STRN-ALK Fusion in a Case of Malignant Peritoneal Mesothelioma: Mixed Response to Crizotinib, Mode of Resistance, and Brigatinib Sequential Therapy

ALK fusions were first described by Morris et al1 in 1994. Several studies have reported genetic alterations of the ALK gene in various tumor types since then, consisting of mutations, amplifications, and fusions.1-3 Fusion proteins have an active C-terminal tyrosine kinase domain in common.3 Here, we describe an STRN-ALK fusion in malignant peritoneal mesothelioma (MPM), which has previously been documented in other neoplasms, including thyroid cancer, renal carcinoma, leukemia, lymphoma, colon adenocarcinoma, head and neck adenocarcinoma, pericardial and peritoneal mesothelioma, and cutaneous squamous cell carcinoma.4-6 MPM is a rare disease with an incidence of approximately seven per million people per year.7 Patients' life expectancy is low (on average 12 months) because of the late clinical presentation with abdominal or pelvic pain or lymphadenopathy.8,9 Recently, ALK rearrangements have gained attention, especially in young female patients with MPM. Hung et al10 identified three ALK fusions in 88 consecutively screened patients with MPM. Fusion partners were ATG16L1, TPM1, and STRN. In another study by Mian et al,11 among 32 patients ≤ 40 years old with mesothelioma (of which 25 were MPM), an ALK rearrangement was detected by fluorescence in situ hybridization in two patients (6%). One of the cases harbored an STRN-ALK fusion as described in the current case. Argani et al12 described additional five cases of ALK fusions in pediatric MPM. Subsequently, three more cases of STRN-ALK rearrangements in MPM have been published individually.6,13,14 In non–small-cell lung cancer (NSCLC), the discovery of specific drugs targeting ALK rearrangements led to significant therapeutic advances. Currently, various ALK inhibitors, namely, ceritinib, crizotinib, and alectinib, are used as first-line treatment in adult ALK-positive advanced NSCLC. Although crizotinib as a first-generation ALK inhibitor has already proven superiority over chemotherapy,15 next-generation ALK inhibitors such as ceritinib yielded even better survival rates.16 Moreover, both brigatinib and alectinib demonstrated superior effectiveness when directly compared with crizotinib.17,18 Unfortunately, resistance is frequently observed following an initial response in all these agents.19 Mechanisms of resistance, which often include ALK mutations, are in general universal although variable mutational frequencies are observed depending on the inhibitor.20 Despite this large base of knowledge for lung cancer, the evaluation of ALK fusions in other entities remains challenging because of limited available data

Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma

Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use. Here, we explored whether a combined treatment of metformin and diclofenac, which is a non-steroidal anti-inflammatory drug (NSAID) shown to inhibit glycolysis by interfering with lactate efflux, may lead to additive or even synergistic effects on BTICs (BTIC-8, -11, -13 and -18) and tumor cell lines (TCs, U87, and HTZ349). Therefore, we investigated the functional effects, including proliferation and migration, metabolic effects including oxygen consumption and extracellular lactate levels, and effects on the protein level, including signaling pathways. Functional investigation revealed synergistic anti-migratory and anti-proliferative effects of the combined treatment with metformin and diclofenac on BTICs and TCs. Signaling pathways did not sufficiently explain synergistic effects. However, we observed that metformin inhibited cellular oxygen consumption and increased extracellular lactate levels, indicating glycolytic rescue mechanisms. Combined treatment inhibited metformin-induced lactate increase. The combination of metformin and diclofenac may represent a promising new strategy in the treatment of glioblastoma. Combined treatment may reduce the effective doses of the single agents and prevent metabolic rescue mechanisms. Further studies are needed in order to determine possible side effects in humans

Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma

Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use. Here, we explored whether a combined treatment of metformin and diclofenac, which is a non-steroidal anti-inflammatory drug (NSAID) shown to inhibit glycolysis by interfering with lactate efflux, may lead to additive or even synergistic effects on BTICs (BTIC-8, -11, -13 and -18) and tumor cell lines (TCs, U87, and HTZ349). Therefore, we investigated the functional effects, including proliferation and migration, metabolic effects including oxygen consumption and extracellular lactate levels, and effects on the protein level, including signaling pathways. Functional investigation revealed synergistic anti-migratory and anti-proliferative effects of the combined treatment with metformin and diclofenac on BTICs and TCs. Signaling pathways did not sufficiently explain synergistic effects. However, we observed that metformin inhibited cellular oxygen consumption and increased extracellular lactate levels, indicating glycolytic rescue mechanisms. Combined treatment inhibited metformin-induced lactate increase. The combination of metformin and diclofenac may represent a promising new strategy in the treatment of glioblastoma. Combined treatment may reduce the effective doses of the single agents and prevent metabolic rescue mechanisms. Further studies are needed in order to determine possible side effects in humans

Feasibility of ABUS as an Alternative to Handheld Ultrasound for Response Control in Neoadjuvant Breast Cancer Treatment

This study evaluated the use of Automated Breast Ultrasound Screening (ABUS) for response control in neoadjuvant chemotherapy. Response controls via ABUS and handheld ultrasound were compared with pathologic tumor size. There was no statistical difference between the measurements with handheld ultrasound or ABUS. ABUS seems to be a suitable method to conduct response control in neoadjuvant breast cancer treatment. Introduction: The Invenia Automated Breast Ultrasound Screening (ABUS) is indicated as an adjunct to mammography for breast cancer screening in asymptomatic women with high-density breast tissue. ABUS provides time-efficient evaluation of the 3-dimensional recordings within 3 to 6 minutes. The role and advantages of ABUS in everyday clinical practice, especially in routine examination during neoadjuvant chemotherapy (NACT), is not clear. The aim of this monocentric, noninterventional retrospective study is to evaluate the use of ABUS in patients who are under NACT treatment for response control. Methods: Regular sonographic response check with handheld ultrasound (HHUS) examination and with ABUS were conducted in 83 women who underwent NACT. The response controls were conducted every 3 to 6 weeks during NACT. The handheld sonography was performed with GE Voluson S8. Handheld sonographic measurements and ABUS measurements were compared with the final pathologic tumor size. Results: There was no statistical difference between the measurements with HHUS examination or ABUS compared with final pathologic tumor size (P =.47). The average difference from ABUS measured tumor size to final pathologic tumor size was 9.8 mm. The average difference from handheld measured tumor size to final pathologic tumor size was 9/3 mm. Both the specificity of ABUS and HHUS examination in predicting pathologic complete remission was 100%. Conclusion: ABUS seems to be a suitable method to conduct response control in neoadjuvant breast cancer treatment. ABUS may facilitate preoperative planning and offers remarkable time saving for physicians compared with HHUS examination and thus should be considered for clinical practice (C) 2021 Elsevier Inc. All rights reserved

Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2

<p>To this day, glioblastoma (GBM) remains an incurable brain tumor. Previous research has shown that metformin, an oral anti-diabetic drug, may decrease GBM cell proliferation and migration especially in brain tumor initiating cells (BTICs). As transforming growth factor β 2 (TGF-β₂) has been reported to promote high-grade glioma and is inhibited by metformin in other tumors, we explored whether metformin directly interferes with TGF-β₂-signaling. Functional investigation of proliferation and migration of primary BTICs after treatment with metformin+/−TGF-β₂ revealed that metformin doses as low as 0.01 mM metformin thrice a day were able to inhibit proliferation of susceptible cell lines, whereas migration was impacted only at higher doses. Known cellular mechanisms of metformin, such as increased lactate secretion, reduced oxygen consumption and activated AMPK-signaling, could be confirmed. However, TGF-β₂ and metformin did not act as functional antagonists, but both rather inhibited proliferation and/or migration, if significant effects were present. We did not observe a relevant influence of metformin on TGF-β₂ mRNA expression (qRT-PCR), TGF-β₂ protein expression (ELISA) or SMAD-signaling (Western blot). Therefore, it seems that metformin does not exert its inhibitory effects on GBM BTIC proliferation and migration by altering TGF-β₂-signaling. Nonetheless, as low doses of metformin are able to reduce proliferation of certain GBM cells, further exploration of predictors of BTICs' susceptibility to metformin appears justified.</p