Identification of glucagon like peptide-1 (GLP-1) in mice stomach.

Glucagon like peptide-1 (GLP-1) is a peptide hormone encoded by the pre-proglucagon gene that serves multiple physiological functions, including incretin action. While GLP-1 is primarily synthesized in the L cells of the lower intestine, recent findings indicate its presence in the stomachs of both rats and humans. However, the role of gastric GLP-1 in other species remains unclear. In this study, we aimed to identify GLP-1-producing cells and examine the localization of GLP-1 production in the mouse stomach. We found that pre-proglucagon mRNA was higher in the corpus than that in the antrum of the stomach. In addition, GLP-1 immunoreactive cells were found in the gastric mucosa, and their cell number was higher in the corpus than that in the antrum. Double immunofluorescence showed that some GLP-1 immunoreactive cells displayed somatostatin immunoreactivity, whereas did not co-localize with ghrelin and gastrin. Moreover, transmembrane G protein-coupled Receptor 5 (TGR5) agonist decreased pre-proglucagon mRNA expression in SG-1 cells in a concentration-dependent manner, and in vivo experiments showed a decrease in its mRNA levels in the gastric corpus but not in the antrum. This study marks the first report of GLP-1 production in the mouse stomach. Our findings suggest that gastric pre-proglucagon mRNA expression is regulated by a distinct mechanism compared to the L cells of the lower intestine.

Salvage surgery improves the treatment outcome of patients with residual/recurrent maxillary sinus cancer after superselective intra-arterial cisplatin infusion with concomitant radiation therapy.

PURPOSE: We have performed superselective intra-arterial cisplatin infusion with concomitant radiotherapy (RADPLAT) for patients with maxillary sinus cancer. The promising treatment outcomes of this non-surgical treatment were reported in past studies. However, few clinical studies have been conducted to evaluate the outcome of salvage surgery following RADPLAT. The purpose of this study was to analyze the treatment outcomes of salvage surgery for patients with recurrent maxillary sinus cancer after RADPLAT. METHODS: We assessed 45 patients who had recurrence following RADPLAT between 1999 and 2017, and conducted a retrospective analysis. We excluded patients who did not complete RADPLAT. Patients were not considered to have completed RADPLAT if they underwent intra-arterial cisplatin less than three times or received a total radiation dose of less than 60 Gy. The primary endpoint was overall survival. The median follow-up period for surviving patients after recurrence was 5.1 years. RESULTS: Twenty-five of the 45 (56%) patients underwent salvage surgery. The 5-year overall survival rate was 68% in patients who underwent salvage surgery, while all patients who did not undergo salvage surgery died during the observation period. Fifteen of 24 (63%) patients with local recurrence underwent salvage surgery. Eight patients did not undergo salvage surgery because of unresectable disease; five of the eight patients had unresectable posterior extension. All nine patients with nodal recurrence underwent neck dissection. CONCLUSION: Treatment outcomes of salvage surgery following RADPLAT were favorable enough for it to be generally recommended. To reduce unresectable recurrence, the posterior section should be eradicated by RADPLAT.

Impact of adaptive radiotherapy on survival in locally advanced nasopharyngeal carcinoma treated with concurrent chemoradiotherapy.

PURPOSE: To investigate the clinical significance of adaptive radiotherapy (ART) in locally advanced nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Eligible patients were treated with concurrent chemoradiotherapy using IMRT. Planning computed tomography in ART was performed during radiotherapy, and replanning was performed. Since ART was started in May 2011 (ART group), patients who were treated without ART up to April 2011 (non-ART group) were used as the historical control. The Kaplan-Meier method was used to calculate overall survival (OS), locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). LRFS for the primary tumor (LRFS_P) and regional lymph node (LRFS_LN) were also studied for more detailed analysis. Statistical significance was evaluated using the log-rank test for survival. RESULTS: The ART group tended to have higher radiation doses. The median follow-up period was 127 months (range, 10 to 211 months) in the non-ART group and 61.5 months (range, 5 to 129 months) in the ART group. Compared to the non-ART group, the ART group showed significantly higher 5-year PFS (53.8% vs. 81.3%, p = 0.015) and LRFS (61.2% vs. 85.3%, p = 0.024), but not OS (80.7% vs. 80.8%, p = 0.941) and DMFS (84.6% vs. 92.7%, p = 0.255). Five-year LRFS_P was higher in the ART group (61.3% vs. 90.6%, p = 0.005), but LRFS_LN did not show a significant difference (91.9% vs. 96.2%, p = 0.541). CONCLUSION: Although there were differences in the patient backgrounds between the two groups, this study suggests the potential effectiveness of ART in improving locoregional control, especially in the primary tumor.

