Echocardiographic changes in diastolic filling and stroke volume during postural alterations and ankle exercise in a patient with congenital defect of the pericardium

Journal of Echocardiography -     

FMS‐like tyrosine kinase 3 (FLT3) amplification in patients with metastatic colorectal cancer

FMS‐like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co‐altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co‐alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non‐FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted.     

Efficacy of modified bevacizumab-XELOX therapy in Japanese patients with stage IV recurrent or non-resectable colorectal cancer

BackgroundNeoadjuvant chemotherapy (NAC) has been conducted for patients with non-resectable colorectal cancer; however, few reports of a systematic approach to NAC exist. At our hospital, bevacizumab with capecitabine and oxaliplatin (B-mab XELOX) has been used as chemotherapy for Stage IV colorectal cancer since 2014. We aimed to evaluate the efficacy and safety of NAC with a molecular-targeting agent for Stage IV colorectal cancer.MethodsA retrospective, single-institute analysis was performed including 27 patients with advanced recurrent cancer following primary tumor resection and 43 patients with non-resectable tumors and remote metastasis. At the time of resection, 17 were receiving chemotherapy. All 70 patients received at least 3 cycles of B-mab XELOX (total: 920 cycles). We determined the 1-year progression-free survival (1Y-PFS), 1-year overall survival (1Y-OS), 3Y-PFS, 3Y-OS, and number of treatment cycles. The objective response rate, clinical benefit rate, and adverse events were assessed. The number of chemotherapy cycles, survival time, and R0 surgery rate were determined for patients who underwent RO conversion surgery.ResultsThe 1Y-PFS was 28.5% [median survival time (MST): 7.4 months], 1Y-OS was 76.6% (MST not reached), 3Y-PFS was 5.5% (MST: 7.4 months), and 3Y-OS was 26.4% (MST: 25.2 months). The mean and median number of cycles of B-mab XELOX was 13.1 and 10.5, respectively. The objective response rate was 28.6%, and the clinical benefit rate was 58.6%. Grade 1 or Grade 2 adverse events occurred in 60 patients (85.7%); however, they all resolved without intervention. A single Grade 4 event (perforation of the primary tumor) occurred in 1 patient (1.4%). RO conversion surgery was performed in 7 patients (10.0%; primary + liver in 2 patients, primary + lung in 1 patient, liver in 3 patients, and primary in 1 patient). These patients received 3 to 10 cycles preoperatively (mean: 7.3; median: 6.5). R0 surgery was achieved in 5 of the 7 patients (71.4%). Postoperative survival ranged from 1 to 26 months (MST: 8 months).ConclusionsThis modified regimen was safe and effective in Japanese patients, and a high quality of life/quality-adjusted life-year was achieved. To further evaluate PFS and OS, more patients are being investigated.     

Primary orbital neuroblastoma in a 1‐month‐old boy

Neuroblastoma is a malignant tumor predominantly occurring in children and usually arising from the adrenal gland or sympathetic ganglia. We describe a neuroblastoma in a 1‐month‐old boy arising from his left orbital cavity. This tumor was refractory to chemotherapy or radiotherapy, requiring enucleation of the left eye for complete removal of the intraorbital tumor. Thereafter, he received high‐dose chemotherapy followed by autologous peripheral blood stem cell transplantation, and has been in complete remission for 3 years. Unlike neuroblastomas arising from the adrenal gland or sympathetic ganglia, primary orbital neuroblastoma may be refractory even in early infancy.     

The area and attachment abnormalities of the gubernaculum in patients with undescended testes in comparison with those with retractile testes

Purpose

In order to evaluate the gubernaculum (GN) abnormalities quantitatively in patients with undescended testes (UDT), the area and attachment site of the gubernaculum were evaluated.

Patients and methods

Sixty-seven testes from 61 patients with an undescended testis treated in the past 11 years at our institution were examined. Using intraoperative photographs or DVDs, the area of the GN inside the processus vaginalis was measured, and the ratio to that of the testis was determined. When the GN was attached to the vas deferens, the GN distance from the testis was also measured, and the ratio to that of the transverse length of the testis (deviation index) was calculated. Reference values were obtained from 23 testes from 15 patients with mobile testes.

