Relapsing Polychondritis following PD-1 Blockade by an Immune Checkpoint Inhibitor.

Immune-related adverse events (irAEs) mimicking rheumatic diseases are observed in 1.5%-22% of patients receiving cancer therapy with immune checkpoint inhibitors (ICIs). Relapsing polychondritis (RP) is a rare autoimmune disease mainly involving auricle, nose, and airway cartilage inflammation. However, knowledge regarding RP as an irAE is scarce. Pembrolizumab, a type of ICI that regulates the programmed cell death protein-1 (PD-1), is used in patients whose cancer cannot be cured with surgery or radiation therapy. We report the first case of pembrolizumab-induced RP with isolated auricular lesions resolved without immunosuppressants. A 49-year-old man with lower lip cancer underwent surgical resection followed by reconstruction. Histopathological investigation confirmed the diagnosis of squamous cell carcinoma. Since multiple metastases 6 months post-surgery rendered the carcinoma inoperative, pembrolizumab was initiated, improving lymph node involvement. However, 4 months later, the patient developed rapidly progressive swelling and pain in both auricles. While no pathogen was detected, C-reactive protein levels were elevated (11.21 mg/dL). Computed tomography (CT) showed swelling of the bilateral auricles; the biopsy of the right auricle revealed cartilage destruction by infiltration of surrounding granulation tissue. Since these characteristic findings were not observed before pembrolizumab was initiated, we clinically diagnosed the patient with RP induced by pembrolizumab. The swelling of the auricles resolved spontaneously 1 month after pembrolizumab discontinuation. 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography/CT revealed no 18F-FDG uptake in reduced auricular lesions. On re-administration of pembrolizumab to maintain antitumor immunity, both auricles swelled again, and pembrolizumab was switched to paclitaxel, considering the risk of tracheobronchial chondritis. Although no recurrence of auricular chondritis was observed, the patient died from cancer progression 8 months after paclitaxel administration. RP can occur as a rheumatic irAE in patients receiving anti-PD-1 therapy, and a literature review with retrospective analysis indicates that PD-1 inhibition-induced RP is unusual and atypical.

LPIN1 downregulation enhances anticancer activity of the novel HDAC/PI3K dual inhibitor FK-A11.

Phosphatidylinositol-3 kinase (PI3K) inhibitor and histone deacetylase (HDAC) inhibitor have been developed as potential anticancer drugs. However, the cytotoxicity of PI3K inhibitor or HDAC inhibitor alone is relatively weak. We recently developed a novel HDAC/PI3K dual inhibitor FK-A11 and confirmed its enhanced cytotoxicity when compared to that of PI3K inhibitor or HDAC inhibitor alone on several cancer cell lines. However, the in vivo antitumor activity of FK-A11 was insufficient. We conducted high-throughput RNA interfering screening and identified gene LPIN1 which enhances the cytotoxicity of FK-A11. Downregulation of LPIN1 enhanced simultaneous inhibition of HDAC and PI3K by FK-A11 and enhanced the cytotoxicity of FK-A11. Propranolol, a beta-adrenoreceptor which is also a LPIN1 inhibitor, enhanced the in vitro and in vivo cytotoxicity and antitumor effect of FK-A11. These findings should help in the development of FK-A11 as a novel HDAC/PI3K dual inhibitor.

In Vitro and in Vivo antitumor activity and the mechanism of siphonodictyal B in human colon cancer cells.

Liphagal, isolated from the marine sponge Aka coralliphaga, exhibits phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitory activity and cytotoxic effects in human cancer cells. Siphonodictyal B, the biogenetic precursor of liphagal, also has PI3K inhibitory activity. However, its cytotoxic or antitumor activities have not been evaluated. In this study, we demonstrated that siphonodictyal B inhibits several kinases such as CDK4/6, CDK7, and PIM2 in addition to PI3K in vitro and that siphonodictyal B exhibits more potent cytotoxic effects than liphagal against human colon cancer cell lines. Furthermore, treatment with siphonodictyal B resulted in increased PARP cleavage, a larger sub-G1 fraction, and a larger annexin V-positive cell population, all of which are indicative of apoptosis induction. As a mechanism of apoptosis induction, we found that siphonodictyal B activates the p38 MAPK pathway, leading the upregulation of proapoptotic factors. Moreover, siphonodictyal B increased ROS levels, thus promoting p38 MAPK pathway activation. NAC, an ROS scavenger, almost completely reversed both the cytotoxic and p38 MAPK pathway-activating effects of siphonodictyal B. These results indicate that the p38 MAPK pathway might be involved downstream of ROS signaling as part of the mechanism of siphonodictyal B-induced apoptosis. Finally, siphonodictyal B displayed antitumor effects in a human colon cancer xenograft mouse model and increased p38 phosphorylation in tumor tissue. These results suggest that siphonodictyal B could serve as the basis of a novel anticancer drug.

Retrospective analysis on the clinical outcomes of recombinant human soluble thrombomodulin for disseminated intravascular coagulation syndrome associated with solid tumors.

BACKGROUND: Recombinant human soluble thrombomodulin (rTM) has been established and introduced in the clinic as a standard treatment for disseminated intravascular coagulation (DIC). However, the efficacy and safety of rTM for DIC associated with solid tumors (DIC-STs) have not been fully established. Here, we performed a retrospective analysis of the clinical outcomes of rTM for DIC-STs and considered a treatment strategy with rTM for DIC-STs. METHODS: Patients with DIC-STs between November 2009 and March 2016 in 2 cancer core hospitals were retrospectively analyzed. Data, including patient background, treatment course, and clinical outcomes of rTM for DIC-STs, were extracted. The clinical outcomes were evaluated by comparing the DIC score, resolution rate, and overall survival (OS) duration. RESULTS: The study included 123 patients with DIC-STs. The median OS in all patients was 41 days. The DIC resolution rate was 35.2%. DIC scores and DIC-related blood test data (fibrin degradation product and prothrombin time-international normalized ratio) significantly improved at the end of rTM administration (P < 0.001). The OS duration was longer in patients who were treated with chemotherapy after DIC onset than in those who were not treated with chemotherapy (median, 178 days vs. 17 days, P < 0.001). In both univariate and multivariate analyses, chemotherapy after DIC onset showed the strongest association with OS. CONCLUSIONS: rTM can at least temporarily improve or maintain the state of DIC-STs. It is suggested that prolongation of survival can be expected when control of DIC and treatment of the underlying disease are compatible.

The G8 screening tool enhances prognostic value to ECOG performance status in elderly cancer patients: A retrospective, single institutional study.

BACKGROUND: Some elderly cancer patients, even with good Eastern Cooperative Oncology Group performance status (ECOG-PS), have poor survival outcomes and cannot tolerate standard therapy. Few studies have detailed the associations between the G8 screening tool, ECOG-PS, and overall survival (OS) in such patients. METHODS: Cancer patients, aged 70 years or older, were assessed for G8 and classified into three groups according to their G8 score: <11 as the low score group, 11-14 as the intermediate score group, and >14 as the high score group. We retrospectively analyzed the association between G8 score and OS in all patients and for each ECOG-PS-categorized group. RESULTS: Out of 264 enrolled patients, most patients (87%) with solid tumor were categorized as TNM stage IV. ECOG-PS was 0 or 1 in 215 patients and ≥2 in 48; there was missing data for one patient. Among all patients, the low score group with a median OS of 7.7 months survived significantly less than both the high score group with a median OS of 25.6 months [Hazard ratio (HR) 3.48; 95% confidence interval (CI), 1.96-6.63; p < 0.0001] and the intermediate score group with a median of 15.6 months (HR 1.83; 95% CI, 1.28-2.65; p < 0.001). In the multivariate analysis, TNM stage and G8 score were independent prognostic factors for OS. When patients with an ECOG-PS of 0 or 1 were analyzed, patients with a lower G8 score showed significantly shorter OS than patients with a higher score when any two groups were compared. CONCLUSION: This novel classification of the G8 score contributes to prompt identification of patients with poor prognosis and improved the prognostic value of ECOG-PS. Using G8 with ECOG-PS may be helpful in deciding treatment for elderly patients with advanced cancer.

Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3-kinase dual inhibitor.

Histone deacetylase (HDAC)/phosphatidylinositol 3-kinase (PI3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and showing synergistic effects. Therefore, development of an HDAC/PI3K dual inhibitor is reasonably attractive. Romidepsin (FK228, depsipeptide) is a potent HDAC inhibitor. We previously reported that depsipeptide and its analogs have an additional activity as PI3K inhibitors and are defined as HDAC/PI3K dual inhibitors. Subsequently, we identified FK-A11 as the most potent analog and reported its biochemical, biological, and structural properties as an HDAC/PI3K dual inhibitor. In this study, we reveal the in vitro and in vivo efficacy of FK-A11 in HT1080 fibrosarcoma and PC3 prostate cancer cell xenograft mouse models. FK-A11 showed in vivo antitumor activity by both i.v. and i.p. administration in a dose-dependent manner. In both xenograft models, FK-A11 showed superior antitumor effects compared to other depsipeptide analogs in accordance with in vitro anti-cell proliferation effects and the potency of HDAC/PI3K dual inhibition. In addition, we showed evidence of HDAC/PI3K dual inhibition accompanying antitumor efficacy in xenograft tumor tissues by immunohistochemistry. We also detailed pharmacokinetic characterization of FK-A11 in mice. These findings will be essential for guiding further preclinical and clinical studies.

Efficacy and Safety Assessment of Paclitaxel in Patients with Docetaxel-Resistant Esophageal Squamous Cell Carcinoma.

BACKGROUND: Incomplete cross-resistances between paclitaxel (PTX) and docetaxel (DTX) has been demonstrated in several types of cancer. The objective of the present study was to assess the existence of cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. METHODS: Patients in the PTX group received PTX without DTX pretreatment, patients in the prior DTX (Pr-DTX) group received PTX after the development of resistance to DTX, and patients in the DTX group received DTX without subsequent PTX treatment. RESULTS: A total of 73 patients were enrolled. The response rates to PTX in the PTX and Pr-DTX groups were 22.7 and 20.0%, respectively. The median progression-free survival times from the first day of PTX treatment in the PTX and Pr-DTX groups were 113 (95% CI 56-154) and 97 days (95% CI 36-189), respectively. The median overall survival times from the first day of DTX treatment in the Pr-DTX and DTX groups were 315 (95% CI 124-453) and 148 days (95% CI 139-177), respectively. CONCLUSIONS: There is no or incomplete clinical cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. Replacement of DTX with PTX is a suitable treatment option for patients with DTX-resistant esophageal squamous cell carcinoma.