Pulmonary Valve Stenosis

TAMPA, Fla., Oct. 3, 2023 /PRNewswire/ -- The Patel Children's Heart Institute at St. Joseph's Children's Hospital achieved a milestone recently, implanting its 250th congenital transcatheter heart valve. "This accomplishment reflects the dedication of our entire congenital cardiac team," said Interventional Cardiologist Dr. Jeremy Ringewald, who is the director of the Cardiac Catheterization Laboratory at St. Joseph's Children's Hospital. "Most importantly, this means that we allowed 250 patients in need of pulmonary or tricuspid valve replacement to avoid open-heart surgery." Continue Reading "I could not be prouder of our entire cardiac team or happier for our patients," said Dr. Jeremy Ringewald. Tweet this Jennifer Carter, DNP, APRN, CPNP-AC; John Pino, recipient of the St. Joseph's Children's Hospital's 250th congenital transcatheter heart valve; and interventional cardiologist Dr. Jeremy Ringewald one day after Pino's cardiac procedure. Jennifer Carter, DNP, APRN, CPNP-AC, and Dr. Jeremy Ringewald, pediatric interventional cardiologist and medical director of the Cardiac Cath Lab at St. Joseph's Children's Hospital in Tampa, load a valve onto its delivery catheter as interventional cardiologist Dr. Jay Patel looks on. Tampa resident John Pino, 57, was the recipient of the 250th valve. He was born with pulmonary stenosis, a heart defect in which the pulmonary valve is narrowed and opens poorly. Pino underwent open-heart surgery when he was 9 years old to open up the narrowed valve, trading blockage for leakage. Eventually, the leakage led to enlargement of his heart and diminished exercise tolerance. "When it was determined that I would need to have my leaky pulmonary valve replaced, I was very happy to discover that Dr. Ringewald could do the repair without the need for another open-heart surgery," said Pino. During the procedure, Dr. Ringewald inserted the valve loaded on its delivery catheter into a vein in Pino's leg and guided the catheter by fluoroscopy to the location of his leaky pulmonary valve. The new valve was deployed inside the old valve and once released, it immediately began functioning. The team at St. Joseph's Children's Hospital has implanted the most transcatheter pulmonary valves in Florida since the program's inception and is one of the leading centers in the United States. "It's been a long, challenging and deeply gratifying odyssey for our congenital cardiac team and program. I could not be prouder of our cardiac crew or happier for our patients," said Dr. Ringewald. Pino's procedure was a success and instead of spending a week in the hospital, which is typical of most open-heart surgical procedures, he was discharged after just one day. "I'm so grateful to Dr. Ringewald and the entire heart team for taking such excellent care of me," said Pino. The Patel Children's Heart Institute at St. Joseph's Children's Hospital is home to the Tampa Bay area's only comprehensive congenital heart disease program. Its team of cardiac physicians perform hundreds of procedures each year to treat heart defects in patients of any age. A partnership between St. Joseph's Children's Hospital and UPMC Children's Hospital of Pittsburgh provides families across Florida with unprecedented access to the highest level of pediatric heart care available. Together, they provide highly specialized cardiovascular care for patients ranging from babies in the womb to adults with congenital heart disease. About St. Joseph's Children's Hospital St. Joseph's Children's Hospital is Tampa Bay's largest provider of children's health services and is committed to providing everything needed for the health and well-being of children. Together, BayCare Kids and St. Joseph's Children's Hospital offer specialized inpatient and outpatient pediatric care to thousands of children and their families each year in multiple locations throughout West Central Florida. From the tiniest baby to the high school quarterback, patients are cared for by doctors who specialize in treating children, in surroundings designed exclusively for kids. About BayCare BayCare is a leading not-for-profit health care system that connects individuals and families to a wide range of services at 16 hospitals and hundreds of other convenient locations throughout the Tampa Bay and central Florida regions. The system is West Central Florida's largest provider of behavioral health and pediatric services and its provider group, BayCare Medical Group, is one of the largest in the region. BayCare's diverse network of ambulatory services includes laboratories, imaging, surgical centers, BayCare Urgent Care locations, wellness centers and one of Florida's largest home care agencies, BayCare HomeCare. BayCare is ranked in the top 20% by Fortune/Merative. BayCare's mission is to improve the health of all it serves through community-owned, health care services that set the standard for high-quality, compassionate care. For more information, visit . SOURCE St. Joseph's Children's Hospital

Peca Labs , a medical device company making vascular grafts and valves with durable polymeric cardiovascular devices designed to fit, grow, and last in pediatric populations, recently announced its first successful in-human implant of the Masa valve. The valve is intended to be used to reconstruct the right ventricular outflow tract (RVOT) and provide a functional pulmonary valve in patients up to age 22. Once implanted, Masa provides a pathway for blood from the right ventricle to the pulmonary arteries, using its design to help prevent backflow into the right ventricle. The valve is a bi-leaflet pulmonary valved conduit . It has an expanded polytetrafluoroethylene (ePTFE) conduit and ePTFE leaflets fixtured to the conduit with polypropylene suture. The device includes a pad-printed design on the outer surface to indicate valve position and direction of flow. Image courtesy of Peca Labs Peca has received Humanitarian Use Device (HUD) and Investigational Device Exemption (IDE) designation from FDA and has begun enrollment for its Masa Valve Early Feasibility Clinical Study at four clinical sites in the United States. One of the study sites included is Children’s Hospital of Philadelphia, which is where the successful first in-human implant recently took place. The valve was reportedly implanted in a 21-month-old child who had previously undergone surgery for a homograft at one year old. The homograft, also known as a human tissue valve, had become severely stenotic and required immediate replacement. In turn, the homograft has been replaced with a 14mm Masa valve and the patient has shown encouraging early results post-procedure, with promising valve functionality on early assessment, according to the company. "This successful implant marks a historic step for our polymeric valve technology that aims to combine the bio-inert benefits of organic tissue and durability of mechanical valves to potentially reduce the need for additional surgeries. The Masa valve materials and design may also help to preserve native tissue that would otherwise be used for a part of the reconstruction and could reduce the amount of medication needed for the patient during their lifetime," Arush Kalra, chief scientific officer and co-founder at Peca Labs, wrote in a statement for MD+DI . "This case brings Masa valve one step closer to being available to children who need such transformational innovation the most, furthering Peca's goal to save and improve lives." Other existing valve implants are made with metal, ceramic or bioprosthetic materials, which can “cause biological responses, lack customizability, cannot be grown, and are destined to fail within five to 10 years,” according to a press release announcing the in-human implant. “Failed conduits require repeat surgeries and interventions, costing more than $100,000 per patient on average, and current interventions for failed implants don’t resolve the core reason for failure.” The Masa valve is named after its inventor, Masahiro Yoshida, MD, PhD , who created the concept after observing issues using biologic valve replacements including calcification, limitations of valve expansion on a growing heart, and shorter times between surgical replacements. Pediatric patients born with valve defects related to a number of congenital heart conditions — pulmonary stenosis, tetralogy of fallot, truncus arteriosus, transposition of great vessels, and pulmonary atresia — require multiple open-heart surgeries from childhood to adulthood. Especially in very young patients, implanted valves and conduits need to be replaced with larger ones as the heart grows. Yoshida, in turn, designed a PTFE implant that was more adaptable to a growing heart, reduced the issues of calcification, and expanded the intervals between replacements. It was years later that three Carnegie Mellon University students formed Peca as a startup near Pittsburgh to commercialize a product based on Dr. Yoshida’s concepts, creating the Masa valve. The company developed the valve to be made entirely out of polymeric materials to help avoid some of the complications that come with the use of biologic valves. Masa does not use biologic or foreign tissue, meaning that the body will not have any immune response to the device. Additionally, its polymeric material helps avoid valve calcification and can be produced in an array of sizes to match each patient’s anatomy. “In designing the Masa valve, we aimed to use our polymer platform to combine the best characteristics of homograft tissue, which reduces the antithrombotic therapy required, and mechanical valves, which offer improved durability, supply availability, and resistance to both calcification and shrinkage,” said Doug Bernstein, CEO at Peca Labs. “We then improved upon them with a novel bi-leaflet design.” Now embarking on the enrollment stage of its clinical study, the company is slated to enroll 10 to 15 patients at up to five sites. The study, which is multi-center, non-randomized, prospective, and interventional, is set to determine the safety and probable benefit of Masa by following implanted subjects for a total of five years post-procedure with a post-op, 30-day, 180-day, and one year follow-up, followed by an annual follow up until five years.

关键词BRAF；肿瘤；研究进展BRAF基因BRAF基因是人类重要的原癌基因，位于染色体7q34位置上，编码RAF家族苏氨酸/丝氨酸蛋白激酶。BRAF蛋白与KRAS蛋白同为RAS-RAF-MEK活化的细胞外信号调节激酶，在MAPK/ERK信号通路中起着举足轻重的作用。BRAF蛋白由783个氨基酸组成，从N端到C端依次为CR1、CR2 和CR3三个保守区。其中CR1区由RAS蛋白结合区和富含半胱氨酸区组成，这两个区域均可与RAS结合；CR2富含丝氨酸/苏氨酸，为调节磷酸化RAF激酶活性；CR3区为 ATP结合位点和激活区，含有酪氨酸和丝氨酸残基及有多个磷酸化位点，磷酸化后可激活BRAF蛋白和诱导性激活ERK，ERK主要参与有丝分裂和增殖。BRAF基因改变类型BRAF基因改变包括BRAF体细胞错义突变(主要)、BRAF胚系突变和BRAF融合。其中BRAF胚系突变与发育障碍有关，如心面皮肤综合征、豹皮综合征和努南综合征等，但几乎不会在实体肿瘤患者中检出。BRAF融合是指BRAF的C末端部分（蛋白激酶结构域）在N末端与另一种蛋白发生融合，被认为是由于BRAF蛋白调节结构域的丢失导致MAPK途径的组成型激活而引起的自身磷酸化，可见于恶性黑色素瘤、神经胶质瘤和多种肿瘤。BRAF体细胞突变以错义突变为主，主要位于CR3激酶结构域的第11外显子及第15外显子，其中BRAF最常见突变形式为第15外显子的第1799位核苷酸上T突变为A，导致其编码的缬氨酸变为谷氨酸，即BRAF V600E突变（约占80%）。这一突变可使BRAF蛋白持续激活，激活后的BRAF成为能够不依赖于上游RAS激酶的单体，导致ERK持续激活。持续激活的ERK蛋白不断进入到细胞核内部，不断地激活下游的各种蛋白，启动下游的各种基因的转录，导致了细胞的无限增殖和分裂。而且，BRAF突变一般与 EGFR、KRAS 等突变相互独立和排斥，不同时出现。除了BRAF V600E突变，BRAF基因突变还包括V600K（约占15%）、V600R/D/M/G（约占5%）。此外，根据信号传导机制和激酶活性，BRAF突变可分为三类：I类为V600突变激酶激活性单体，强烈激活BRAF激酶活性，包括BRAF V600D/E/K/R突变；II类为激酶激活性二聚体，包括BRAF K601，L597，G464和G469突变；III类为激酶失活性异源二聚体，包括BRAF G466，N581，D594和D596突变。其中I类和II类不依赖RAS信号，III类依赖于RAS信号。研究发现，BRAF基因在所有人体肿瘤中突变率大约为8%，但不同肿瘤中突变发生率不同，多见于毛细胞白血病（100%）、黑色素瘤（50%）、甲状腺乳头状癌（45%）、结直肠癌(约10%)和非小细胞肺癌(约10%)等瘤种。BRAF抑制剂点燃BRAF突变阳性实体瘤治疗新希望BRAF突变是多种实体瘤的重要治疗靶点之一，以BRAF抑制剂为代表的靶向联合疗法已成为多种BRAF突变阳性实体瘤的主要治疗手段之一。目前，已获批的BRAF抑制剂根据作用靶点主要分为非特异性BRAF抑制剂（如索拉非尼 、瑞戈非尼和培唑帕尼等）和特异性BRAF抑制剂。非特异性BRAF抑制剂对包括BRAF在内的多种激酶有抑制作用，具有广谱的抗肿瘤及抗血管生成作用，适应症较广。已获批的药物包括索拉非尼（Sorafenib） 、瑞戈非尼（Regorafenib） 、培唑帕尼（Pazopanib）、多纳非尼（Donafenib），其中索拉非尼作为首款获批的BRAF抑制剂，是目前临床晚期肝癌及肾癌的一线治疗药物。特异性BRAF抑制剂包括维罗非尼(Vemurafenib，Zelboraf)、达拉非尼（Dabrafenib，Tafinlar）、康奈非尼（Encorafenib，Braftovi）。其中维罗非尼最早于2011年被FDA批准用于治疗BRAF V600E突变阳性、不可切除性或转移性黑色素瘤成人患者，2017年又被FDA批准批准扩大用于BRAF V600突变阳性的Erdheim-Chester病（ECD）成人患者。此外，维罗非尼还被批准联合MEK抑制剂考比替尼（Cobimetinib，Cotellic）用于治疗BRAF V600E或V600K突变阳性不可切除性或转移性黑色素瘤，以及联合MEK抑制剂考比替尼和PD-L1单抗阿替利珠单抗（atezolizumab，Tecentriq）用于治疗BRAF V600突变阳性的晚期黑色素瘤。达拉菲尼是GSK开发的一款选择性BRAF抑制剂，2013年5月被FDA批准单药治疗携带BRAF V600E突变的手术不可切除性黑色素瘤或转移性黑色素瘤成人患者。2015年8月，达拉非尼被欧盟批准联合MEK抑制剂曲美替尼（trametinib，Mekinist），用于治疗携带BRAF V600突变阳性不可切除性或转移性黑色素瘤成人患者。此外，“达拉非尼+曲美替尼”组合疗法还被获批多个适应症：用于携带BRAF V600E/K突变且淋巴结受累黑色素瘤患者完成手术切除后的辅助治疗；用于治疗携带BRAF V600E突变的转移性非小细胞肺癌（NSCLC）患者；用于治疗没有满意的局部治疗选择、携带BRAF V600E突变的局部晚期或转移性间变性甲状腺癌（ATC）患者；用于治疗先前疗法治疗后病情进展且没有令人满意的可选治疗方案、携带BRAF V600E突变的不可切除性或转移性实体瘤成人患者（≥18岁）和儿科患者（≥6岁）；用于治疗1岁及以上需要全身治疗的BRAF V600E突变的低级别胶质瘤（LGG）儿童患者。康奈非尼于2018年6月被FDA批准联合MEK抑制剂贝美替尼（Binimetinib,Mektovi)用于治疗存在BRAF V600E或BRAF V600K突变的不可切除性或转移性黑色素瘤患者。2020年4月，“康奈非尼+贝美替尼”组合疗法又被批准用于治疗经治、携带BRAF V600E突变的转移性结直肠癌（mCRC）成人患者。百济神州、复宏汉霖等国内药企积极布局BRAF抑制剂除了上述药物，目前全球还有多款在研BRAF抑制剂，详见下表。在研BRAF抑制剂大多处于早期临床，主要被开发用于治疗BRAF突变实体瘤。除了小分子化药，还出现了针对BRAF V600X突变选择性蛋白降解药物，如CFT1946。该药专门针对V600X 突变的黑色素瘤、非小细胞肺癌（NSCLC）、结直肠癌等实体瘤。在临床前研究中，CFT1946在体内和体外对BRAF V600E驱动疾病模型和对BRAF抑制剂耐药模型均有活性。值得一提的是，我国药企也积极布局BRAF抑制剂领域，如百济神州、璧辰医药、复宏汉霖、正大天晴等。其中百济神州布局了两款BRAF抑制剂，且就这两款药物与SpringWorks Therapeutics先后达成两项合作。全球部分在研BRAF抑制剂资料来源：公开资料Naporafenib（LXH254）Naporafenib（LXH254）是一种有效的、选择性的BRAF和CRAF抑制剂，在NRAS突变(NRASm)黑色素瘤和其他RAS/MAPK途径驱动的肿瘤中具有潜在的first-in-class和best-in-class的潜力。2022年12月，Erasca与诺华就naporafenib达成全球独家许可协议。FORE8394FORE8394是一种新型BRAF选择性抑制剂，旨在靶向广泛的BRAF突变，同时保留不影响野生型RAF的活性。临床前研究和临床试验表明：FORE8394独特的作用机制不仅可以有效抑制第一代RAF抑制剂靶向的组成型活性BRAFV600单体，还可以破坏组成型活性二聚体BRAF 2类突变体、融合体、剪接变异体等。已公布的1/2a期临床试验中期数据显示：在未使用过MAPK抑制剂的BRAF V600+人群中确认的单药ORR为43%，中位反应持续时间为17.8个月，71%的患者的临床获益超过24周。此外，在包括高级别和低级别胶质瘤在内的原发性中枢神经系统肿瘤中也观察到了FORE8394的疗效。安全性方面，FORE8394具有良好的耐受性。2023年3月，该药被FDA授予孤儿药资格，治疗原发性脑和中枢神经系统（CNS）恶性肿瘤。HLX208HLX208具有全新的化学母核结构，是具备“同类最佳”潜力的BRAF V600E小分子抑制剂。临床前研究结果表明，HLX208具有单一稳定晶型，良好的口服生物利用度及显著的肿瘤抑制活性。早期临床研究也展现出HLX208具有良好的安全性、耐受性和有效性。2021年5月，复宏汉霖与润新生物达成独家合作，获得后者HLX208（RX208）在中国（包括香港、澳门和台湾地区）进行研究、开发、生产、商业化及再许可等的独家权利。而润新生物将获得9750万元的首付款，最高可达约10.775亿元的相关临床开发、注册和销售里程碑付款，以及产品上市后的销售提成。2022年11月，HLX208联合H药汉斯状®（斯鲁利单抗注射液）及其相关联合疗法（+/-西妥昔单抗或曲美替尼）用于BRAF V600E或BRAF V600突变阳性晚期实体瘤治疗的1b/2期临床试验申请获NMPA批准。2023年3月，该药被CDE纳入突破性治疗品种，适应症为BRAF V600E突变的成人朗格汉斯细胞组织细胞增生症（LCH）和Erdheim-Chester病（ECD）。BGB-3245BGB-3245是一款针对特定单聚体和二聚体BRAF激活突变型的在研口服高选择性小分子抑制剂，针对包括BRAF V600突变型、BRAF非V600突变型和RAF融合在内的单聚体和二聚体BRAF激活突变。在多个临床前肿瘤模型中，BGB-3245展示出抗肿瘤活性，包括那些带有BRAF二类突变、RAF融合以及接受BRAF V600治疗后产生的间接BRAF抗性突变。2019年6月，百济神州与SpringWorks Therapeutics宣布成立MapKure，共同开发BGB-3245。据协议，SpringWorks对MapKure进行股权投资，而百济神州则贡献在亚洲以外国家和地区（包括日本）开发及商业化BGB-3245的独家版税和里程碑授权，以换取MapKure的多数所有权。此外，百济神州还曾于2018年9月与SpringWorks Therapeutics达成全球临床合作，评估其RAF二聚体抑制剂Lifirafenib与SpringWorks Therapeutics在研MEK抑制剂PD-0325901的联合疗法在晚期实体瘤患者中的安全性、耐受性和初步疗效。2022年10月，SpringWorks Therapeutics发起一项BGB-3245联合MEK抑制剂的Mirdametinib 治疗晚期转移性或不可切除的实体癌患者的1/2a期临床试验。ABM-1310ABM-1310是一种高选择性、高水溶性的新一代口服BRAF抑制剂，具有理想的血脑屏障渗透率。在临床前的脑转移和脑原位瘤动物模型试验中，ABM-1310显著优于维罗替尼，同等剂量的ABM-1310将中位生存期延长了一倍，有望成为治疗各种恶性肿瘤脑转移的新一代BRAF抑制剂。2019年11月，该药在美国获批临床。2021年11月，ABM-1310在国内获批临床，用于BRAF突变的晚期实体瘤。KIN-2787KIN-2787是一种口服小分子泛RAF抑制剂，被设计用于靶向突变BRAF激酶的单体和二聚体形式，除了涵盖I类BRAF突改变外，还可针对II类和III类BRAF突变。2022年9月，该药被FDA授予快速通道资格，用于治疗II或III类BRAF突变阳性和/或NRAS突变阳性IIb至IV期转移性或不可切除恶性黑色素瘤患者。小结BRAF是多种实体瘤治疗的重要靶点，以BRAF抑制剂为代表的靶向联合疗法已成为多种BRAF突变阳性实体瘤的主要治疗手段之一。非特异BRAF抑制剂由于作用靶点多，适应症广泛。目前，选择性BRAF抑制剂也已显露头角，适应症涉及黑色素瘤、甲状腺癌、结肠癌等，其中达拉非尼+曲美替尼作为首个不限癌种疗法，已被批准用于治疗先前疗法治疗后病情进展且没有令人满意的可选治疗方案、携带BRAF V600E突变的不可切除性或转移性实体瘤患者，也是首次获批应用于儿科患者的BRAF/MEK制剂组合。值得一提的是，BRAF抑制剂往往要联合MEK抑制剂/EGFR单抗才能够有效改善该类患者的生存现状及预后。而且，BRAF抑制剂的新搭档也已出现，如ERK抑制剂。2023年1月，捷思英达启动ERK1/2抑制剂联合达拉非尼治疗BRAF V600E/K 突变局部晚期或转移性实体瘤的1期临床。目前，BRAF突变实体瘤市场仍有待进一步挖掘，在研BRAF抑制剂大多处于早期临床，期待未来有更多选择性BRAF抑制剂获批上市。END👇关注药渡数据媒体矩阵