High-grade B-cell lymphoma, not otherwise specified, presenting as primary peritoneal lymphomatosis and successfully treated with dose-adjusted EPOCH-R.

Peritoneal lymphomatosis (PL) is a rare lymphoma-associated condition defined as the dissemination of lymphoma cells in the peritoneum. An 82-year-old man presented with abdominal pain, heartburn, and high fever. Radiological findings, including positron emission tomography-computed tomography (PET-CT), and gastrointestinal fiberscopy, showed diffuse thickening of the peritoneum, omentum, and mesentery; however, no lymphadenopathy, hepatosplenomegaly, or gastrointestinal lesions were observed. Under suspicion of peritonitis carcinomatosa of unknown origin, exploratory laparoscopy was performed that revealed multiple white nodules and masses on the surfaces of the peritoneum, mesentery, and intestinal serosa. The histopathological and cytogenetic findings of the peritoneum revealed high-grade B-cell lymphoma, not otherwise specified, and a gain of MYC by fluorescence in-situ hybridization. The patient was treated with two cycles of R-CHOP therapy, followed by six cycles of dose-adjusted EPOCH-R therapy, and a complete metabolic response was confirmed by PET-CT. Since there are no specific radiological findings to confirm the diagnosis of PL, a histopathological diagnosis is usually required. Most PL exhibit an aggressive lymphoma phenotype and can be cured by appropriate chemotherapy. Therefore, early diagnosis and treatment are desirable.

Pemphigus vulgaris as an immune-related adverse event in recurrent metastatic esophageal squamous cell carcinoma treated with ipilimumab plus nivolumab: a case report and literature review.

Ipilimumab plus nivolumab therapy is approved for patients with unresectable advanced esophageal squamous cell carcinoma (ESCC). Although a combination of immune checkpoint inhibitors (ICIs), compared to conventional chemotherapy, can improve overall survival in patients with advanced ESCC, this increases the incidence of immune-related adverse events (irAEs). Here, we describe an ESCC case that developed pemphigus vulgaris (PV), an extremely rare cutaneous irAE, during ipilimumab plus nivolumab treatment. The patient achieved a partial response to treatment. The PV was successfully managed after the cessation of ipilimumab and the use of a topical steroid. We should thus re-treat ESCC with nivolumab monotherapy. In the era of ICIs as standard cancer therapeutics, diagnostic criteria for blistering diseases need to be established to properly manage patients with cutaneous irAEs.

Achievement of a durable response with eribulin for relapsed cardiac metastasis of uterine leiomyosarcoma after surgery: a case report and literature review.

BACKGROUND: Uterine leiomyosarcoma (U-LMS) is an aggressive malignancy linked to a high risk of metastasis to distant major organs. Although cardiac metastasis of U-LMS is extremely rare, it is often associated with life-threatening conditions, leading to dismal prognosis. Currently, there is no established therapy for patients with unresectable/relapsed cardiac metastasis of U-LMS. In this article, we report a case of locally relapsed cardiac metastasis of U-LMS, which occurred 3 years after surgical resection, successfully treated with eribulin. CASE DESCRIPTION: A 69-year-old female with cardiac symptoms (e.g., dyspnea, tachycardia, and easy fatigability) was sequentially treated with doxorubicin plus ifosfamide, gemcitabine plus docetaxel, and pazopanib. However, cardiac metastasis continued to grow despite treatment. Hence, eribulin was administered as fourth-line therapy. Exceptionally, eribulin markedly improved cardiac symptoms, and the patient achieved a durable response for 17 months without the development of severe adverse events. Moreover, the volume of the metastatic cardiac tumor was decreased by 70%. Despite the poor prognosis of this condition, the patient survived for 8 years from the diagnosis of cardiac metastasis due to surgery and the continuous administration of chemotherapies. CONCLUSIONS: Eribulin may be an effective and accessible treatment option for cardiac metastasis of U-LMS in patients with life-threatening conditions for whom surgery is not indicated. Additionally, the expression levels of phosphorylated AKT (p-AKT) may be a predictive biomarker for the sensitivity of patients with U-LMS to treatment with eribulin.

Complete Response to Eribulin in a Patient with Unresectable Liposarcoma: A Case Report and Implications of New Biomarkers.

We herein report a rare case of unresectable liposarcoma that showed a complete response to eribulin. Furthermore, a low expression of phosphorylated AKT (p-AKT) on an immunohistological evaluation was observed. This result is consistent with our previous preclinical study that demonstrated the significance of p-AKT signaling for eribulin resistance in multiple subtypes of soft tissue sarcoma (STS) cells. This case highlights the potential benefits of eribulin as well as the mechanism underlying resistance to eribulin in patients with unresectable or metastatic STS, especially liposarcoma.

Six-transmembrane epithelial antigen of the prostate 1 accelerates cell proliferation by targeting c-Myc in liver cancer cells.

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) has emerged as an ideal target in cancer therapeutics. However, the functions of STEAP1 in liver cancer remain unexplored. The current study aimed to characterize the biological roles of STEAP1 in liver cancer. STEAP1 expression was upregulated in tumor tissues, and high STEAP1 expression was associated with poor clinical outcomes in patients with liver cancer, according to several publicly available datasets. STEAP1 silencing using small interfering RNA inhibited cell proliferation and was accompanied by G1 arrest induced by the suppression of cyclin D1 and the promotion of p27. STEAP1 silencing suppressed c-Myc expression, which was identified as a component in STEAP1 signal transduction by mining publicly available datasets and was then confirmed by PCR array. In conclusion, the knockdown of STEAP1 in liver cancer cell lines led to inhibition of cell proliferation involving G1 arrest by suppressing c-Myc. The present study provides a preclinical concept for STEAP1 as a druggable target in liver cancer.

Survival benefit of conversion surgery after intensive chemotherapy for unresectable metastatic gastric cancer: a propensity score-matching analysis.

PURPOSE: The clinical benefit of conversion surgery (CS) for unresectable gastric cancer (GC), whereby unresectable GC responds to chemotherapy and subsequently receives curative-intent surgery, remains unclear. Here, we aimed to clarify the clinical value of CS. METHODS: In this retrospective cohort study, we analyzed 175 unresectable GC, who received triple combined chemotherapy between 2004 and 2019. We divided patients into two groups: those who underwent CS and those receiving chemotherapy only (CS and C groups, respectively). Propensity score matching was used to minimize confounding bias. RESULTS: Of 175 cases, 61 (34.9%) underwent CS. R0 resection was obtained in 85.2%. After matching, 44 pairs were selected; there were no significant differences in baseline covariants. Group CS had a significantly better median overall survival (OS) (18.8 vs. 46.0 months, p < 0.001), and prolonged progression-free survival (7.4 vs. 25.8 months, p < 0.001). Subgroup analysis of OS showed a favorable trend for CS for almost all subgroups. Multivariate analysis revealed that good ECOG performance status and CS were associated with a longer OS. CONCLUSION: The survival benefit of CS was consistently demonstrated in the univariate and multivariate analysis, even in the matched cohort. Additional large-scale trials are needed for further validation.

Successful mycophenolate mofetil treatment of a patient with severe steroid-refractory hepatitis evoked by nivolumab plus ipilimumab treatment for relapsed bladder cancer.

Mycophenolate mofetil resulted in rapid improvement of steroid-refractory immune-related adverse event hepatitis, induced by nivolumab plus ipilimumab.

Case series of three patients with hereditary diffuse gastric cancer in a single family: Three case reports and review of literature.

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome often associated with germline mutations in the CDH1 gene. However, the frequency of CDH1 mutations is low in patients with HDGC in East Asian countries. Herein, we report three cases of HDGC harboring a missense CDH1 variant, c.1679C>G, from a single Japanese family. CASE SUMMARY: A 26-year-old female (Case 1) and a 51-year-old male (father of Case 1), who had a strong family history of gastric cancer, were diagnosed with advanced diffuse gastric cancer. After genetic counselling, a 25-year-old younger brother of Case 1 underwent surveillance esophagogastroduodenoscopy that detected small signet ring cell carcinoma foci as multiple pale lesions in the gastric mucosa. Genetic analysis revealed a CDH1 c.1679C>G variant in all three patients. CONCLUSION: It is important for individuals suspected of having HDGC to be actively offered genetics evaluation. This report will contribute to an increased awareness of HDGC.

Successful Treatment by Surgery and Lenvatinib of a Patient with Adrenal Metastasis of Papillary Thyroid Cancer.

Papillary thyroid cancer (PTC) is considered an indolent cancer, but some PTC patients do present with distant metastases and treatment strategies for such patients are not well established. Recently, lenvatinib, an inhibitor of multiple tyrosine kinases, has been introduced to treat patients with advanced PTC but carries a risk of serious adverse events such as hemorrhage. Here, we report a PTC patient with a left adrenal metastasis and lenvatinib-induced hemorrhage who underwent successful surgical resection and was subsequently treated with a lower dose of lenvatinib. The patient has now been in a stable state with no adverse events for nearly two years. This case highlights the importance of surgical resection of metastatic PTC and subsequent lenvatinib therapy, even when the tumor is at an advanced stage.

FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells.

OBJECTIVES: Pancreatic cancer (PC) is highly aggressive with multiple oncogenic mutations. The efficacy of current chemotherapy is poor, and new therapeutic targets are needed. The forkhead box (FOX) proteins are multidirectional transcriptional factors strongly implicated in malignancies. Their expression is consistently suppressed by several oncogenic pathways such as PI3K/AKT signaling activated in PC. A recent study showed that class IIa histone deacetylases (HDAC) can act as a transcriptional suppressor. In this study, we hypothesized that HDAC class IIa inhibition would upregulate FOXO3a expression, thereby inducing its transcription-dependent antitumor effects. METHODS: We confirmed the change of FOXO3a expression and the effect of the cell growth inhibition by HDAC class IIa inhibition in AsPC-1 cells. Because FOXO3a is subject to ubiquitylation-mediated proteasome degradation, we examined the synergistic activation of FOXO3a by HDAC class IIa selective inhibitor TMP269 combined with proteasome inhibitor carfilzomib. RESULTS: We observed that TMP269 induced FOXO3a expression in a dose-dependent manner and inhibited cell growth in AsPC-1 cells. G1/S arrest was observed. FOXO3a expression was further increased and cell growth inhibition was dramatically enhanced by TMP269 combined with carfilzomib. CONCLUSIONS: Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC.

Management of Multiple Arteriovenous Malformations of the Small Bowel.

A 62-year-old Japanese female was referred to our hospital with gastrointestinal bleeding. Although small-bowel bleeding was suspected, no bleeding source was identified by enhanced computed tomography (CT), video capsule endoscopy (VCE), and double-balloon enteroscopy (DBE). Five years later, the patient had recurrent intermittent bloody stools with a significant decrease in hemoglobin levels. Although no active bleeding was observed on antegrade DBE, we detected a pulsatile submucosal uplift accompanied by a small red patch on the top of the uplift in the jejunum. Arteriovenous malformation (AVM) was suspected as the cause of small-bowel bleeding. Multiple-phase CT showed a number of small vascular ectasias during the arterial phase in the jejunum, and we confirmed the presence of multiple AVMs in the jejunum by selective angiography. To identify the location of the lesions and determine the minimal surgical margins, we performed intraoperative selective angiography with indocyanine green (ICG) injection. This technique allowed us to clearly observe the region and perform segmental small-bowel resection with minimal surgical margin. The patient reported that she has had no gastrointestinal bleeding at the two years follow-up visit.

Exceptionally rapid response to pembrolizumab in a SMARCA4-deficient thoracic sarcoma overexpressing PD-L1: A case report.

SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a new clinical entity characterized by SMARCA4 inactivation and has a dismal prognosis because of rapid growth. Effective treatments for SMARCA4-DTS have not yet been developed. Most recently, anti-programmed cell death 1 receptor (PD-1) blockade has been effective for SMARCA4-deficient lung cancer and malignant rhabdoid tumor-like tumors. Here, we describe a patient with SMARCA4-DTC who experienced a marked response to the administration of pembrolizumab. A 70-year-old female was referred to our department for treatment of SMARCA4-DTC. Positron emission tomography-computed tomography had revealed a left mediastinal tumor, peritoneal dissemination and multiple cutaneous metastases at diagnosis. Immunohistochemical analyses revealed 60% of tumor cells expressed programmed cell death ligand 1 (PD-L1). The patient was given pembrolizumab as first-line treatment. Pembrolizumab suppressed tumor growth dramatically, with only one dose leading to a partial response. Our case suggests the immunohistochemical analysis of PD-L1 expression be undertaken for patients with SMARCA4-DTS and that pembrolizumab treatment may be a promising strategy for PD-L1-positive SMARCA4-DTS.

Pneumothorax as an Adverse Event in Patients with Lung Metastasis of Soft Tissue Sarcoma under Eribulin Treatment.

