Phase I clinical and pharmacokinetic study ofN 4-behenoyl-1-β-d-arabinofuranosylcytosine

A phase I study ofN ⁴-behenoyl-1-β-d-arabinofuranosylcytosine (BHAC) was conducted in 66 patients, 41 with solid tumors and 25 with hematological malignancies. The patients received either a 2-h single intravenous (i.v.) drip infusion (Schedule 1) or consecutive daily 2-h i.v. infusions (Schedule 2). In Schedule 1 the daily dose was initiated with 1.5 mg kg^?1 which was escalated up to 7 mg kg^?1. Side-effects were mild, and included nausea, vomiting, epilation, and hot flushes. Because of the presence of the solvent vehicle, HCO-60 and in consideration of the mechanism of action of BHAC, the dose escalation was stopped at 7 mg kg^?1. In Schedule 2, the daily dose was started with 1.5 mg kg^?1 which was escalated up to 8 mg kg^?1 and given for 2–16 days. Myelosuppression was found to be dose-limiting toxicity. The maximum tolerated dose (MTD) in patients with non-hematological solid tumors was assumed to be 5 mg kg^?1 daily × 5 days. The plasma disappearance curve of BHAC looked biphasic, and when 4 mg kg^?1 of BHAC were administered the half-lives of the initial phase (t _1/2α) and the second phase (t _1/2β) were calculated as 0.798 and 5.76 h respectively. In Schedule 2 complete remission was observed in 5 out of 21 patients with acute leukemia, one partial remission in Hodgkin’s disease, and one 1-B response (Karnofsky) in thyroid papillary adenocarcinoma.     

Modified load sharing rip-stop technique in patients with traumatic transtendinous rotator cuff tear: Surgical technique and clinical outcomes

BackgroundTranstendinous rotator cuff tear is likely to occur due to trauma in sports activities, with a frequency of <2% of total rotator cuff tears. These tears are difficult to treat because of limited tendon tissue in the proximal stump, and standard repair techniques are sometimes ineffective. Few studies have reported on the repair technique and clinical outcomes for transtendinous rotator cuff tear, and an appropriate repair technique has, therefore, not been established. The purpose of this study was to use our modified load sharing rip-stop technique to repair transtendinous rotator cuff tear and to clarify the clinical effectiveness of this technique.MethodsThis was a retrospective case series review of eight patients who underwent the modified load sharing rip-stop technique for repairing traumatic transtendinous rotator cuff tear between January 2013 and June 2017. The eight patients were followed up for at least 2 years (range: 24–41 months). Cuff integrity was evaluated using magnetic resonance imaging at 12 months after surgery using the Sugaya classification. We evaluated the pre- and postoperative ranges of motion, American Shoulder and Elbow Surgeons score, Constant Shoulder Score, and muscle strength at 90° abduction. Data were analyzed using the Mann–Whitney U test and Fisher's exact tests. P < .05 was considered to indicate statistical significance.ResultsSix patients were classified as Sugaya I and two as Sugaya II. ASES score (38.5–90.2, P = .0008), Constant shoulder score (36.5–79, P = .002), flexion (85°–158.1°, P = .002), abduction (85°–157.5°, P = .001), external rotation (38.8°–55°, P = .024), and muscle strength at 90° abduction (2.95–5.39 kg, P = .028) improved significantly. Six patients were able to return to their previous sports activity.ConclusionUsing our modified load sharing rip-stop technique for repair of transtendinous rotator cuff tear, patients obtained good clinical outcomes and could return to sports activities.     

