Assessment of the albumin-bilirubin grade as a prognostic factor in patients with non-small-cell lung cancer receiving anti-PD-1-based therapy.

INTRODUCTION: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. METHODS: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan-Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. RESULTS: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan-Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. CONCLUSION: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

Cell therapy for medication-related osteonecrosis of the jaw: update on treatment strategies.

Bioactive glasses (BAG) are used as bone-graft substitutes in orthopaedic surgery. A specific BAG scaffold was developed by sintering BAG-S53P4 granules. It is hypothesised that this scaffold can be used as a bone substitute to fill bone defects and induce a bioactive membrane (IM) around the defect site. Beyond providing the scaffold increased mechanical strength, that the initial inflammatory reaction and subsequent IM formation can be enhanced by coating the scaffolds with poly(DL-lactide-co-glycolide) (PLGA) is also hypothesised. To study the immunomodulatory effects, BAG-S53P4 (± PLGA) scaffolds were placed on monolayers of primary human macrophage cultures and the production of various pro- and anti-inflammatory cytokines was assessed using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and ELISA. To study the osteogenic effects, BAG-S53P4 (± PLGA) scaffolds were cultured with rabbit mesenchymal stem cells and osteogenic differentiation was evaluated by RT-qPCR and matrix mineralisation assays. The scaffold ion release was quantified and the BAG surface reactivity visualised. Furthermore, the pH of culture media was measured. BAG-S53P4 scaffolds had both anti-inflammatory and osteogenic properties that were likely attributable to alkalinisation of the media and ion release from the scaffold. pH change, ion release, and immunomodulatory properties of the scaffold could be modulated by the PLGA coating. Contrary to the hypothesis, the coating functioned by attenuating the BAG surface reactions and subsequent anti-inflammatory properties, rather than inducing an elevated inflammatory response compared to BAG-S53P4 alone. These results further validated the use of BAG-S53P4 (± PLGA) scaffolds as bone substitutes and indicate that scaffold properties can be tailored to a specific clinical need.

Single-blind randomized clinical trial of transinguinal preperitoneal repair using self-expanding mesh patch vs. Lichtenstein repair for adult male patients with primary unilateral inguinal hernia.

PURPOSE: The aim of the study was to compare proportions of chronic postoperative inguinal pain (CPIP) and other surgical outcomes between transinguinal preperitoneal repair with modified Kugel patch (MK) and Lichtenstein repair (LR). METHODS: Two-hundred adult male patients with primary unilateral inguinal hernia were randomized into MK or LR groups. The primary endpoint was CPIP, pain at 6 months after surgery. Secondary outcomes included recurrence rate, incidence of postoperative complications, time until return to activities, inguinal pain and sensory disturbances assessed at 1 week, 1 month, 3, 6, and 12 months after the operation using an 11-point numerical rating scale (NRS). The study was an intention-to-treat analysis. RESULTS: In comparison of MK (n = 100) and LR (n = 100) with similar backgrounds, proportions of CPIP were similar (7.2 vs. 11.1%, p = 0.3452). Favorable outcomes for MK were duration of operation (32 vs. 40 min, p < 0.0001), NRS of foreign body sensation at 1 year (0 [0-1] vs. 0 [0-2], p = 0.0067), and NRS of numbness at 1 month (0 [0-1] vs. 0 [0-3], p = 0.0078) after the operation. CONCLUSIONS: In regard to CPIP, the short-term results of MK and LR were similar.

Eldecalcitol (ED-71)-induced exosomal miR-6887-5p suppresses squamous cell carcinoma cell growth by targeting heparin-binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1).

Heparin-binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1) was purified from A431 cell-conditioned media based on its capacity to bind to fibroblast growth factor 1 and 2 (FGF-1 and FGF-2). HBp17/FGFBP-1 has been observed to induce the tumorigenic potential of epithelial cells and is highly expressed in oral cancer cell lines and tissues. HBp17/FGFBP-1 is also recognized as a pro-angiogenic molecule as a consequence of its interaction with FGF-2. We have previously reported that Eldecalcitol (ED-71), an analog of 1α,25(OH)2D3, downregulated the expression of HBp17/FGFBP-1 and inhibited the proliferation of squamous cell carcinoma (SCC) cells in vitro and in vivo through NF-κb inhibition. To explore the possibility of microRNA (miRNA) control of HBp17/FGFBP-1, we analyzed exosomal miRNAs from medium conditioned by A431 cells treated with ED-71. Microarray analysis revealed that 12 exosomal miRNAs were upregulated in ED-71-treated A431 cells. Among them, miR-6887-5p was identified to have a predicted mRNA target matching the 3' untranslated region (3'-UTR) of HBp17/FGFBP-1. The 3'-UTR of HBp17/FGFBP-1 was confirmed to be a direct target of miR-6887-5p in SCC/OSCC cells, as assessed with a luciferase reporter assay. Functional assessment revealed that overexpression of miR-6887-5p in SCC/OSCC cells inhibited cell proliferation and colony formation in vitro, and inhibited tumor growth in vivo compared with control. In conclusion, our present study supports a novel anti-cancer mechanism involving the regulation of HBp17/FGFBP-1 function by exosomal miR-6887-5p in SCC/OSCC cells, which has potential utility as a miRNA-based cancer therapy.

Metastasis of carcinoma ex pleomorphic adenoma to the brain without previous metastasis to the lungs or bones: a case report.

Carcinoma ex pleomorphic adenoma is a rare type of cancer of the salivary gland that involves the malignant transformation of a primary or recurrent pleomorphic adenoma, which often metastasises to the lungs or bones, or both. To the best of our knowledge, however, nobody has reported a distant metastasis of this lesion to the brain without such previous metastasis. We report a case in a 64-year-old man.

Pathological factors involved in local failure in squamous cell carcinoma of the oral cavity: retrospective study and proposal of a new clinical classification.

The control of local failure (LF) is essential to improve outcomes in patients with squamous cell carcinoma of the oral cavity (OSCC). In this study, LF of OSCC was classified into three clinical types: deep recurrence (type 1R), adjacent superficial recurrence (type 2R), and distant primary tumour (type 3R). LF was analyzed after surgical resection of OSCC to determine the validity and usefulness of this classification system. Of 257 patients with OSCC, 58 experienced LF; 21 had type 1R, 23 had type 2R, and 20 had type 3R. Clinical factors influencing LF were analyzed by log-rank test and Cox test. Type 1R was significantly related to the TN classification, resection margin status, and invasive pattern. Type 2R was strongly associated with the grade of epithelial dysplasia at the surgical margins. Type 1R rarely developed more than 1year after surgery, whereas type 2R did not develop within 2 years. Type 1R may be caused by residual cancer cells in the deep margins, and type 2R by precancerous cells remaining in the marginal epithelium and gradually becoming invasive cancer. Type 3R may be considered an independent tumour. The newly proposed clinical classification is convenient and roughly reflects the causes and mechanisms of relapse.

Correlation between dermoscopic and histopathological findings of leucoplakia of the tongue: a case report.

A 75-year-old Japanese man presented at our outpatient clinic with pain on the right side of his tongue. Comparison of histological and dermoscopic images showed that areas with hyperkeratosis were opaque white, areas above the papillary dermis were reddish, and that the lesion looked whiter on dermoscopy the longer the epithelial rete ridges were. A dermatocope shows structural information from the epidermis as well as the upper dermis, and could improve early diagnosis of oral mucosal squamous carcinoma in situ.

Usefulness of chemoradiotherapy for inoperable gastric cancer.

Introduction Radiotherapy is not commonly used for the treatment of gastric cancer in Japan, where surgery is the standard local treatment. We report the results of chemoradiotherapy in patients with advanced or recurrent gastric cancer which was deemed difficult to treat surgically. Methods Twenty-one patients with gastric cancer (including sixteen with advanced/recurrent gastric cancer and five with poor general condition) underwent chemo-radiotherapy, for whom the therapeutic efficacy, toxicity and survival period were analysed. Results The tumour response to chemoradiotherapy was categorised as complete, partial, stable or progressive in 5, 9, 3, and 4 patients, respectively, with an overall response rate of 67%. No serious complications such as gastrointestinal perforation or bleeding occurred, and no cardiac, hepatic or renal dysfunction developed during the follow-up period. The mean survival time was 19.8 months (range, 3-51 months). One patient died of another disease, 18 died of primary cancer and the cause of death was unknown in 2 patients. Conclusions Chemoradiotherapy appears to be an effective treatment for localised gastric cancer without distant metastases, but further studies are needed to determine the indications for chemoradiotherapy and late adverse effects, as well as the chemotherapy regimens to be used.

Eldecalcitol (ED-71), an analog of 1α,25-dihydroxyvitamin D3 as a potential anti-cancer agent for oral squamous cell carcinomas.

We have previously reported that 1,25(OH)2D3 inhibits NF-κB activity and thus inhibits growth of OSCC cells in serum-free culture and down-regulates HBp17/FGFBP-1 expression, which is important for cancer cell growth and angiogenesis. Here, we have investigated the effects of ED-71, an analog of vitamin D3 (VD) on OSCC cell lines in serum-free culture. It is known that ED-71 has a stronger inhibitory effect on bone resorption compared to VD and other VD analogs. To the best of our knowledge, there was no report examining the potential of ED-71 as an anti-cancer agent for OSCC. We found that ED-71 is able to inhibit the growth of cancer cell lines at a concentration of hundred times lower than calcitriol. As Cyp24A1 was reportedly induced in cancer cells, we measured the expression of CYP24A1 in OSCC cell lines (NA and UE), A431 epidermoid carcinoma and normal fibroblast cell (gfi) in serum-free culture. As a result, CYP24A1 mRNA and the protein expression in the OSCC cells treated with ED-71 increased in a dose-dependent manner. However, in vivo experiment, in which the A431 cells were implanted in mice, tumor formation was reduced by the ED-71 treatment with no significant difference between Cyp24A1 expression in the tumors of ED-71-treated and control group, as analyzed by western blotting and immunohistochemistry. These results suggest that ED-71 is a potential anti-cancer agent for OSCC.

Anterior mediastinal solid tumours in adults: characterisation using dynamic contrast-enhanced MRI, diffusion-weighted MRI, and FDG-PET/CT.

AIM: To find significant parameters to characterise anterior mediastinal solid tumours in adults using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion-weighted MRI (DWI), and combined 2-[(18)F]-fluoro-2-deoxy-d-glucose positron-emission tomography/computed tomography (FDG-PET/CT). MATERIALS AND METHODS: Forty-eight histologically confirmed anterior mediastinal solid tumours in 48 patients (24 men, 24 women; age range 21-83 years, mean 50.7 years) were examined. The parameters analysed were maximal diameter, presence of capsule/septa on T2-weighted images, time-signal intensity curves (TICs), apparent diffusion coefficient (ADC), and maximum standardised uptake value (SUVmax). Also examined was whether any differences between histological types could be seen in these parameters. In a validation study, 42 anterior mediastinal solid tumours in 42 patients were examined consecutively. RESULTS: The washout pattern on TIC was seen only in thymic epithelial tumours (20/32). SUVmax of lymphoma (mean, 17.9), malignant germ cell tumours (14.2), and thymic carcinomas (15.6) were significantly higher than that of thymomas (6.1). The mean maximal diameter of thymic epithelial tumours was significantly smaller than that of lymphomas (p<0.01) and malignant germ cell tumours (p<0.05). The validation study also yielded high accuracy (38/42, 91%) in differentiation among the anterior mediastinal solid tumours. CONCLUSION: The SUVmax, TIC pattern on DCE-MRI, and maximal diameter might be useful to differentiate anterior mediastinal solid tumours in adults.

Comparison of the prognosis of bisphosphonate-related osteonecrosis of the jaw caused by oral and intravenous bisphosphonates.

Bisphosphonates (BPs) have been used in medical practice for the treatment of osteoporosis, bone metastasis, and multiple myeloma. Although many studies have been published, the treatment and prognosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) remain unclear. This study included 59 patients with BRONJ: 29 had taken oral BPs and 30 had taken intravenous (IV) BPs. All received conservative treatments. When separated sequestra were seen, a sequestrectomy was performed. Segmental mandibular resection was performed when pathological fractures were diagnosed. The outcomes of treatments were compared between groups. For patients treated with oral rinses or mandibular resection, the number in whom clinical healing was observed did not differ between the oral BP and IV BP groups. With regard to sequestrectomy, 94% of patients in the oral BP group showed improvement with this treatment compared to 50% in the IV BP group. The number of patients in whom clinical healing of BRONJ was achieved was statistically better in the oral BP group than in the IV BP group after 6 months of treatment (P<0.001). The results showed that >90% of patients treated with oral BPs could be cured. However, 50% of patients treated with IV BPs did not show an improvement. Additional research is needed to further increase the therapeutic efficacy for the resolution of BRONJ.

Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo. METHODS: Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression. RESULTS: We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens. CONCLUSIONS: Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Characteristics of flexed knee gait and functional outcome of a patient who underwent knee reconstruction with a hingeless prosthesis for bone tumor resection: a case report with gait analysis and comparison with healthy subjects.

We report on a patient after knee reconstruction for osteosarcoma in the distal femur using a hingeless prosthesis K-MAX KNEE system K-5 who walked without ipsilateral knee extension in the latter half of the stance phase (flexed knee gait). We evaluated the patient using three-dimensional gait analysis and isokinetic knee strength measurement, and compared the patient with five healthy subjects. The Musculoskeletal Tumor Society (MSTS) score was also used for evaluation. The patient kept his operated knee flexed during mid stance. The maximal ankle plantarflexion internal moment was lower on the ipsilateral side than on the contralateral side, and lower than in the healthy subjects. The negative ankle power during the stance phase was generally stronger on the ipsilateral side than on the contralateral side, and also in the healthy subjects. Unusual contralateral hip flexion occurred after the initial contact, indicating increased joint load on the ipsilateral ankle and the contralateral hip. The ratios of the peak knee extension/flexion torque were 0.7 on the ipsilateral side, 1.9 on the contralateral side, and 1.7 in the healthy subjects. The MSTS score of the patient was 23/30 (76.6%). Flexed knee gait might account for the reduction of ipsilateral hip flexion and ankle plantarflexion moment during the late stance phase. These results suggest the importance of focusing more on the ipsilateral ankle joint and the contralateral hip joint to maintain the function of the entire limb joints of the patients with flexed knee gait.

Modified Kugel herniorrhaphy using standardized dissection technique of the preperitoneal space: long-term operative outcome in consecutive 340 patients with inguinal hernia.

PURPOSE: The aim of this study was to evaluate the outcome, with a special reference to recurrence and postoperative chronic pain, of the modified Kugel herniorrhaphy (MKH) using standardized dissection of the preperitoneal space. PATIENTS AND METHODS: Operative results were examined based on medical records and questionnaire surveys in 340 consecutive cases of MKH performed at a single institution. The operation was performed with an original 3-stage dissection of the preperitoneal space only via the internal inguinal ring. RESULTS: The mean follow-up period was 50.5 ± 24.3 months. The mean operating time was 42.2 ± 13.1 min, and by Nyhus classification, significant difference was observed between types IIIA and IIIB (39.5 ± 10.8 vs. 45.6 ± 15.6 min, P = 0.0279). Eight surgeons performed 10 or more operations, and no significant difference was found in their operating time. Thirty-one patients used additional analgesics postoperatively (9.1 %) and the length of postoperative stay was 1.2 ± 0.7 days. Seven patients (2.1 %) developed complications related to the hernia operation, but none of them required re-operation. The period required to return to normal daily activities was 3 ± 3.2 days. Questionnaire forms were returned from 77.7 % of all the patients, in which 12 patients reported chronic pain (4.7 %). Visual analog scale for patients with chronic pain scored 3.8 ± 2.4, with no patient indicating restrictions on daily life. Recurrence was observed in only one case (0.3 %). CONCLUSION: MKH using standardized dissection of the preperitoneal space is a highly reproducible procedure with acceptable rate of postoperative chronic pain and recurrence.

Hoxb8 regulates expression of microRNAs to control cell death and differentiation.

Hoxb8 overexpression immortalises haematopoietic progenitor cells in a growth-factor-dependant manner and co-operates with interleukin-3 (IL-3) to cause acute myeloid leukaemia. To further understand how Hoxb8 contributes to myeloid cell immortalisation, we generated IL-3-dependant myeloid cells expressing Hoxb8 under the control of an inducible promoter. Downregulation of Hoxb8, in the presence of IL-3, caused cell-cycle arrest and apoptosis in the majority of cells. Apoptosis was dependant on Bax and Bak and, in part, on Bim, which was repressed by Hoxb8. Deletion of the miR-17∼92 seed sequences in the Bim 3'UTR abolished Hoxb8-dependant regulation of Bim reporter constructs. Expression of all six miRNAs from this cluster were elevated when Hoxb8 was overexpressed. The miR-17∼92 cluster was required for repression of Bim in Hoxb8-immortalised cells and deletion of the miR-17∼92 cluster substantially inhibited Hoxb8, but not Hoxa9, mediated survival and proliferation. Hoxb8 appears to promote miR-17∼92 expression through c-Myc, a known transcriptional regulator of the miR-17∼92 cluster. We have uncovered a previously unrecognised link between Hoxb8 expression and microRNAs that provides a new insight into the oncogenic functions of Hoxb8.

Characteristics of flexed knee gait and functional outcome of a patient who underwent knee reconstruction with a hingeless prosthesis for bone tumor resection: a case report with gait analysis and comparison with healthy subjects.

We report on a patient after knee reconstruction for osteosarcoma in the distal femur using a hingeless prosthesis K-MAX KNEE system K-5 who walked without ipsilateral knee extension in the latter half of the stance phase (flexed knee gait). We evaluated the patient using three-dimensional gait analysis and isokinetic knee strength measurement, and compared the patient with five healthy subjects. The Musculoskeletal Tumor Society (MSTS) score was also used for evaluation. The patient kept his operated knee flexed during mid stance. The maximal ankle plantarflexion internal moment was lower on the ipsilateral side than on the contralateral side, and lower than in the healthy subjects. The negative ankle power during the stance phase was generally stronger on the ipsilateral side than on the contralateral side, and also in the healthy subjects. Unusual contralateral hip flexion occurred after the initial contact, indicating increased joint load on the ipsilateral ankle and the contralateral hip. The ratios of the peak knee extension/flexion torque were 0.7 on the ipsilateral side, 1.9 on the contralateral side, and 1.7 in the healthy subjects. The MSTS score of the patient was 23/30 (76.6%). Flexed knee gait might account for the reduction of ipsilateral hip flexion and ankle plantarflexion moment during the late stance phase. These results suggest the importance of focusing more on the ipsilateral ankle joint and the contralateral hip joint to maintain the function of the entire limb joints of the patients with flexed knee gait.