Results

In cases with mobile testes, the GN attached to the bottom of the testis, and involved the lower pole of the epididymis. Even though the GN was attached to the bottom of the testis in 43 testes in the UDT patients (64 %), the GN was found to be elongated. The mean GN area ratio was 1.58 (1SD, 0.6) in the UDT cases, in comparison to 0.47 (0.2) in the cases with mobile testes. The GN was attached to the vas deferens in 24 testes (36 %). The deviation index was 1.34 (1.0), but the GN area ratio of these cases was 1.56 (0.7), which was similar to that of the GN attached to the bottom of the testis.

Conclusion

The present study revealed that an increase in the GN area ratio was the most common imaging abnormality in cases with UDT.     

Do consensus indications for resection in branch duct intraductal papillary mucinous neoplasm predict malignancy? A study of 147 patients

BACKGROUND AND AIMS: Recent consensus guidelines suggest that presence of > or =1 of the following is an indication for resection (IR) of branch duct intraductal papillary mucinous neoplasm (IPMN-Br): cyst-related symptoms, main pancreatic duct diameter > or =10 mm, cyst size > or =30 mm, intramural nodules, or cyst fluid cytology suspicious/positive for malignancy. Among a cohort of patients with IPMN-Br we determined if the consensus IR (CIR), presence of multifocal IPMN-Br, or growth of cyst size on follow-up predict malignancy. METHODS: We identified 147 patients with IPMN-Br of whom 66 underwent surgical resection at diagnosis and 81 were followed conservatively, of whom 11 were resected during follow-up. Clinical, imaging, histological, and cyst fluid characteristics from all 147 patients with IPMN-Br were obtained from clinical records and/or by contacting the patients. In all cases, presence of CIR at baseline and during follow-up (N = 66), presence of multifocal cysts (N = 57), and increase in cyst size (N = 38) were noted. RESULTS: Among the 77 resected IPMN-Brs, at initial evaluation 61 had at least one CIR and 16 had none. Malignancy was present in 9/61 (15%) with CIR and 0/16 without IR (P= 0.1). When presence of any one of the CIR was taken as an indicator of malignancy, the CIR had a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 23%, 14%, and 100%, respectively. Prevalence of malignancy in those with single versus multifocal IPMN-Br was similar (13%vs 11%). No patient has developed malignancy after a median follow-up of 15 months. So far, none of the 38 patients with increase in cyst size on follow-up has developed malignancy related symptoms. CONCLUSIONS: Suggested consensus indications for resection identify all patients with malignancy; however, their specificity is low. In the short term it would be safe to follow patients without these features.     

Phase I/II Study of Erlotinib to Determine the Optimal Dose in Patients With Non‐Small Cell Lung Cancer Harboring Only EGFR Mutations

The recommended daily dose of erlotinib was determined for patients with all types of non‐small cell lung cancer (NSCLC). We determined the optimal dose (OD) in patients with NSCLC harboring only epidermal growth factor receptor (EGFR) sensitizing mutations. EGFR‐tyrosine kinase inhibitor‐naïve patients with sensitizing mutations were eligible. Clinical OD was determined in a phase I/II study based on the continual re‐assessment method (CRM) of both disease control and dose‐limiting toxicity, defined as any toxicity of grade 2 (G2) or higher within 8 weeks. We also determined the pharmacologic OD via a pharmacokinetic (PK) study. Thirty‐eight patients were enrolled. Clinical OD was 25 mg/day by the CRM. Median progression‐free survival (mPFS) was 9.3 months. In receiver operating characteristic (ROC) analysis of mPFS, the trough concentration ( Cminss) was ≥ 0.30 μg/mL. The area under the curve (AUC) and Cminss were predicted via population PK (PopPK) or a bootstrap of 100 iterations (PopPK₁₀₀). TOX20 was defined as < 20% duration of any toxicity ≥ G2 during the PFS period. In ROC analysis of mPFS and TOX20 in the PopPK₁₀₀ study, Cminss was ≥ 0.17 and < 0.32 μg/mL, respectively. In ROC analysis of mPFS and TOX20 in the PopPK₁₀₀ study, Cminss was ≥ 0.15 and < 0.31 μg/mL, AUC was ≥ 14.4 and < 14.5 μg/mL•hour, and the dosage was ≥ 58.4 and < 58.8 mg/day, respectively. Clinical and pharmacologic ODs were 25 by CRM and 50–60 mg/day by PK, respectively. The proposed starting OD is 50–60 mg/day, with personalized adjustment of 0.15–0.31 μg/mL based on Cminss as determined by PopPK monitoring.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ The recommended daily dose of erlotinib was determined for patients with all types of non‐small cell lung cancer (NSCLC). Many patients suffer severe and long‐term adverse events related to treatment despite tumors harboring sensitizing mutations.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What is the optimal dose of erlotinib for patients with NSCLC harboring sensitizing mutations?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ In terms of therapy with a reduced dose of erlotinib, modest benefit was achieved when all patients received the same reduced dose, but greater benefit is obtained if each patient receives a personalized optimal dose via population pharmacokinetic monitoring based on interpatient variations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The method can be adapted to determine the optimal dose of molecular targeting agents other than erlotinib. The most benefit for patients is realized if their tumors are treated with a personalized optimal dose of molecular targeting agent, balancing toxicity and efficacy to adjust to interpatient differences.

Five epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) are currently available for use in clinical practice. ¹ All of these EGFR‐TKIs improve progression‐free survival (PFS) compared with standard chemotherapy as first‐line treatment for patients with non‐small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. ² , ³ Erlotinib is a first‐generation EGFR‐TKI with a recommended once‐daily oral dose of 150 mg. This dose was intended to target all types of EGFR (i.e., wild type and any EGFR mutations) based on dose‐escalation experiments in a phase I study of cytotoxic agents ⁴ and is the maximum tolerated dose. EGFR‐tyrosine kinase sensitizing mutations include exon 19 deletions (E19DEL) and a point mutation in exon 21 (L858R); thus, erlotinib exhibits excellent efficacy in patients with NSCLC harboring these sensitizing mutations. ⁵ At a 150 mg/day dose, the mean trough steady‐state concentration ( Cminss) of erlotinib is > 2.5 µM. ⁴ However, several basic research studies reported a 50% growth inhibitory concentration in NSCLC cell lines harboring sensitizing mutations of < 0.1 µM. ⁶ , ⁷ , ⁸ It is, therefore, likely that erlotinib can be given at doses < 150 mg/day while maintaining clinical efficacy.A postmarketing surveillance study of erlotinib in Japan involving 3,488 patients ⁹ reported the following rates of adverse events (AEs) of grade 2 (G2) or higher; eruptions = 38.8%, paronychia = 3.4%, diarrhea = 7.1%, hepatic disorders = 5.4%, and interstitial lung disease = 3.7%. About 90% of the patients were given 150 mg/day of erlotinib during treatment in this surveillance study. Because 55.1% of the patients had a history of gefitinib treatment and patients with all types of EGFR were eligible for this study, median PFS was only 64 days (95% confidence interval (CI) 60–68 days). Several AEs induced by erlotinib persisted during treatment. Long‐term, persistent AEs, even of low grade, can restrict patients’ normal activities and adversely affect their quality of life (QOL). ¹⁰ In interpatient dose escalation, the degree of AEs became more and more severe depending on increasing the daily dose of erlotinib from 25 to 200 mg/day. ⁴ During long‐term treatment, reduced toxicity can lead to improved QOL. It is, therefore, likely that reducing the required dose of erlotinib would have beneficial toxicity and QOL effects.The purpose of the present two‐phase study was to determine the optimal dose (OD) of erlotinib in patients with NSCLC harboring only sensitizing mutations. The first phase determined the minimum effective dose (MED) and OD of erlotinib in the target patient population, and the second phase determined the clinical and pharmacologic ODs. The study’s overall goal was to facilitate personalized dosing of erlotinib with the objective of balancing toxicity and efficacy.