High HNRNPA3 expression is associated with lymph node metastasis and poor prognosis in patients treated with radical cystectomy

ObjectiveWe sought to identify heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) expression in bladder cancer and its relationship to clinicopathological findings and prognosis.MethodsImmunohistochemical staining for HNRNPA3 was performed on 122 archived radical cystectomy specimens, with immunoreactivity being stratified on a 0 to 3 scale. The percentage of HNRNPA3 expressing tumor cells was calculated and multiplied by the staining score over an average of 5 areas to obtain a semiquantitative H-score (maximum value: 300). HNRNPA3 expression was categorized as high (≥80) or low (<80).ResultsThe patients’ median age was 70 years, and the median follow-up period was 39.4 months. High HNRNPA3 expression was significantly associated with lymph node metastasis (P= 0.014) and S100A8, S100A9 and uroplakin III expression (P= 0.028, 0.002, and 0.047, respectively). Log-rank tests indicated that high HNRNPA3 expression was significantly associated with disease progression and cancer-specific death (P= 0.013 and 0.006, respectively). In the Cox proportional hazards regression analysis, only lymph node metastasis was associated with disease progression and cancer-specific survival.ConclusionHNRNPA3 may be a new biomarker to predict biologically aggressive cancers and determine the appropriate treatment modality in patients after radical cystectomy.     

The impacts of breast conserving treatment and mastectomy on the quality of life in early-stage breast cancer patients

The quality of life (QOL) in 55 early-stage breast cancer patients after surgery was prospectively assessed using a newly developed Japanese QOL questionnaire: The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD). The impacts of breast conserving treatment (BCT) (22 cases) and modified radical mastectomy (MRM) (33 cases) on the QOL in those subjects were compared. The overall QOL scores were evaluated during four periods (before surgery, 0–2, 3–12, and 13–24 months after surgery). The mean scores of the four categories of the QOL-ACD (activity, physical condition, psychological condition, and social relationships) were also compared. The results demonstrated that a significant improvement was observed in the overall QOL scores among the three periods after surgery (0–2, 3–12, and 13–24 months) only in the BCT group (P<0.05). There were no significant differences between the two groups in the overall QOL scores during any of the three periods after surgery, and the mean score of the ‘psychological condition’ during 0–2 months period in the BCT group was significantly lower than that in the MRM group (P< 0.05).     

Matrix metalloproteinase-2 status in stromal fibroblasts, not in tumor cells, is a significant prognostic factor in non-small-cell lung cancer.

PURPOSE: The purpose is to assess clinical significance of matrix metalloproteinase (MMP)-2 and MMP-9 status, especially MMP-2 status, in stromal cells in non-small-cell lung cancer (NSCLC) because experimental studies have revealed that stromal MMP-2 plays important roles in progression of malignant tumors, but most clinical studies focused on tumoral MMP-2 expression, not stromal MMP-2 expression. EXPERIMENTAL DESIGN: We conducted a retrospective study on MMP-2 and MMP-9 expression as evaluated immunohistochemically in a total of 218 consecutive patients with completely resected pathological stage I-IIIA, NSCLC. RESULTS: Strong MMP-2 expression in tumor cells and stromal fibroblasts were documented in 54 (24.8%) and 132 (60.6%) patients, respectively. Strong MMP-2 expression in stromal fibroblasts was more frequently seen in squamous cell carcinoma (72.7%) than in adenocarcinoma (54.9%; P = 0.016). Tumors showing strong MMP-2 expression in stromal fibroblasts showed a significantly higher intratumoral microvessel density (IMVD) than weak stromal MMP-2 tumors (mean intratumoral microvessel density, 50.9 versus 32.4, P = 0.003). In addition, postoperative prognosis of strong stromal MMP-2 patients was significantly poorer than that of weak stromal MMP-2 patients (5-year survival rate, 77.5 versus 60.2%, P = 0.032), and the prognostic significance was enhanced in squamous cell carcinoma patients but disappeared in adenocarcinoma patients. Multivariate analyses confirmed that strong stromal MMP-2 expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients, not in adenocarcinoma patients. In contrast, MMP-2 or MMP-9 status in tumor cells was not a significant prognostic factor. CONCLUSIONS: MMP-2 status in stromal fibroblasts, not in tumor cells, was a significant prognostic factor associated with angiogenesis in NSCLC.     