Deformed dose restoration to account for tumor deformation and position changes for adaptive proton therapy.

BACKGROUND: Online adaptation during intensity-modulated proton therapy (IMPT) can minimize the effect of inter-fractional anatomical changes, but remains challenging because of the complex workflow. One approach for fast and automated online IMPT adaptation is dose restoration, which restores the initial dose distribution on the updated anatomy. However, this method may fail in cases where tumor deformation or position changes occur. PURPOSE: To develop a fast and robust IMPT online adaptation method named "deformed dose restoration (DDR)" that can adjust for inter-fractional tumor deformation and position changes. METHODS: The DDR method comprises two steps: (1) calculation of the deformed dose distribution, and (2) restoration of the deformed dose distribution. First, the deformable image registration (DIR) between the initial clinical target volume (CTV) and the new CTV were performed to calculate the vector field. To ensure robustness for setup and range uncertainty and the ability to restore the deformed dose distribution, an expanded CTV-based registration to maintain the dose gradient outside the CTV was developed. The deformed dose distribution was obtained by applying the vector field to the initial dose distribution. Then, the voxel-by-voxel dose difference optimization was performed to calculate beam parameters that restore the deformed dose distribution on the updated anatomy. The optimization function was the sum of total dose differences and dose differences of each field to restore the initial dose overlap of each field. This method only requires target contouring, which eliminates the need for organs at risk (OARs) contouring. Six clinical cases wherein the tumor deformation and/or position changed on repeated CTs were selected. DDR feasibility was evaluated by comparing the results with those from three other strategies, namely, not adapted (continuing the initial plan), adapted by previous dose restoration, and fully optimized. RESULTS: In all cases, continuing the initial plan was largely distorted on the repeated CTs and the dose-volume histogram (DVH) metrics for the target were reduced due to the tumor deformation or position changes. On the other hand, DDR improved DVH metrics for the target to the same level as the initial dose distribution. Dose increase was seen for some OARs because tumor growth had reduced the relative distance between CTVs and OARs. Robustness evaluation for setup and range uncertainty (3 mm/3.5%) showed that deviation in DVH-bandwidth for CTV D95% from the initial plan was 0.4% ± 0.5% (Mean ± S.D.) for DDR. The calculation time was 8.1 ± 6.4 min. CONCLUSIONS: An online adaptation algorithm was developed that improved the treatment quality for inter-fractional anatomical changes and retained robustness for intra-fractional setup and range uncertainty. The main advantage of this method is that it only requires target contouring alone and saves the time for OARs contouring. The fast and robust adaptation method for tumor deformation and position changes described here can reduce the need for offline adaptation and improve treatment efficiency.

Evaluation of short-term gastrointestinal motion and its impact on dosimetric parameters in stereotactic body radiation therapy for pancreatic cancer.

Background: The aim of this study is to quantify the short-term motion of the gastrointestinal tract (GI-tract) and its impact on dosimetric parameters in stereotactic body radiation therapy (SBRT) for pancreatic cancer. Methods: The analyzed patients were eleven pancreatic cancer patients treated with SBRT or proton beam therapy. To ensure a fair analysis, the simulation SBRT plan was generated on the planning CT in all patients with the dose prescription of 40 Gy in 5 fractions. The GI-tract motion (stomach, duodenum, small and large intestine) was evaluated using three CT images scanned at spontaneous expiration. After fiducial-based rigid image registration, the contours in each CT image were generated and transferred to the planning CT, then the organ motion was evaluated. Planning at risk volumes (PRV) of each GI-tract were generated by adding 5 mm margins, and the volume receiving at least 33 Gy (V33) < 0.5 cm3 was evaluated as the dose constraint. Results: The median interval between the first and last CT scans was 736 s (interquartile range, IQR:624-986). To compensate for the GI-tract motion based on the planning CT, the necessary median margin was 8.0 mm (IQR: 8.0-10.0) for the duodenum and 14.0 mm (12.0-16.0) for the small intestine. Compared to the planned V33 with the worst case, the median V33 in the PRV of the duodenum significantly increased from 0.20 cm3 (IQR: 0.02-0.26) to 0.33 cm3 (0.10-0.59) at Wilcoxon signed-rank test (p = 0.031). Conclusion: The short-term motions of the GI-tract lead to high dose differences.

Distribution of human papilloma virus genotypes and treatment outcomes in definitive radiotherapy for cervical cancer.

Most oncogenic human papilloma virus (HPV) genotypes stratify into two species, α-7 HPV and α-9 HPV. There are several studies that evaluate the relationship between HPV species and treatment outcomes and reports that HPV species is prognostic. The HPV genotyping was conducted using biopsy specimens which had been stored in these studies. We conducted the study using the HPV test performed by cytology specimens which is less invasive and more useful in clinical settings. This study enrolled 46 patients who received HPV genotyping before the definitive radiotherapy. The results of the HPV genotyping were classified into HPVα-7, HPVα-9 and negatives. Of the 46 patients, 10 were positive for HPVα-7, 21 positive for HPVα-9 and 15 were negative. The median follow-up period was 38 months (range 4-142). The HPVα-7, HPVα-9 and negative groups showed the 3-year overall survival (OS; 59.3%, 80.4% and 72.2% [P = 0.25]); local control (LC; 67.5%, 81% and 80% [P = 0.78]); pelvic control (PC) (50%, 81% and 72.7% [P = 0.032]); pelvic lymph node (PLN) control (78.7%, 95% and 92.3% [P = 0.012]); distant metastasis free (DMF) survival (50%, 75.4% and 42.8% [P = 0.098]); and progression free survival (PFS) rate of patients (30%, 66.7% and 38.9% [P = 0.085]), respectively. Patients with HPVα-7 showed statistically significant poorer PC than the HPVα-9 group, in multivariate analysis. This result is consistent with previous studies for HPV positive patients. The HPV negativity rate was higher in this study than in other studies and further work on this may be needed for clinical use.

Predicting the daily gastrointestinal doses of stereotactic body radiation therapy for pancreatic cancer based on the shortest distance between the tumor and the gastrointestinal tract using daily computed tomography images.

Objectives: We aimed to investigate whether daily computed tomography (CT) images could predict the daily gastroduodenal, small intestine, and large intestine doses of stereotactic body radiation therapy (SBRT) for pancreatic cancer based on the shortest distance between the gross tumor volume (GTV) and gastrointestinal (GI) tract. Methods: Twelve patients with pancreatic cancer received SBRT of 40 Gy in five fractions. We recalculated the reference clinical SBRT plan (PLANref) using daily CT images and calculated the shortest distance from the GTV to each GI tract. The maximum dose delivered to 0.5 cc (D0.5cc) was evaluated for each planning at-risk volume of the GI tract. Spearman's correlation test was used to determine the association between the daily change in the shortest distance (Δshortest distance) and the ratio of ΔD0.5cc dose to D0.5cc dose in PLANref (ΔD0.5cc/PLANref) for quantitative analysis. Results: The median shortest distance in PLANref was 0 mm in the gastroduodenum (interquartile range, 0-2.7), 16.7 mm in the small intestine (10.0-23.7), and 16.7 mm in the large intestine (8.3-28.1 mm). The D0.5cc of PLANref in the gastroduodenum was >30 Gy in all patients, with 10 (83.3%) having the highest dose. A significant association was found between the Δshortest distance and ΔD0.5cc/ PLANref in the small or large intestine (p < 0.001) but not in the gastroduodenum (p = 0.404). Conclusions: The gastroduodenum had a higher D0.5cc and predicting the daily dose was difficult. Daily dose calculations of the GI tract are recommended for safe SBRT. Advances in knowledge: This study aimed to predict the daily doses in SBRT for pancreatic cancer from the shortest distance between the GTV and the gastrointestinal tract.Daily changes in the shortest distance can predict the daily dose to the small or large intestines, but not to the gastroduodenum.

Treatment outcomes of radiotherapy with concurrent weekly cisplatin in older patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Tri-weekly cisplatin and radiotherapy (CDDP + RT) is a standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) but is sometimes challenging to complete in older patients. Weekly CDDP + RT has shown mild toxicity compared to tri-weekly CDDP + RT for LA-HNSCC and is a promising option for older adults. We aimed to report the treatment outcomes and prognostic factors in patients with LA-HNSCC treated with weekly CDDP + RT. METHODS: We analyzed patients aged ≥ 70 years who started weekly CDDP + RT for LA-HNSCC between July 2006 and October 2022. LA-HNSCC includes cancer in the oropharynx, hypopharynx, or larynx with a clinical stage of 3 or 4 without distant metastases based on the Union for International Cancer Control staging system 8th edition. The radiation dose of 70 Gy was delivered in 35 fractions by 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, or proton beam therapy. The primary endpoint was the 3-year overall survival (OS), and the secondary endpoints were the 3-year progression-free survival (PFS) and 3-year cause-specific survival (CSS). The Kaplan-Meier method was used to calculate survival rates, and the log-rank test was used to evaluate statistical significance. A Cox proportional hazards model was used for the multivariate analysis of prognostic factors. RESULTS: The median age of the 49 patients was 72 (range: 70-78) years. The median CDDP dose was 200 (40-280) mg/ m2, and 47 patients completed scheduled radiotherapy. Forty-eight patients (98.0%) had a performance status of ≥ 1 at the initial visit. The 3-year OS, PFS, and CSS were 80.9% (95% confidence interval [CI]: 64.8-90.7), 68.3% (95% CI 51.8-81.2), and 85.0% (95% CI 68.7-93.4), respectively. In the multivariate analysis, the cumulative CDDP dose (< 200 or ≥ 200 mg/m2) was a significant factor for OS (hazard ratio: 0.29 [95% CI 0.08-0.97], p = 0.044). There was one case of early mortality. Grade 3 or higher late adverse events were observed in four patients (8.2%). CONCLUSIONS: Weekly CDDP + RT in older patients led to good survival outcomes with an acceptable rate of adverse events. CDDP should be administered at a dose of at least 200 mg/m2 in older patients. Trial registration Retrospectively registered.

Detailed analysis of failure patterns using deformable image registration in hypopharyngeal cancer patients treated with sequential boost intensity-modulated radiotherapy.

INTRODUCTION: Sequential boost intensity-modulated radiotherapy (SQB-IMRT) uses two different planning CTs (pCTs) and treatment plans. SQB-IMRT is a form of adaptive radiotherapy that allows for responses to changes in the shape of the tumour and organs at risk (OAR). On the other hand, dose accumulation with the two plans can be difficult to evaluate. The purpose of this study was to analyse patterns of loco-regional failure using deformable image registration (DIR) in hypopharyngeal cancer patients treated with SQB-IMRT. METHODS: Between 2013 and 2019, 102 patients with hypopharyngeal cancer were treated with definitive SQB-IMRT at our institution. Dose accumulation with the 1st and 2nd plans was performed, and the dose to the loco-regional recurrent tumour volume was calculated using the DIR workflow. Failure was classified as follows: (i) in-field (≥95% of the recurrent tumour volume received 95% of the prescribed dose); (ii) marginal (20-95%); or (iii) out-of-field (<20%). RESULTS: After a median follow-up period of 25 months, loco-regional failure occurred in 34 patients. Dose-volume histogram analysis showed that all loco-regional failures occurred in the field within 95% of the prescribed dose, with no marginal or out-of-field recurrences observed. CONCLUSION: The dosimetric analysis using DIR showed that all loco-regional failures were within the high-dose region. More aggressive treatment may be required for gross tumours.

Brain metastases in Japanese NSCLC patients: prognostic assessment and the use of osimertinib and immune checkpoint inhibitors-retrospective study.

BACKGROUND: The Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed. METHODS: We retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results. RESULTS: The median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, and 2.5‒3.0) were 3.2, 11.0, and 16.0 months (p = 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p = 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p = 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months). CONCLUSIONS: We confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patients with BM, and ICI was effective in patients with high PD-L1 expressions.

Safety and efficacy of anagrelide in Japanese post-marketing surveillance, with subgroup analyses on the effect of previous cytoreductive therapies, age, and starting dose.

BACKGROUND: In Japan, anagrelide has been approved for use in patients with essential thrombocythemia. Here, the safety and efficacy of anagrelide was assessed in clinical practice as post-marketing surveillance. Subgroup analyses were conducted to compare patients (1) with or without a history of cytoreductive therapy (CRT), (2) <60 or ≥60 years of age, and (3) with an anagrelide starting dose of ≤0.5 mg/day or 1.0 mg/day. METHODS: Data were collected for all patients who received anagrelide, with an observation period of 12 months after treatment initiation. RESULTS: Of the 648 patients, 54.3% experienced adverse drug reactions (ADRs). The most commonly reported ADRs were headaches, palpitations, and anemia. No significant difference was observed in overall ADRs across patient subgroups. A significantly higher incidence of headaches was observed in patients < 60 years versus those ≥ 60 years (P < 0.001). The incidence of anemia and serious ADRs were significantly higher in patients ≥ 60 years, and those with a history of CRT (P < 0.05). The discontinuation rate at 6 months was significantly lower in patients started at the lower anagrelide dose (P < 0.05). Platelet counts decreased in all analyzed groups. CONCLUSIONS: This surveillance showed that anagrelide has a tolerable safety and efficacy profile.

Hyperfractionated intensity-modulated proton therapy for pharyngeal cancer with variable relative biological effectiveness: A simulation study.

BACKGROUND: The relative biological effectiveness (RBE) of proton is considered to be dependent on biological parameters and fractional dose. While hyperfractionated photon therapy was effective in the treatment of patients with head and neck cancers, its effect in intensity-modulated proton therapy (IMPT) under the variable RBE has not been investigated in detail. PURPOSE: To study the effect of variable RBE on hyperfractionated IMPT for the treatment of pharyngeal cancer. We investigated the biologically effective dose (BED) to determine the theoretical effective hyperfractionated schedule. METHODS: The treatment plans of three pharyngeal cancer patients were used to define the ΔBED for the clinical target volume (CTV) and soft tissue (acute and late reaction) as the difference between the BED for the altered schedule with variable RBE and conventional schedule with constant RBE. The ΔBED with several combinations of parameters (treatment days, number of fractions, and prescribed dose) was comprehensively calculated. Of the candidate schedules, the one that commonly gave a higher ΔBED for CTV was selected as the resultant schedule. The BED volume histogram was used to compare the influence of variable RBE and fractionation. RESULTS: In the conventional schedule, compared with the constant RBE, the variable RBE resulted in a mean 2.6 and 2.7 Gy reduction of BEDmean for the CTV and soft tissue (acute reaction) of the three plans, respectively. Moreover, the BEDmean for soft tissue (late reaction) increased by 7.4 Gy, indicating a potential risk of increased RBE. Comprehensive calculation of the ΔBED resulted in the hyperfractionated schedule of 80.52 Gy (RBE = 1.1)/66 fractions in 6.5 weeks. When variable RBE was used, compared with the conventional schedule, the hyperfractionated schedule increased the BEDmean for CTV by 7.6 Gy; however, this was associated with a 7.8 Gy increase for soft tissue (acute reaction). The BEDmean for soft tissue (late reaction) decreased by 2.4 Gy. CONCLUSION: The results indicated a potential effect of the variable RBE on IMPT for pharyngeal cancer but with the possibility that hyperfractionation could outweigh this effect. Although biological uncertainties require conservative use of the resultant schedule, hyperfractionation is expected to be an effective strategy in IMPT for pharyngeal cancer.

Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors.

PURPOSE: Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly. METHODS AND MATERIALS: A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA. RESULTS: Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P < .01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies. CONCLUSIONS: Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan.

BACKGROUND: Gaucher disease (GD) is caused by reduced lysosomal enzyme ß-glucocerebrosidase activity. Heterogeneous genotypes and phenotypes have been observed within GD types and across ethnicities. Enzyme replacement therapy is generally recommended for patients with type 1 GD, the least severe form of GD. In Japan, velaglucerase alfa has a broad indication covering type 1, 2 or 3 GD.  METHODS: All patients with type 1, 2, or 3 GD administered velaglucerase alfa 60 U/kg every 2 weeks via intravenous infusion after its launch date in Japan in 2014, were enrolled in a non-interventional, observational post-marketing surveillance (PMS). Individual patient data were reported via case report forms (CRFs). Key safety endpoints investigated included the incidence of infusion-related reactions (IRRs), the safety of velaglucerase alfa in patients with types 2 and 3 GD, from patients under one year of age to elderly patients (≥ 65 years of age). Long-term efficacy was also assessed.  RESULTS: In total, 53 patients with GD were registered. CRFs were available for 41 (77.4%) patients at the 6-year interim analysis. Fourteen adverse drug reactions (ADRs) were reported in seven patients. All reported ADRs occurred in patients with type 2 GD. ADRs were reported by 63.6% (7/11) of patients with type 2 GD. Ten ADRs were reported in five patients aged < 4 years. No elderly patients experienced any ADR during the surveillance period. Five ADRs occurring in three (10.0%) patients were classified as IRRs, with one case of vomiting (moderate severity) resulting in treatment discontinuation. Ten serious adverse events were reported in five (16.7%) patients. Three fatal events were considered to be unrelated to treatment with velaglucerase alfa. Platelet counts increased after the administration of velaglucerase alfa and were generally maintained within the normal range over the administration period. Among eleven patients tested for neutralizing anti-velaglucerase alfa antibodies, two (18.2%) were assessed as positive results.  CONCLUSION: PMS data from patients with types 1-3 GD in Japan indicate that long-term treatment with velaglucerase alfa was well-tolerated and associated with increased platelet counts, which is consistent with observations made in studies outside of Japan. TRIAL REGISTRATION: NCT03625882 registered July 2014.