OBJECTIVE:The survival benefit of thrombolysis compared with surgical pulmonary embolectomy for high-risk pulmonary embolism has not been established, although current guidelines advocate thrombolysis as first-line therapy. This study compared the short-term outcomes of surgical pulmonary embolectomy and thrombolysis to determine the optimal treatment for high-risk pulmonary embolism. METHODS:Patients with high-risk pulmonary embolism who underwent surgical pulmonary embolectomy or thrombolysis within 2 days of admission were identified using a nationwide inpatient administrative database in Japan between July 2010 and March 2023. The primary outcome was in-hospital mortality, and secondary outcomes were complications, length of hospital stay, and total hospitalization costs. Outcomes were compared using overlap weighting, with sensitivity analyses conducted using inverse probability of treatment weighting and multivariate logistic regression model. RESULTS:Of the 2813 eligible patients, 526 underwent surgical pulmonary embolectomy, and 2287 underwent thrombolysis. After overlap weighting, surgical pulmonary embolectomy was associated with lower in-hospital mortality (22.2% vs 30.1%, P = .002), more favorable neurological outcomes at discharge (72.5% vs 66.7%, P = .040), and higher total costs ($30,548 vs $13,374, P < .001) than thrombolysis. No significant differences were observed in complications or length of hospital stay between the 2 groups. Sensitivity analyses yielded results consistent with the primary analyses. CONCLUSIONS:These findings suggest potential benefits of surgical pulmonary embolectomy over thrombolysis for high-risk pulmonary embolism. Surgical pulmonary embolectomy may be considered a reasonable reperfusion therapy option for suitable patients. Further research is needed to confirm these findings.

Hypopituitarism has been reported in patients receiving continuous infusions of prostaglandin I2 (PGI2) analogues for pulmonary hypertension (PH). However, these patients' clinical characteristics, treatment, and prognoses remain unclear. This retrospective multicentre study included 22 patients who developed hypopituitarism while on continuous PGI2 analogue infusion between 1999 and 2021. All patients were female, and idiopathic pulmonary arterial hypertension was the most common underlying condition (63.6%). Their mean age was 38.8 ± 7.9 years. Epoprostenol was the predominant PGI2 analogue used (90.9%). At the time of hypopituitarism onset, the median PGI2 dose was 67.2 ng/kg/min (31.8-88.7 ng/kg/min), and the median treatment duration was 889.0 days (450.5-1941.5 days), suggesting that hypopituitarism occurred independent of its dose or treatment duration. Diagnoses were based on decreased adrenocorticotropic hormone levels. The hypopituitarism classification revealed isolated pituitary dysfunction in 54.5% of the cases, partial dysfunction in 18.1%, and complete dysfunction in 27.2%. Most cases could be managed without requiring specific therapies. After hypopituitarism onset, 63.6% of the patients continued to receive the same PGI2 analogue. Hydrocortisone therapy was administered to 81.8% of the patients, leading to clinical stabilisation. No deaths were reported. In conclusions, hypopituitarism may occur during continuous PGI2 analogue infusion for PH, irrespective of its dose or treatment duration. Initiating hydrocortisone therapy may be important for stabilising the clinical course.

The basic treatment for chronic thromboembolic pulmonary hypertension (CTEPH) includes lifelong anticoagulant therapy and pulmonary endarterectomy; moreover, balloon pulmonary angioplasty (BPA) and vasodilators are also known to be effective. Surgery is the standard treatment for localized lung cancer. However, no established treatment guidelines exist for cases of coexisting CTEPH and lung cancer. The patient was a 55-year-old woman who experienced dyspnea on exertion. She was diagnosed with non-small cell lung cancer, and surgery was scheduled; however, she was also diagnosed with CTEPH during preoperative examinations. She was referred to our hospital, where right heart catheterization revealed a mean pulmonary artery pressure (mPAP) of 39 mmHg. We prioritized the treatment of CTEPH, starting oral riociguat followed by BPA three times. The mPAP decreased to 27 mmHg. Then, right upper lobectomy and lymph node dissection were performed. After surgery, there was no significant worsening of right heart failure, and no recurrence of the lung cancer. This case report presents a method for managing both CTEPH and primary lung cancer. The essence was the intensification of CTEPH treatment in anticipation of lobectomy.

Pulmonary arterial hypertension (PAH) remains a significant challenge in cardiology, necessitating advancements in treatment strategies. This study explores the safety and efficacy of transitioning patients from beraprost to selexipag, a novel selective prostacyclin receptor agonist, within a Japanese cohort. Employing a multicenter, open-label, prospective design, 25 PAH patients inadequately managed on beraprost were switched to selexipag. Key inclusion criteria included ongoing beraprost therapy for ≥3 months, a diagnosis of PAH confirmed by mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, and current treatment with endothelin receptor antagonists and/or phosphodiesterase type 5 inhibitors. Outcomes assessed were changes in hemodynamic parameters (mPAP, cardiac index, pulmonary vascular resistance) and the 6 min walk distance (6-MWD) over 3–6 months. The study found no statistically significant changes in these parameters post-switch. However, a subset of patients, defined as responders, demonstrated improvements in all measured hemodynamic parameters, suggesting a potential benefit in carefully selected patients. The transition was generally well-tolerated with no serious adverse events reported. This investigation underscores the importance of personalized treatment strategies in PAH, highlighting that certain patients may benefit from switching to selexipag, particularly those previously on higher doses of beraprost. Further research is needed to elucidate the predictors of positive response to selexipag and optimize treatment regimens for this complex condition.

Background: Functional exercise capacity in pulmonary hypertension (PH) is routinely assessed using the 6-min walking test (6MWT). However, alternative tests are useful because of resource requirements. This study aimed to evaluate whether the 1-min sit-to-stand test (1STST) is useful and safe in PH and whether it can replace the 6MWT. Methods: Adult patients with PH were recruited from our hospital between September 2023 and April 2024. The correlations between the number of 1STST repetitions (1STSTr) and 6-min walk distance (6MWD), pulmonary hemodynamic parameters, and quadriceps muscle strength; adverse events; and vital sign fluctuations during the tests were evaluated, and a questionnaire with an 11-point Likert scale (-5, 6MWT favor; 5, 1STST favor) was administered. Results: Twenty-one patients with PH were enrolled in this study. The 1STSTr and 6MWD were 23.8 f 7.8/min and 425.8 f 116.8 m, respectively, with a strong correlation (r = 0.771). 1STSTr was significantly correlated with brain natriuretic peptide, but not with other pulmonary hemodynamic markers, respiratory function, or quadriceps muscle strength. No serious adverse events or motor impairments occurred with the 1STST. The minimum SpO2 during the tests was significantly lower with the 6MWT (92.6 f 3.1 vs. 88.0 f 11.0). The questionnaire showed a predominant preference for the 1STST (3.2 f 2.6). Conclusions: To our knowledge, this is the first study in Japan to adapt the 1STST to PH patients. The 1STST is a reliable alternative to the 6MWT for measuring exercise capacity in PH patients. Trial registration: This study was registered with the UMIN-CTR (number UMIN000052010).

Abstract Residual pulmonary hypertension (PH) negatively impacts long‐term results following pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). We sought to reveal whether modern PH therapy with PH‐targeted medicine and balloon pulmonary angioplasty (BPA) improved long‐term results of residual PH after PEA. Long‐term findings of 80 patients who survived PEA between 2011 and 2019 were retrospectively investigated. One month after PEA, 30 patients developed residual PH defined as mean pulmonary artery pressure (mPAP) ≥25 mmHg, of whom 23 were treated by PH‐targeted medicine and 9 by BPA. Patients with residual PH acquired considerably better functional status and exercise capacity after PEA, however, exhibited significantly worse survival rates than those without. Eleven patients died during follow‐up: 8 patients with residual PH and 3 controls. Among patients with residual PH, the deceased had a significantly lower %decrease in mPAP from 1 month to 1 year following PEA (7.4 [−32.6 to 8.0] % vs. 10.4 [3.7−27.8] %, p = 0.03) and higher mPAP at 1 year following PEA (39.5 [33.25−42.5] vs. 27 [26−34] mmHg, p < 0.01) despite PH‐targeted medicine than the survived. No patients passed away from right heart failure, and there was no difference between the groups in CTEPH‐related mortality. Modern PH therapy was used to address the majority of residual PH. Long‐term survival after PEA was negatively impacted by residual PH, but it appeared that long‐term mortality was also correlated with unrelieved residual PH despite PH‐targeted medicine. Modern PH therapy may have enhanced functional status and excercise capacity, and averted fatal right heart failure.

BACKGROUND Pulmonary arterial hypertension (PAH) is a rare, progressive disease. The treatment landscape for PAH in Japan has evolved considerably in recent years, but there is limited knowledge of the changes in treatment practices or patient characteristics. OBJECTIVES The aim of this study was to evaluate the changes in characteristics and initial treatments for PAH in Japan over time. METHODS This study used data from the Japan Pulmonary Hypertension Registry (JAPHR) to compare patient characteristics and treatment practices between 2008-2015 (n = 316) and 2016-2020 (n = 315). RESULTS The mean f standard deviation age at diagnosis increased from 47.9 f 16.7 years in 2008-2015 to 52.7 f 16.9 years in 2016-2020. The mean pulmonary arterial pressure decreased from 45.4 f 15.0 to 38.6 f 13.1 mm Hg. Idiopathic/hereditary PAH was the most common etiology in both periods (50.0% and 51.1%, respectively). The proportion of patients prescribed oral/inhaled combination therapies increased from 47.8% to 57.5%. Oral/inhaled combination therapies were frequently prescribed to patients with congenital heart disease-related PAH (81.8%). There was no significant trend in prescribing practices based on French low-risk criteria: among patients with 0, 1, 2, 3, or 4 criteria, 53.8%, 68.8%, 52.8%, 66.7%, and 39.4% were prescribed oral/inhaled combination therapies, and 0%, 16.7%, 27.0%, 17.3%, and 15.2% were prescribed oral/inhaled monotherapies. Macitentan, tadalafil, selexipag, and epoprostenol were the most frequently prescribed drugs. CONCLUSIONS The severity of PAH decreased over time in Japan. Oral/inhaled combination therapies were generally preferred. Physicians generally prescribed therapies after considering the patients' hemodynamics and clinical severity. (Japan Pulmonary Hypertension Registry [JAPHR]; UMIN000026680) (JACC: Asia 2022;2:273-284) (c) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Abstract Background The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is considered to be associated with chronic inflammation; however, the underlying mechanism remains unclear. Recently, altered gut microbiota were found in patients with pulmonary arterial hypertension (PAH) and in experimental PAH models. The aim of this study was to characterize the gut microbiota in patients with CTEPH and assess the relationship between gut dysbiosis and inflammation in CTEPH. Methods In this observational study, fecal samples were collected from 11 patients with CTEPH and 22 healthy participants. The abundance of gut microbiota in these fecal samples was assessed using 16S ribosomal ribonucleic acid (rRNA) gene sequencing. Inflammatory cytokine and endotoxin levels were also assessed in patients with CTEPH and control participants. Results The levels of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1α were elevated in patients with CTEPH. Plasma endotoxin levels were significantly increased in patients with CTEPH (P < 0.001), and were positively correlated with TNF-α, IL-6, IL-8, and MIP-1α levels. The 16S rRNA gene sequencing and the principal coordinate analysis revealed the distinction in the gut microbiota between patients with CTEPH (P < 0.01) and control participants as well as the decreased bacterial alpha-diversity in patients with CTEPH. A random forest analysis for predicting the distinction in gut microbiota revealed an accuracy of 80.3%. Conclusion The composition of the gut microbiota in patients with CTEPH was distinct from that of healthy participants, which may be associated with the elevated inflammatory cytokines and endotoxins in CTEPH.

Neurologic adverse events (NAEs) are a major complication after pulmonary endarterectomy (PEA) performed under periods of deep hypothermic circulatory arrest (HCA) for chronic thromboembolic pulmonary hypertension. We modified the PEA strategy to prevent NAEs and evaluated the effectiveness of these modifications. We reviewed the surgical outcomes of 87 patients divided into the following three groups based on the surgical strategy used: group S (n = 49), periods of deep HCA with alpha-stat strategy; group M1 (n = 19), deep HCA with modifications of slower cooling and rewarming rates and the pH–stat strategy for cooling: and group M2 (n = 13), multiple short periods of moderate HCA. PEA provided significant improvement of pulmonary hemodynamics in each group. Sixteen (29

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension caused by persistent thromboembolism of the pulmonary arteries. In clinical practice, CTEPH patients often show obstructive ventilatory impairment, even in the absence of a smoking history. Recent reports imply a tendency for CTEPH patients to have a lower FEV1.0; however, the mechanism underlying obstructive impairment remains unknown. Methods We retrospectively analyzed CTEPH patients who underwent a pulmonary function test and respiratory impedance test to evaluate their exertional dyspnea during admission for right heart catheterization from January 2000 to December 2019. We excluded patients with a smoking history to rule out the effect of smoking on obstructive impairment. Results A total of 135 CTEPH patients were analyzed. The median FEV1.0/FVC was 76.0%, %FEV (1.0) had a negative correlation with the mean pulmonary artery pressure and pulmonary vascular resistance and the CT Angiogram (CTA) obstruction score. A multivariate regression analysis revealed that the CTA obstruction score was an independent factor of a lower %FEV1.0. In the 54 patients who underwent pulmonary endarterectomy, %FEV1.0 was improved in some cases and was not in some. Mean PAP largely decreased after PEA in the better %FEV1.0 improved cases, suggesting that vascular involvement in CTEPH could be associated with spirometry obstructive impairment. Conclusion %FEV1.0 had a significant correlation with the CTA obstruction score. Obstructive impairment might have an etiological relationship with vascular involvement. Further investigations could shed new light on the etiology of CTEPH.

It is generally considered that there is an increase in glycolysis in the hypertrophied right ventricle (RV) during pulmonary hypertension (PH), which leads to a decrease in glucose oxidation through the tricarboxylic acid (TCA) cycle. Although recent studies have demonstrated that fatty acid (FA) and glucose accumulated in the RV of patients with PH, the details of this remain to be elucidated. The purpose of the current study was to assess the metabolic remodeling in the RV of rats with PH using a metabolic analysis. Male rats were treated with the vascular endothelial growth factor receptor blocker SU5416 followed by 3 weeks of hypoxic conditions and 5 weeks of normoxic conditions (Su/Hx rats). Hemodynamic measurements were conducted, and the RV was harvested for the measurement of metabolites. A metabolomics analysis revealed a decreasing trend in the levels of alanine, argininosuccinic acid and downstream TCA cycle intermediates, including fumaric and malic acid and an increasing trend in branched‑chain amino acids (BCAAs) in Su/Hx rats compared with the controls; however, no trends in glycolysis were indicated. The FA metabolomics analysis also revealed a decreasing trend in the levels of long‑chain acylcarnitines, which transport FA from the cytosol to the mitochondria and are essential for beta‑oxidation. The current study demonstrated that the TCA cycle was less activated because of a decreasing trend in the expression of fumaric acid and malic acid, which might be attributable to the expression of adenylosuccinic acid and argininosuccinic acid. These results suggest that dysregulated BCAA metabolism and a decrease in FA oxidation might contribute to the reduction of the TCA cycle reactions.

Background Portopulmonary hypertension (PoPH) refers to the simultaneous presentation of pulmonary arterial and portal hypertension. However, few reports have included the characteristics and treatments for patients with PoPH of Asian population; thus, we investigated the clinical characteristics, treatment, and survival of these patients in a Japanese cohort. Methods Pulmonary arterial hypertension (PAH) has been included in the National Research Project on Intractable Disease in Japan; therefore, we extracted data of patients with PoPH from the forms of newly registered cases of the project from 2012 to 2013 (for 2 years), and updated cases of the project in 2013 (Study 1, n = 36 newly registered forms, n = 46 updated forms). Additionally, for Study 2, we performed a retrospective, observational cohort study at Chiba University Hospital (n = 11). We compared the characteristics between patients with PoPH and those with idiopathic/heritable PAH (I/H-PAH). Results Both studies showed higher cardiac outputs (COs) and cardiac indexes (CIs), lower pulmonary vascular resistance (PVR), and less treated with combination therapy in patients with PoPH than those with I/H-PAH. In Study 2, the overall and disease-specific survival between PoPH and I/H-PAH were similar. Conversely, many patients (45%) had to change their PAH-specific medicine because of adverse effects. Conclusion As seen in western countries, Japanese patients with PoPH showed higher COs and CIs, better exercise tolerance, and lower PVRs than patients with I/H-PAH. Further studies are needed to improve PoPH treatments.

Heritable pulmonary arterial hypertension (HPAH) is a type of familial pulmonary arterial hypertension, while pulmonary arteriovenous malformations (PAVMs) are abnormal communications between pulmonary arteries and veins that occur frequently in patients with hereditary hemorrhagic telangiectasia (HHT). A 21-year-old woman on continuing medication for HPAH was hospitalized. She had been diagnosed with HPAH at age 4 years and had been receiving epoprostenol infusion from age of 9 years. Although lung perfusion scintigraphy showed a shunt fraction of 18.9% at age of 19 years, the cause of the shunt was unclear. At the time of the present hospitalization, enhanced computed tomography (CT) of the chest and four-dimensional reconstructed images revealed multiple abnormal communications between the peripheral pulmonary arteries and veins. Furthermore, right heart catheterization revealed an elevated mean pulmonary arterial pressure. Wedged angiography of the pulmonary artery of the right lower lobe revealed several PAVMs. Multiple PAVMs and suspected HHT with HPAH was diagnosed. The possibility of PAVMs should be considered even in patients with HPAH. Moreover, evaluation of the shunt fraction by lung perfusion scintigraphy and morphological examination of PAVM by contrast-enhanced CT may facilitate PAVM detection in patients with HPAH

Background: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is associated with inflammation as withother types of pulmonary hypertension. Recently, the involvement of altered gut microbiota has been reported in patients with pulmonary arterial hypertension (PAH) (Kim S, et al. Hypertension 2020: 75: 1063-1071) and a SU5416/hypoxia-induced PAH animal model (Sanada TJ, et al. Pulm Circ 2020: 10: 2045894020929147). The aim of this study was to characterise the gut microbiota in CTEPH patients and assess the relationship between the pathogenesis of CTEPH and gut microbiota. Methods: Faecal samples were collected from 11 CTEPH patients at diagnosis, and components of gut microbiota were assessed using 16S rRNA gene sequencing. Control data were collected from the database of the National Institutes of Biomedical Innovation, Health, and Nutrition and were compared with those of CTEPH patients. The age, sex, and body mass index were matched between CTEPH patients and healthy control. Results: The principal coordinate analysis revealed the difference in components of the gut microbiota between CTEPH patients and controls. Compared to healthy controls, in CTEPH patients, the bacterial alpha diversity was lower (p<0.05), some butylate-producing bacteria were significantly reduced (p<0.05), and serum concentration of endotoxin was significantly higher (p<0.001). A gram-negative bacteria (Bacteria X) composition in CTEPH patients was correlated with pulmonary arterial resistance (p<0.05). Conclusion: The gut microbiota composition of CTEPH patients and healthy controls was different. This alteration might be associated with inflammation and the pathogenesis of CTEPH.

Abstract Background The 6th World Symposium on Pulmonary Hypertension (Nice 2018) proposed a new definition of pre-capillary pulmonary hypertension (PH) as a condition with mean pulmonary artery pressure (mPAP) > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) ≥ 3 Wood units (WU). The characteristics and prognosis of patients with pre-capillary PH, according to this new definition, is unclear. Therefore, we determined the characteristics and survival of patients with borderline pre-capillary PH. Methods We retrospectively enrolled 683 patients who underwent their first right heart catheterization at Chiba University, Japan. Among them, 489 patients met the pre-capillary PH requirement with mPAP ≥ 25 mmHg (conventional pre-capillary PH group), while 22 patients met the borderline pre-capillary PH criteria (borderline pre-capillary PH group). Additionally, 16 patients with a mean PAP of 20–25 and PVR of 2–3 WU were also examined. Results The borderline pre-capillary PH group comprised 4.3% of the total patients with pre-capillary PH, and the majority was in Group 3 (40.9%) or 4 (45.5%). The survival of the borderline pre-capillary PH group tended to be better than that of the conventional pre-capillary PH group. The prognosis of Group3 PH was the worst among the patients with borderline precapillary PH. There was no significant difference in survival between the borderline pre-capillary PH group with PVR ≥ 3 WU and that with PVR of 2–3 2WU, although none of the patients in the latter group died due to right heart failure. Conclusions This is the first study conducted in a PH center in an Asian country to reveal the characteristics of patients with pre-capillary PH, according to the Nice 2018 definition. They comprised 4.3% of the total population with pre-capillary PH, and the majority of the pre-capillary PH cases were in either Group3 or 4. The prognosis may be affected by the patients’ underlying diseases. Further prospective studies are needed to determine whether the new definition, including the PVR cut-off, is beneficial in clinical practice.

The pathogenesis of pulmonary arterial hypertension is closely associated with dysregulated inflammation. Recently, abnormal alterations in gut microbiome composition and function were reported in a pulmonary arterial hypertension experimental animal model. However, it remains unclear whether these alterations are a result or the cause of pulmonary arterial hypertension. The purpose of this study was to investigate whether alterations in the gut microbiome affected the hemodynamics in SU5416/hypoxia rats. We used the SU5416/hypoxia rat model in our study. SU5416/hypoxia rats were treated with a single SU5416 injection (30 mg/kg) and a three-week hypoxia exposure (10% O-2). Three SU5416/hypoxia rats were treated with a combination of four antibiotics (SU5416/hypoxia + ABx group) for four weeks. Another group was exposed to hypoxia (10% O-2) without the SU5416 treatment, and control rats received no treatment. Fecal samples were collected from each animal, and the gut microbiota composition was analyzed by 16S rRNA sequencing. The antibiotic treatment significantly suppressed the vascular remodeling, right ventricular hypertrophy, and increase in the right ventricular systolic pressure in SU5416/hypoxia rats. 16S rRNA sequencing analysis revealed gut microbiota modification in SU5416/hypoxia + ABx group. The Firmicutes-to-Bacteroidetes ratio in SU5416/hypoxia rats was significantly higher than that in control and hypoxia rats. Compared with the control microbiota, 14 bacterial genera, includingBacteroidesandAkkermansia, increased, whereas seven bacteria, includingRothiaandPrevotellaceae, decreased in abundance in SU5416/hypoxia rats. Antibiotic-induced modification of the gut microbiota suppresses the development of pulmonary arterial hypertension. Dysbiosis may play a causal role in the development and progression of pulmonary arterial hypertension.

Background: The emPHasis-10 questionnaire is a disease-specific patient-reported outcome assessment of quality of life (QOL) in pulmonary hypertension (PH). The aim of this study was to psychometrically validate a linguistically validated Japanese version of the emPHasis-10. Methods and Results: Japanese patients with PH (age ≥18 years) and no change in functional status, or initiation or change in PH-specific treatment during the past 3 months were recruited from 5 institutions from August 2018 to July 2019. A set of questionnaires was administered twice. The validity and reliability of the emPHasis-10 were assessed using the data of 76 patients. On concurrent validity analysis, a moderate-to-strong correlation was seen with the total score of all 5 external criteria (the Minnesota Living with Heart Failure modified for PH [MLHFQ-PH], Hospital Anxiety and Depression Scale, Dyspnea-12 questionnaire, European Quality of Life-5 Dimensions questionnaire [EQ-5D], and 6-min walk test), with a notably strong correlation with the MLHFQ-PH (0.77) and EQ-5D (-0.64). On known-group validity, a linear increasing trend of the emPHasis-10 score was observed across 4 World Health Organization functional status groups (Jonckheere-Terpstra test, 1-sided, P<0.001). Intraclass correlation coefficient for test-retest reliability was 0.86, and the Cronbach's α for internal consistency was 0.89. Conclusions: The Japanese emPHasis-10 questionnaire is psychometrically valid to evaluate QOL in Japanese PH patients in a clinical setting.

We read with great interest the Letter to the Editor by Aubertin et al.1 in which they reported that 100% of 39 tested oral squamous cell carcinoma (OSCC) samples contained wild-type sequence in codon 697 of the FGF receptor 3 gene. These results appear to contradict our own finding that 62% of 71 tested OSCC samples possessed a somatic missense mutation, which resulted in a glycine to cysteine substitution at position 697 (G697C) of FGFR3.2 As we also found that this mutated form of FGFR3 had higher autophosphorylation activity than wild-type FGFR3, we suggested that FGFR3 and the G697C activating mutation might play an important role in the development of SCC in oral epithelia. As pointed out by Aubertin et al., the patient populations in these 2 studies were different: their OSCC patients were likely Caucasians from northeastern France while our patients were exclusively Japanese. We suspect that the discrepancy in our experimental results stem from these different patient populations. There may be ethnic, lifestyle or environmental factors, which are not found in northeastern France, that predispose OSCC patients in the Hiroshima area to develop tumors via a mechanism involving the G697C mutation. These potential variations in patient populations are reminiscent of somatic mutations in the epidermal growth factor receptor that rendered Japanese patients with nonsmall cell lung carcinoma generally more responsive to gefitinib (Iressa) than nonsmall cell lung carcinoma patients in the United States.3, 4 Our report and that of Aubertin et al. serve to emphasize that there are likely multiple mechanistic pathways leading to OSCC. We believe that a survey of 110 OSCC patients from 2 geographic areas is insufficiently large to determine whether or not FGFR3 G697C is a common oncogenic mutation in OSCC. However, for OSCC patients with G697C-positive tumors, this diagnosis may have prognostic value. Yours sincerely, Yan Zhang, Yoshiko Hiraishi, Hua Wang, Ken-Saku Sumi, Yasutaka Hayashido, Shigeaki Toratani, Mikio Kan, John Denry Sato, Tetsuji Okamoto.