Urgent transjugular retrograde obliteration for prophylaxis of rebleeding from gastric varices in patients with a spontaneous portosplenorenal shunt

BACKGROUND: Bleeding isolated gastric varices with a spontaneous portosplenorenal shunt are difficult to control. The urgent use of transjugular retrograde obliteration (TJO) to prevent early rebleeding and to improve early mortality has not yet been demonstrated. We report our experience with this technique in patients with isolated gastric varices after treatment of acute bleeding. METHODS: We reviewed our experience of 6 patients with isolated gastric varices with a spontaneous portosplenoral shunt treated with TJO after treatment of acute bleeding. We basically applied endoscopic glue embolization using cyanoacrylate monomer for treatment of acute bleeding. TJO was a method using an occlusive balloon catheter to control a spontaneous portosplenorenal shunt flow while injecting sclerosant retrograde into the gastric varices. RESULTS: Treatment of acute bleeding was achieved immediately by endoscopic glue embolization, endoscopic variceal ligation, and ligating the varices with sutures following anterior gastrotomy in 4, 1 and 1 patients, respectively, and then TJO was performed. Permanent hemostasis and variceal eradication was achieved in these 6, and they all survived. They were alive for 6-66 months without gastric variceal recurrence. CONCLUSIONS: We conclude that urgent TJO is effective in the prophylaxis of early and late rebleeding from isolated gastric varices in patients with a spontaneous portosplenorenal shunt.     

Spontaneous regression of malignant pleural mesothelioma

We describe the spontaneous regression of a malignant pleural mesothelioma with left pleural effusion, chest pain, and a high fever (38° to 39°C) in a 37-year-old man. The patient was referred to us because multiple nodules were seen on his chest radiograph after he was successfully treated with thoracocentesis and conventional antibiotic therapy for pleural effusion. Our diagnosis was malignant pleural mesothelioma, based on histologic findings in a biopsy specimen obtained during thoracoscopy. Interestingly, the tumors markedly regressed without treatment, and the patient was doing well more than 5 months after the cancer was diagnosed. The spontaneous regression of malignant pleural mesothelioma is rare, and this may represent the first case report.     

Highly sensitive detection of melanoma at an early stage based on the increased serum secreted protein acidic and rich in cysteine and glypican-3 levels.

PURPOSE: There are no available tumor markers detecting primary melanoma at an early stage. The identification of such serum markers would be of significant benefit for an early diagnosis of melanoma. We recently identified glypican-3 (GPC3) as a novel tumor marker but could diagnose only 40% of melanomas. Thereby, we focused out attention on secreted protein acidic and rich in cysteine (SPARC) overexpressed in melanoma as another candidate for tumor marker. EXPERIMENTAL DESIGN: Secreted SPARC protein was quantified using ELISA in the sera from 109 melanoma patients, five patients with large congenital melanocytic nevus, 61 age-matched healthy donors, and 13 disease-free patients after undergoing a surgical removal. We also quantified GPC3 and 5-S-cysteinyldopa in the same serum samples and compared these markers for their diagnostic value. RESULTS: The serum SPARC concentrations in melanoma patients were greater than those in healthy donors (P = 0.001). When we fixed a cutoff value at the mean concentration plus 2 SD of the healthy donors, the serum SPARC was found to have increased in the sera of 36 of the 109 (33%) melanoma patients, whereas there were three (4.9%) false-positive cases of 61 healthy donors. Surprisingly, 19 of 36 patients showing increased SPARC levels were in stages 0 to II. The serum SPARC level decreased under the cutoff level in 10 of 13 patients after surgical removal. Using SPARC and GPC3 in combination thus enabled us to diagnose 47 of 75 (66.2%) melanoma patients at an early stage (0-II). CONCLUSIONS: SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage.