various amphipathic organic compounds is mediated by organic anion transporting polypeptides (OATPs in humans, Oatps in rodents), which belong to the solute carrier family 21A (SLC21A/Slc21a). Several of these transporters exhibit a broad and overlapping substrate specificity and are expressed in a variety of different tissues. We have isolated and functionally characterized OATP-F (SLC21A14), a novel member of the OATP family. The cDNA (3059 bp) contains an open reading frame of 2136 bp encoding a protein of 712 amino acids. Its gene containing 15 exons is located on chromosome 12p12. OATP-F exhibits 47-48% amino acid identity with OATP-A, OATP-C, and OATP8, the genes of which are clustered on chromosome 12p12. OATP-F is predominantly expressed in multiple brain regions and Leydig cells of the testis. OATP-F mediates high affinity transport of T(4) and reverse T(3) with apparent K(m) values of approximately 90 nM and 128 nM, respectively. Substrates less well transported by OATP-F include T(3), bromosulfophthalein, estrone-3-sulfate, and estradiol-17beta-glucuronide. Furthermore, OATP-F-mediated T(4) uptake could be cis-inhibited by L-T(4) and D-T(4), but not by 3,5-diiodothyronine, indicating that T(4) transport is not stereospecific, but that 3',5'-iodination is important for efficient transport by OATP-F. Thus, in contrast to most other family members, OATP-F has a more selective substrate preference and may play an important role in the disposition of thyroid hormones in brain and testis.

FISH analysis of gene aberrations (MYC, CCND1, ERBB2, RB, and AR) in advanced prostatic carcinomas before and after androgen deprivation therapy.

Genetic mechanisms leading to androgen-independent growth in advanced prostatic carcinomas (PC) are still poorly understood. Analysis of genes potentially involved in the regulation of tumor cell proliferation and apoptosis might confer better insight into this process and might lead to improved therapeutic strategies. Fluorescence in situ hybridization (FISH) analysis of dissociated nuclei with DNA probes for MYC (8q24)/#8, cyclin D1 gene (CCND1; 11q13)/#11, ERBB2 (17q13)/#17, the androgen receptor gene (AR; Xq12)/#X, and the retinoblastoma gene (RB; 13q14) was applied to formalin-fixed tissue from 63 patients with advanced PC after androgen deprivation therapy (ADT); matched tumor tissue before ADT was also available in 22 of these cases. The cut-points used were: "increased copy number," > or = 30% of all nuclei with increased FISH signals (centromere and/or gene); "amplification," > or = 15% of nuclei with "increased gene copy number." CCND1 and MYC gene "amplifications" were present before ADT in 25% and 33% of the cases, respectively; the frequency of these "amplifications" increased to 37% and 57% after ADT. Loss of the RB gene was nearly four times more frequent after ADT than before therapy (22% versus 6%). AR and ERBB2 gene "amplifications" occurred only after ADT in 36% and 30% of cases, respectively. With the exception of the AR gene, the copy number increase was low. After treatment, MYC and AR gene "amplifications" correlated with the proliferation rate (Ki-67/MIB1 index; p = 0.01 and p = 0.04), whereas ERBB2 "amplifications" were associated with increased apoptotic index (PCD/TUNEL; p = 0.016). However, no correlation between FISH results and clinical follow-up could be established. FISH analysis of genes putatively involved in PC progression revealed characteristic patterns of aberrations in advanced PC before and after ADT. Distinct changes in gene copy number before and after therapy suggests possible involvement of these genes in the escape from androgen control.

Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy: prognostic significance of p21/WAF1/CIP1 expression.

The molecular mechanisms leading to androgen-independent growth in prostate cancer (PC) are poorly understood. Androgen deprivation therapy (ADT) results physiologically in a decrease in proliferation and an increase in programmed cell death (PCD)/apoptosis. The aim of our study was to get more insight into these processes in prostatic carcinomas before and after ADT. For this purpose, immunohistologic staining for the androgen receptor (AR) molecule, the Ki-67 antigen, the bcl-2 oncoprotein, the p53 protein and its physiologic effector, p21/WAF1, was performed on archival material. PCD was visualized by enzymatic detection of DNA fragmentation. Specimens from 69 PC patients after ADT were studied in correlation to histopathology and prognosis. In 42 cases, corresponding tumour tissue from the untreated primary tumours could be analysed comparatively. Before ADT, histologic grade was associated with Ki-67 index (P < 0.0001, Spearman correlation) and PCD rate (P < 0.05, Spearman correlation). Ki-67 index correlated with PCD rate (P < 0.05, Spearman correlation) and p21/WAF1 expression (P < 0.01, Fisher's exact test). p21/WAF1 expression was the only statistically significant prognostic factor for shorter survival (P < 0.002, log-rank test). All p21/WAF1-positive cases showed high Ki-67 index and high histologic grade. After ADT, loss of AR expression was associated with high Ki-67 index, whereas histologic signs of regression correlated negatively with Ki-67 index (P < 0.001, Pearson chi2 test). p21/WAF1 expression increased significantly (P < 0.02, McNemar test) and correlated with p53 accumulation (P < 0.0001, Pearson chi2 test). Most significant prognostic parameter after conventional ADT was high-rate p21/WAF1 expression (> 50% of tumour cells; P < 0.00001, log-rank test). This study demonstrates that p21/WAF1 overexpression before and after ADT characterizes a subgroup of advanced PC with paradoxically high proliferation rate and significantly worse clinical outcome. This finding might be clinically useful for planning therapy in these patients.