Efficacy of Second-line Cabozantinib after Immune Checkpoint Inhibitor Therapy for Clear Cell Renal Cell Carcinoma with Tumor Thrombus

Surgical resection greatly benefits patients with renal cell carcinoma (RCC). However, patients with locally advanced RCC, including tumor thrombus and adjacent organ involvement, are at risk for perioperative complications and perioperative death. Therefore, in some cases, a multimodal approach with systemic therapy should be planned before radical surgery. A 65-year-old female patient with unresectable locally advanced left clear cell carcinoma (ccRCC) with tumor thrombus, who was considered difficult to undergo radical recection, treated with systemic therapy. The tumor responded well to second-line cabozantinib treatment after combination immunotherapy and was completely resected after surgery. This case demonstrates the efficacy of cabozantinib after immune checkpoint inhibition for locally advanced ccRCC and the importance of multimodal therapy in ccRCC.journal articl

Fumarate Hydratase-deficient Renal Cell Carcinoma Successfully Treated with Cabozantinib: A Case Report

Fumarate hydratase-deficient renal cell carcinoma arises from mutations in the fumarate hydratase (FH) gene, representing a rare subset of renal cell carcinoma (RCC). Approximately 19% of patients formerly diagnosed with type 2 papillary RCCs are FH deficient. FH-deficient RCC typically exhibits an aggressive course and is associated with hereditary leiomyomatosis and RCC syndrome in cases with germline mutations. Herein, we report the case involving a 34-year-old Japanese man who experienced a 20-kg weight loss. Computed tomography identified a left renal tumor, leading to a subsequent left nephrectomy. Pathological analysis confirmed FH-deficient RCC. Following diagnosis, the patient underwent treatment with ipilimumab and nivolumab for liver metastasis. Due to disease progression, cabozantinib was administered as second-line therapy, achieving a partial response. Currently, no established standard therapy exists for FH-deficient RCC. Nevertheless, in this case, the multi-kinase inhibitor cabozantinib was effective in combating resistance to immune checkpoint inhibitors.journal articl

Membrane Protein Location-Dependent Regulation by PI3K (III) and Rabenosyn-5 in Drosophila Wing Cells

The class III phosphatidylinositol-3 kinase (PI3K (III)) regulates intracellular vesicular transport at multiple steps through the production of phosphatidylinositol-3-phosphate (PI(3)P). While the localization of proteins at distinct membrane domains are likely regulated in different ways, the roles of PI3K (III) and its effectors have not been extensively investigated in a polarized cell during tissue development. In this study, we examined in vivo functions of PI3K (III) and its effector candidate Rabenosyn-5 (Rbsn-5) in Drosophila wing primordial cells, which are polarized along the apical-basal axis. Knockdown of the PI3K (III) subunit Vps15 resulted in an accumulation of the apical junctional proteins DE-cadherin and Flamingo and also the basal membrane protein β-integrin in intracellular vesicles. By contrast, knockdown of PI3K (III) increased lateral membrane-localized Fasciclin III (Fas III). Importantly, loss-of-function mutation of Rbsn-5 recapitulated the aberrant localization phenotypes of β-integrin and Fas III, but not those of DE-cadherin and Flamingo. These results suggest that PI3K (III) differentially regulates localization of proteins at distinct membrane domains and that Rbsn-5 mediates only a part of the PI3K (III)-dependent processes

Rbsn-5 is a PI(3)P target protein.

<p>(A) Rbsn-5 (red) was co-localized in the pupal wing discs, mainly with GFP-2xFYVE, Rab5 and Rab7 (arrowheads), but not with Rab11. The scale bars represent 20 µm. (B) Rbsn-5 (red) was clearly reduced in the <i>dVps15</i>-knockdown region (the left sides of the dotted lines). In the knockdown region, <i>D</i>E-Cadherin (green) accumulated intracellularly as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007306#pone-0007306-g004" target="_blank">Figure 4</a>. (C) Adult wings in which dsRNAs were expressed by <i>dpp</i>-Gal4 driver. Malformation was observed near the third vein where the dsRNAs for <i>dVps15</i>, <i>dVps34</i> or <i>Rbsn-5</i> were expressed. This malformation was synergistically enhanced by co-expression of dsRNAs for both <i>dVps15</i> and <i>dVps34</i> or both <i>dVps15</i> and <i>Rbsn-5</i>, whereas no such enhancement was observed by co-expression of dsRNAs for both <i>PI3K class I</i> and <i>Rbsn-5</i> or both <i>PI3K class I</i> and <i>dVps34</i>. (D) Horizontal (upper) and vertical (lower) sections of the pupal wings expressing dsRNAs for <i>Rbsn-5</i> and/or <i>dVps15</i>. β-integrin (red) was not localized in the double knockdown region (indicated by double headed arrow in the left panel) whereas marginal defects were observed in the single knockdown (indicated by double headed arrows in the middle and right panels). The right sides of the panels represent the internal control where β-integrin was normally localized to the basal junctions. The scale bars represent 10 µm.</p