Pneumothorax has been reported as a pazopanib-associated adverse event in patients with lung metastases of soft tissue sarcoma (STS). However, pneumothorax triggered by eribulin treatment has never been reported. We herein report two cases of spontaneous pneumothorax in patients with STS treated with eribulin. Both patients experienced pneumothorax accompanied by sudden dyspnea on day 9 or 10 of eribulin treatment. These two cases suggest that spontaneous pneumothorax may occur as an adverse event of eribulin treatment in such patients. We should therefore be alert for the potential development of pneumothorax during eribulin treatment of patients with STS and lung metastases.

Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells.

An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth in vivo as well as in vitro. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.

Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer.

The over-expression of six-transmembrane epithelial antigen of the prostate 1 (STEAP1) underlies the pathogenesis of a large subset of human cancers. Expressed on the cancer cell surface, STEAP1 is an attractive target for antibody-based therapy or immunotherapy. However, its role in modulating the pathophysiology of colorectal cancer (CRC) remains relatively unexplored. In this study, we first demonstrated that the STEAP1 transcript level was significantly higher in CRC tissues than in normal colonic tissues. Of note, STEAP1 expression negatively correlated with overall survival as determined from a publicly accessible gene expression profile data set. A loss-of-function approach in cultured CRC cell lines revealed that STEAP1 silencing suppressed cell growth and increased reactive oxygen species (ROS) production, followed by apoptosis, through an intrinsic pathway. Mechanistically, the inhibition of STEAP1 was associated with decreased expression of antioxidant molecules regulated by the transcription factor, nuclear erythroid 2-related factor (NRF2), in CRC cells. Taken together, we identified high STEAP1 transcript levels leading to reduced ROS production that prevented apoptosis via the NRF2 pathway in CRC cells as a pathological mechanism in CRC. This study highlights the STEAP1-NRF2 axis as a therapeutic target for CRC and its manipulation as a novel strategy to conquer CRC.

Neoadjuvant chemotherapy with docetaxel, nedaplatin, and fluorouracil for resectable esophageal cancer: A phase II study.

Cisplatin plus 5-fluorouracil is regarded as standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma (ESCC) in Japan, but the prognosis remains poor. We have previously described how definitive chemoradiotherapy with docetaxel, nedaplatin, and 5-fluorouracil (DNF) led to a very high response rate and promising survival times. We therefore undertook a phase II trial to evaluate the feasibility and efficacy of neoadjuvant DNF. The study included patients with clinical stage Ib-III ESCC. Chemotherapy consisted of i.v. docetaxel (30 mg/m2 ) and nedaplatin (50 mg/m2 ) on days 1 and 8, and a continuous infusion of 5-fluorouracil (400 mg/m2 /day) on days 1-5 and 8-12, every 3 weeks. After three courses of chemotherapy, esophagectomy was carried out. The primary end-point was the completion rate of the protocol treatment. Twenty-eight patients were enrolled (cStage Ib/II/III, 2/3/23) and all received at least two cycles of chemotherapy. Twenty-five patients underwent surgery, all of whom achieved an R0 resection, leading to a completion rate of 89.3%. The overall response rate was 87.0%. A pathological complete response was confirmed in eight (32.0%) cases. Grade 3/4 adverse events included leukopenia (32.1%), neutropenia (39.3%), febrile neutropenia (10.7%), thrombocytopenia (10.7%), and diarrhea (14.3%), but were manageable. Treatment-related deaths and major surgical complications did not occur. Estimated 2-year progression-free and overall survival rates were 70.4% and 77.2%, respectively. Thus, DNF therapy was well tolerated and deemed feasible, with a strong tumor response in a neoadjuvant setting for ESCC. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014305).

Trastuzumab-Based Combination Chemotherapy in Patients with Human Epidermal Growth Factor Receptor-2-Positive Metastatic Carcinoma ex Pleomorphic Adenoma.

BACKGROUND: Carcinoma ex pleomorphic adenoma (CXPA) is a rare histologic subtype of lacrimal gland and submandibular gland cancer. Currently, there is no standard treatment for metastatic CXPA, although some case reports have explored the role of targeted agents in chemotherapy. A few histopathologic analyses have shown that some of these tumors overexpress human epidermal growth factor receptor-2 (HER2), suggesting a potential role for HER2-based therapy. We report here two cases of metastatic CXPA that were treated with trastuzumab-based chemotherapy (IRB approved) with rapid and significant responses. CASE REPORT 1: A 66-year-old male was diagnosed as HER2-positive CXPA of the right lacrimal gland with multiple bone and lymph node metastases. Combination chemotherapy with trastuzumab (Tmab) and nanoparticle albumin-bound paclitaxel (nabPTX) was initiated. A rapid response was confirmed, and after seven cycles of treatment, CR(complete response) was achieved. CASE REPORT 2: A 67-year-old female was diagnosed with HER2 positive CXPA of the right submandibular gland. Multiple pulmonary metastatic lesions were detected after surgery, and combination chemotherapy with Tmab and nab-PTX was initiated. A rapid partial response (PR) was confirmed, and she eventually became disease-free. CONCLUSION: In the absence of definitive clinical trials, which are unlikely to be performed due to the rarity of HER2-positive CXPA, therapeutic information must be obtained from case reports. Some reports, such as this one, have suggested a potential utility of trastuzumab-based chemotherapy.

Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma.

Reactive oxygen species (ROS) are normal byproducts of a wide variety of cellular processes. ROS have dual functional roles in cancer cell pathophysiology. At low to moderate levels, ROS act as signaling transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS induce cell death. In multiple myeloma (MM), ROS overproduction is the trigger for apoptosis induced by several anticancer compounds, including proteasome inhibitors. However, no drugs for which oxidative stress is the main mechanism of action are currently used for treatment of MM in clinical situations. In this study, we demonstrate that the p53-activating small molecule CP-31398 (CP) effectively inhibits the growth of MM cell lines and primary MM isolates from patients. CP also suppresses the growth of MM xenografts in mice. Mechanistically, CP was found to induce intrinsic apoptosis in MM cells via increasing ROS production. Interestingly, CP-induced apoptosis occurs regardless of the p53 status, suggesting that CP has additional mechanisms of action. Our findings thus indicate that CP could be an attractive candidate for treatment of MM patients harboring p53 abnormalities; this satisfies an unmet clinical need, as such individuals currently have a poor prognosis.

Activated p53 with Histone Deacetylase Inhibitor Enhances L-Fucose-Mediated Drug Delivery through Induction of Fucosyltransferase 8 Expression in Hepatocellular Carcinoma Cells.

BACKGROUND: The prognosis of advanced hepatocellular carcinoma (HCC) is dismal, underscoring the need for novel effective treatments. The α1,6-fucosyltransferase (fucosyltransferase 8, FUT8) has been reported to accelerate malignant potential in HCC. Our study aimed to investigate the regulation of FUT8 expression by p53 and develop a novel therapeutic strategy for targeting HCC cells using L-fucose-mediated drug delivery. METHODS: Binding sites for p53 were searched for within the FUT8 promoter region. FUT8 expression was assessed by immunoblotting. Chromatin immunoprecipitation (ChIP) assays were performed to analyze p53 binding to the FUT8 promoter. The delivery of Cy5.5-encapsulated L-fucose-liposomes (Fuc-Lip-Cy5.5) to a Lens Culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3)-expressing HCC cells was analyzed by flow cytometry. The induction of FUT8 by histone deacetylase inhibitor (HDACi) -inducing acetylated -p53 was evaluated by immunoblotting. Flow cytometric analysis was performed to assess whether the activation of p53 by HDACi affected the uptake of Fuc-Lip-Cy5.5 by HCC cells. The cytotoxicity of an L-fucose-bound liposome carrying sorafenib (Fuc-Lip-sorafenib) with HDACi was assessed in vivo and in vitro. RESULTS: The knock down of p53 with siRNA led to decreased FUT8 expression. ChIP assays revealed p53 binds to the FUT8 promoter region. Flow cytometric analyses demonstrated the specific uptake of Fuc-Lip-Cy5.5 into AFP-L3-expressing HCC cells in a p53- and FUT8-dependent manner. HDACi upregulated the uptake of Fuc-Lip-Cy5.5 by HCC cells by increasing FUT8 via acetylated -p53. The addition of a HDACi increased apoptosis induced by Fuc-Lip-sorafenib in HCC cells. CONCLUSIONS: Our findings reveal that FUT8 is a p53 target gene and suggest that p53 activated by HDACi induces Fuc-Lip-sorafenib uptake by HCC cells, highlighting this pathway as a promising therapeutic intervention for HCC.

The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/ß-catenin signaling in human multiple myeloma.

Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/ß-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling.