Reactive capillary hemangiomas: a novel dermatologic toxicity following anti-PD-1 treatment with SHR-1210

Objective: SHR-1210 is a new and promising anti-PD-1 agent for solid tumors. During the phase I study of SHR-1210, we encountered a novel but prevalent immune-related dermatologic toxicity: reactive capillary hemangiomas(RCHs). Thus we tried to summarize the features of RCHs and estimate their relationship with tumor response.Methods: This prospective observational study systematically enrolled 98 patients with advanced solid tumors from April 27th,2016 to June 8th, 2017 in the context of the phase I clinical study of SHR-1210. This report focused on the skin toxicities. Patients underwent entire skin inspection every two weeks while taking medication. The clinical course of RCHs was recorded and their association with tumor response was estimated. The data cut-off date was November 15th, 2017.Results: After a median follow-up of 242(range, 29–567) days, RCHs were observed in 85.7%(84/98) of patients on cutaneous/mucosal surfaces; 84.5%(71/84) of the RCHs were evaluated as grade 1 adverse events. No grade 3 or 4 RCHs were observed. The time of onset of RCHs was dose dependent and shortest in the 400 mg-dose cohort(P < 0.001). Spontaneous and complete regression of RCHs was observed both during and after treatment. The objective response rate of tumors for patients with RCHs was 28.9%(24/83). However, no responders were observed among the patients without RCHs.Conclusions: RCHs were prevalent but manageable during treatment with SHR-1210. It might add to the expanding literature regarding immune-related dermatologic adverse events.

Radiofrequency ablation for hepatic hemangiomas: A consensus from a Chinese panel of experts

Recent studies have shown that radiofrequency(RF) ablation therapy is a safe, feasible, and effective procedure for hepatic hemangiomas, even huge hepatic hemangiomas. RF ablation has the following advantages in the treatment of hepatic hemangiomas: minimal invasiveness, definite efficacy, high safety, fast recovery, relatively simple operation, and wide applicability. It is necessary to formulate a widely accepted consensus among the experts in China who have extensive expertise and experience in the treatment of hepatic hemangiomas using RF ablation, which is important to standardize the application of RF ablation for the management of hepatic hemangiomas, regarding the selection of patients with suitable indications to receive RF ablation treatment, the technical details of the techniques, therapeutic effect evaluations, management of complications, etc. A final consensus by a Chinese panel of experts who have the expertise of using RF ablation to treat hepatic hemangiomas was reached by means of literature review, comprehensive discussion, and draft approval.

Klippel-Trenaunay syndrome with gastrointestinal bleeding,splenic hemangiomas and left inferior vena cava

Klippel-Trenaunay syndrome is a congenital vascular anomaly characterized by a triad of varicose veins,cutaneous capillary malformation,and hypertrophy of bone and(or)soft tissue.Gastrointestinal vascular malformations in Klippel-Trenaunay syndrome may present with gastrointestinal bleeding.The majority of patients with spleenic hemangiomatosis and/or left inferior vena cava are asymptomatic.We herein report a case admitted to the gastroenterology clinic with life-threatening hematochezia and symptomatic iron deficiency anemia.Due to the asymptomatic mild intermittent hematochezia,splenic hemangiomas and left inferior vena cava,the patient did not seek any help for gastrointestinal bleeding until his admittance to our department for evaluation of massive gastrointestinal bleeding.He was referred to angiography because of his serious pathogenetic condition and inefficiency of medical therapy.The method showed that hemostasis was successfully achieved in the hemorrhage site by embolism of corresponding vessels.Further endoscopy revealed vascular malformations starting from the stomach to the descending colon.On the other hand,computed tomography revealed splenic hemangiomas and left inferior vena cava.To the best of our knowledge,this is the first Klippel-Trenaunay syndrome case presenting with gastrointestinal bleeding,splenic hemangiomas and left inferior vena cava.The literature on the evaluation and management of this case is reviewed.

Topical Propranolol Hydrochloride Gel for Superficial Infantile Hemangiomas

The clinical efficacy and safety of topical propranolol hydrochloride gel in the treatment of superficial infantile hemangiomas (IHs) were assessed. Fifty-one cases of IHs from Oct. 2010 to Sept. 2011 were subjected to the topical propranolol hydrochloride gel intervention in Fuzhou General Hospital of Nanjing Military Commands, China. Changes in size, texture, color, peak systolic velocity of the hemangiomas, resistance index and adverse effects were observed. The results were evaluated by using Achauer system, and responses of IHs to pranpronolol were considered scaleⅠ(poor) in 4 patients (17.24%), scaleⅡ(moderate) in 18 patients (24.14%), scale Ⅲ (good) in 22 patients (44.83%) and scale Ⅳ (excellent) in 7 patients (13.79%). The response of superficial hemangiomas was significantly better than other hemangiomas (P<0.05), and no differences in response were found among different primary sites (P>0.05). Our study indicates that topical application of 3% propranolol hydrochloride gel is effective and safe in treating IHs.

Hemolymphangioma with multiple hemangiomas in liver of elderly woman with history of gynecological malignancy: A case report

BACKGROUND Hepatic hemolymphangioma is an extremely rare benign congenital malformation composed of cystically dilated lymphatic and blood vessels,and they have nonspecific clinical symptoms and laboratory results.In this study,hepatic hemolymphangioma with multiple hemangiomas in an elderly woman was initially reported and analyzed.CASE SUMMARY A 61-year-old female patient,with a history of hysterectomy and bilateral adnexectomy,was referred to the hepatobiliary surgery department with the complaint of multiple hepatic hemangiomas that had been diagnosed 2 years prior in a preoperative contrast-enhanced computed tomography(CECT)examination.Upon entering our hospital,no abnormal physical examination and laboratory data were found.The latest CECT revealed a new 7.0 cm×6.2 cm cystic-solid lesion with multiple internal divisions in segment II of the liver,with delayed CECT enhancement characteristics that presented as solid parts with internal division.On the positron emission tomography(PET)/CT,no significant uptake of 18F-fluorodeoxyglucse was observed.Finally,hepatic hemolymphangioma was confirmed based on the pathological and immunohistochemical results after surgery.At 1-year follow-up,her posthepatectomy evaluation was uneventful,and she had recovered full activity.In addition,no postoperative recurrent or residual lesion was found on CECT imaging.CONCLUSION Hepatic hemolymphangioma with multiple hemangiomas was reported and observed by CECT and PET/CT imaging.

Transnasal endoscopic approach for orbital apical cavernous hemangiomas:a case report

Cavernous hemangioma is the most primary benign orbital tumor in adults,and majority of cases could be easily settled by surgical treatment.However,cavernous hemangioma lodged deep in the orbital apex remained a challenge because the surgery may pose a high risk of injury to the optic nerve and significant visual loss.This presentation would report a case of cavernous hemangioma located in orbital apex who presented superonasal and inferotemporal peripheral vision defect.The patient received fully transnasal endoscopic surgery,and a 2 cm×1.5 cm tumor was successfully removed from the left orbital apex.The treatment results were satisfactory,with no after-effects and adverse reactions during follow-up.This case highlighted that transnasal endoscopic surgery is a promising technique for cavernous hemangiomas that are located deep in orbital apex.This approach provides direct pathway to tumor with limiting morbidity,maximal surgical field and ample illumination.The procedure represents a safe and less invasive management.

Characteristic MR imaging findings and surgical treatment of cavernous hemangiomas in cavernous sinus

Objective To analyze the imaging character and surgical therapy of cavernous hemangiomas in cavernous sinus(CSHs).Methods From 2001 to 2008,13 patients with CSHs were surgically treated in our department. The diameters of CSHs varied from 3. 5 cm to 6. 0 cm. Results All the patients were operated on with no mortality.

Giant cavernous liver hemangiomas： is it the time to change the size categories？

BACKGROUND： Four different sizes （4, 5, 8 and 10 cm in diameter） can be found in the literature to categorize a liver hemangioma as giant. The present review aims to clarify the appropriateness of the size category ＂giant＂ for liver heman- gioma. DATA SOURCES： We reviewed the reports on the categoriza- tion of hemangioma published between 1970 and 2014. The number of hemangiomas, size criteria, mean and range of hemangioma sizes, and number of asymptomatic and symp- tomatic patients were investigated in patients aged over 18 years. Liver hemangiomas were divided into four groups： 〈5.0 cm, 5.0-9.9 cm, 10.0-14.9 cm and 〉15.0 cm in diameter. Inclu- sion criteria were noted in 34 articles involving 1972 （43.0%） hemangiomas （〉4.0 cm）. RESULTS： The patients were divided into the following groups： 154 patients （30.0%） with hemangiomas less than 5.0 cm in diameter （small）, 182 （35.5%） between 5.0 cm and 9.9 cm （large）, 75 （14.6%） between 10.0 and 14.9 cm （giant）, and 102 （19.9%） more than 15.0 cm （enormous）. There were 786 （39.9%） asymptomatic patients and 791 （40.1%） symptomatic patients. Indications for surgery related to symptoms were reported in only 75 （3.8%） patients. Operations including 137 non-anatomical resection （12.9%） and 469 enudeation （44.1%） were undearly related to size and symptoms.CONCLUSIONS： The term ＂giant＂ seems to be justified for liver hemangiomas with a diameter of 10 cm. Hemangiomas categorized as ＂giant＂ are not indicated for surgery. Surgery should be performed only when other symptoms are apparent.

Laparoscopic vs computerized tomography-guided radiofrequency ablation for large hepatic hemangiomas abutting the diaphragm

AIM: To compare safety and therapeutic efficacy of laparoscopic radiofrequency(RF) ablation vs computed tomography(CT)-guided RF ablation for large hepatic hemangiomas abutting the diaphragm.METHODS: We retrospectively reviewed our sequential experience of treating 51 large hepatic hemangiomas abutting the diaphragm in 51 patients by CT-guided or laparoscopic RF ablation due to either the presence of symptoms and/or the enlargement of hemangioma.Altogether, 24 hemangiomas were ablated via a CTguided percutaneous approach(CT-guided ablation group), and 27 hemangiomas were treated via a laparoscopic approach(laparoscopic ablation group).RESULTS: The mean diameter of the 51 hemangiomas was 9.6 ± 1.8 cm(range, 6.0-12.0 cm). There was nodifference in the diameter of hemangiomas between the two groups(P > 0.05). RF ablation was performed successfully in all patients. There was no difference in ablation times between groups(P > 0.05). There were 23 thoracic complications in 17 patients: 15(62.5%, 15/24) in the CT-guided ablation group and2(7.4%, 2/27) in the laparoscopic ablation group(P< 0.05). According to the Dindo-Clavien classification,two complications(pleural effusion and diaphragmatic rupture grade Ⅲ) were major in two patients. All others were minor(grade Ⅰ). Both major complications occurred in the CT-guided ablation group. The minor complications were treated successfully with conservative measures, and the two major complications underwent treatment by chest tube drainage and thoracoscopic surgery, respectively. Complete ablation was achieved in 91.7%(22/24) and 96.3%(26/27) in the CT-guided and the laparoscopic ablation groups,respectively(P > 0.05).CONCLUSION: Laparoscopic RF ablation therapy should be used as the first-line treatment option for large hepatic hemangiomas abutting the diaphragm.It avoids thermal injury to the diaphragm and reduces thoracic complications.

Spontaneous rupture of hepatic hemangiomas:A review of the literature

Hepatic hemangiomas are congenital vascular malformations,considered the most common benign mesenchymal hepatic tumors,composed of masses of blood vessels that are atypical or irregular in arrangement and size. Hepatic hemangiomas can be divided into two major groups:capillary hemangiomas and cavernous hemangiomas These tumors most frequently affect females (80%) and adults in their fourth and fifth decades of life. Most cases are asymptomatic although a few patients may present with a wide variety of clinical symptoms,with spontaneous or traumatic rupture being the most severe complication. In cases of spontaneous rupture,clinical manifestations consist of sudden abdominal pain,and anemia secondary to ahaemoperitoneum. Disseminated intravascular coagulopathy can also occur. Haemodynamic instability and signs of hypovolemic shock appear in about one third of cases. As the size of the hemangioma increases,so does the chance of rupture. Imaging studies used in the diagnosis of hepatic hemangiomas include ultrasonography,dynamic contrast-enchanced computed tomography scanning,magnetic resonance imaging,hepatic arteriography,digital subtraction angiography,and nuclear medicine studies. In most cases hepatic hemangiomas are asymptomatic and should be followed up by means of periodic radiological examination. Sur gery should be restricted to specific situations. Absolute indications for surgery are spontaneous or trau m atic rupture with hemoperitoneum,intratumoral blee ding and consumptive coagulopathy (Kassabach-Merrit syndrome). In a patient presenting with acute abdo minal pain due to unknown abdominal disease,sponta neous rupture of a hepatic tumor such as a hemangio ma should be considered as a rare differential diagnosis.

肝的周期性的巨大的 hemangiomas : 有文学评论的二个稀罕案例的报告

Most hepatic hemangiomas(HHs) are small,asymptomatic and do not require clinical intervention.Surgical resection is only indicated for symptomatic hemangiomas.We report here cases of recurrent HHs in 2 women of 37 and 40 years old,who initially presented with abdominal pain and mass.Radiological examination of each tumor revealed a solitary tumor of 14 and 20 cm in diameter,respectively.Surgical liver segmental resections were performed in both,and the diagnosis of cavernous hemangioma was confirmed.Both patients had recurrent tumor on subsequent radiological examination 4-5 years after the initial surgery.In the first patient,a 15 cm recurrent hemangioma was resected,but multiple hemangiomas were again detected 8 years later occupying the other hepatic lobe,which was not amendable for resection.In the second patient,a 16 cm hemangioma was seen on radiogram,and because the lesion was not symptomatic,conservative observation was offered.Recurrence after liver resection of giant hemangioma is extremely rare.The pathogenesis of tumor progression and recurrence is unknown,as is the management of these patients with recurrent hemangioma,particularly when it is extensive and unresectable.

Clinical observations on the treatment of infantile hemangiomas with topical imiquimod 5% cream

Objective： To observe the efficacy and safety of topical imiquimod 5% cream in the treatment of uncomplicated infantile hemangiomas （IHs）. Methods： A total of 68 IHs were treated with topical imiquimod 5% cream. Among them, 36 were superficial, 22 were mixed, and 10 were deep. The size of IHs ranged from 1.0 cm × 1.5 cm to an area of a whole forearm. All the hemangiomas were in a proliferative stage. Imiquimod was applied 3 times weekly in 44 patients and 5 times weekly in 24 patients for up to 36 weeks. Results： All superficial IHs improved, and 18 achieved complete clinical resolution, 10 had excellent improvement, 5 showed moderate improvements, and 3 patients displayed minimal improvement. Two mixed IHs showed excellent improvement, 3 showed moderate improvement and 5 manifested minimal improvements. The remaining 12 mixed IHs and all deep IHs did not respond to the therapy. The total incidence of local adverse events was 58.82%（40/68）, which included erythema or edema, local itching, incrustation or peeling, erosion or ulceration, although most of these were mild to moderate reactions and did not affect the treatment. Scarring occurred in 2 mixed IHs. No systemic side effects developed. Conclusion： Imiquimod 5% cream may be a safe and effective alternative for the treatment of superficial IHs and some mixed IHs in which the superficial component predominates. An appropriate treatment duration for proliferative IHs treated with this therapy may be 24 weeks. Some local adverse events, such as crusting and erosion with possible scarfing potential may occur and should be addressed by prompt, but temporary, discontinuation of the imiquimod. Topical imiquimod 5% cream can be prudently used in the treatment of IHs larger than 5.0 cm × 5.0 cm in newborns and infants less than 6 months of age. To our knowledge, this is the largest IH group treated with imiquimod that has been reported in the literature to date.

Polidocanol sclerotherapy for multiple gastrointestinal hemangiomas:A case report

BACKGROUND Gastrointestinal(GI)hemangioma has a low incidence among systemic hemangiomas,and some GI hemangiomas occur in the intestine,stomach,and esophagus.Polidocanol has been increasingly used in sclerotherapy.However,this paper reports that minimally invasive treatment of multiple hemangiomas with large diameters can achieve satisfactory results by multipoint injection.CASE SUMMARY A 46-year-old female patient was hospitalized in another hospital for cough.We accidentally found thickening of the lower esophagus by chest computed tomography.The patient was eventually diagnosed with multiple GI hemangiomas and underwent a series of examinations including esophagogastroduodenoscopy(EGD),endoscopic ultrasound,and magnetic resonance imaging.We calculated the dose of polidocanol according to the volumes of the hemangiomas,fixed the target vein with the help of a transparent cap,and then administered polidocanol via multipoint injection into the hemangiomas under endoscopic guidance.EGD and endoscopic ultrasound showed that the hemangiomas disappeared.The color of the esophageal mucosa returned to normal 1 mo after sclerotherapy.CONCLUSION Sclerotherapy may be a safe and effective method for treating multiple hemangiomas of the alimentary canal.

Treatment of large size cavernous hemangiomas in oromaxillo-facial region by microwave tissue thermo-coagulation:a primary report of 76 cases

From July 1988 to May 1991,the authors had used the microwave tissue thermo-co-agulation method(MTTC)to treat 76 cases of large cavernous hemangiomas in the oro-maxillo-facial region.When a microwave antenna-pin was inserted into the tumor,blood and tissuewithin the tumor began coagulating due to high temperature produced by the mierowave ma-chine.Along with a full coagulation,the tumor may be removed surgically without bleeding.This method has many advantages:(1)less bleeding with little need of blood transfusion;(2)convenience for excision;(3)time for operation markedly shortened;(4)suitability for opera-tion-contraindicated patients.The authors consider that the microwave tissue thermo-coagula-tion method is a rather ideal method for treating large cavernous hemangiomas in the oro-maxil-lo-facial region.In this paper are reported 76 eases of clinical application and animal experimentof microwave tissue thermo-coagulation influences on the muscles and vessels.

Ultrasonographic Diagnosis of Hemangiomas of Soft Tissue

Presented in this paper are the results of ultrasounic examination in 29 cases of hemangiomas of soft tissue. Out of the 29 cases, 20 lesions were revealed as heterogeneous echoic masses; 6 as anechoic areas and 3 as solid masses. Hyperechoic foci of calcifications or phlebolithes were detected in 16 cases. Intramuscular hemangiomas were sonographically diagnosed in 15 patients; hemangiomas of soft tissue in 8, pseudoaneurysm in 3; deformity of the arteriovenous fistula in 1 and hemangiosarcoma in 2. The diagnosis in 28 patients were surgically and pathologically confirmed and the remaining one was confirmed by aspiration and cytological examination. The diagnostic accuracy of the ultrasound was 100%.

Evaluation of Mast Cells in Dermal versus Subcutaneous Hemangiomas and Hemangiosarcomas in Dogs

This study investigated the role of mast cells in canine cutaneous vascular tumors, and is the first such study to distinguish between tumors arising in the dermis versus the subcutis. Mast cell numbers in canine cutaneous hemangiomas (HA) and hemangiosarcomas (HSA) were evaluated to identify a relationship between mast cells, tumor type (HA, HSA), histologic location (dermis, subcutis) and tumor recurrence. One hundred and sixty-seven biopsies from 148 dogs were evaluated. Using only one biopsy from each dog, mast cell counts (MCC) for each tumor (n = 148) were obtained by averaging the number of mast cells counted in ten 400× fields. A significant difference in mean MCC was found only between tumor types, with HA having more mast cells than HSA (4.2 ± 4.2 vs. 2.2 ± 2.6;p < 0.001). No significant difference in mean MCC existed between tumors that recurred and those that did not. There was no difference in recurrence rate between tumor type or histologic location. Our results indicate that benign HA contain more mast cells than malignant endothelial cell tumors, regardless of histologic location;whether this is a cause or effect relationship remains to be determined.

A Case of Incidentally Found Bilateral Retroperitoneal Cavernous Hemangiomas

A 59-year-old male was admitted to our hospital because of incidentally found right retroperitoneal tumor. He had undergone removal of a hemangioma in the left oral cavity four years before. An abdominal CT scan performed in our hospital revealed poorly enhanced bilateral retroperitoneal tumors adjacent to kidneys. Those tumors were of low signal intensity on T1-weighted images and high on T2-weighted images by magnetic resonance imaging. The right retroperitoneal tumor of 2.5 cm in size was surgically removed and histopathological examination indicated cavernous hemangioma. The smaller left retroperitoneal tumor of 1.1 cm in size was left untouched to be followed up, as we supposed that it has the same benign pathology. There have been no previous cases of retroperitoneal cavernous hemangioma as a presentation of multiple hemangiomas.

Early Pulsed Dye Laser Treatment for Infantile Hemangiomas: An Open Study for 50 Japanese Infancies

Infantile hemangiomas, occurring at birth or during the first weeks of life, are benign vascular tumors with an initial proliferative phase and a later involutional phase. The massive proliferation on the key regions and unpredicted regression may threaten?life. Thus, early management of infantile hemangiomas is necessary for affected infancies. Recent studies showed that propranolol for infantile hemangiomas had high efficacy for disappearance or reduction of infantile hemangiomas. However, a most recent study demonstrated existence of propranolol-resistant infantile hemangiomas. Therefore, we retrospectively evaluated efficacy of established early pulsed dye laser treatment for infantile hemangiomas in the 50 Japanese infancies which were applied in the period from 2000 to 2005, because our series included from the plaque subtype to the more proliferative tumor subtype. High efficacy in both subtypes suggests that early pulsed dye laser treatment can still be included as the first option for the mixed type of infantile hemangiomas and that pulsed dye laser treatment may be useful as the second line for the propranolol-resistant mixed type of infantile hemangiomas.

Facial nerve hemangiomas: A review

Facial nerve hemangiomas are rare benign vascular tumors with primary symptoms including progressive facial nerve palsy and hearing loss. They can involve various segments of the facial nerve, especially the geniculate ganglion （G.G.）. Preoperative MRI and CT imagining is of great importance for early diagnosis of such lesions. The most accepted treatment for facial nerve hemangiomas is surgical excisiont and the type of approach depends on tumor location, preoperative bearing level and tumor size. In consideration of the difficulties in differential diagnosis, otologists should pay attention to avoid missed or incorrect diagnosis in hemangiomas of facial nerve.

Somatic GJA4 mutation in intracranial extra-axial cavernous hemangiomas

Objective Extra-axial cavernous hemangiomas(ECHs)are sporadic and rare intracranial occupational lesions that usually occur within the cavernous sinus.The aetiology of ECHs remains unknown.Methods Whole-exome sequencing was performed on ECH lesions from 12 patients(discovery cohort)and droplet digital polymerase-chain reaction(ddPCR)was used to confirm the identified mutation in 46 additional cases(validation cohort).Laser capture microdissection(LCM)was carried out to capture and characterise subgroups of tissue cells.Mechanistic and functional investigations were carried out in human umbilical vein endothelial cells and a newly established mouse model.Results We detected somatic GJA4 mutation(c.121G>T,p.G41C)in 5/12 patients with ECH in the discovery cohort and confirmed the finding in the validation cohort(16/46).LCM followed by ddPCR revealed that the mutation was enriched in lesional endothelium.In vitro experiments in endothelial cells demonstrated that the GJA4 mutation activated SGK-1 signalling that in turn upregulated key genes involved in cell hyperproliferation and the loss of arterial specification.Compared with wild-type littermates,mice overexpressing the GJA4 mutation developed ECH-like pathological morphological characteristics(dilated venous lumen and elevated vascular density)in the retinal superficial vascular plexus at the postnatal 3 weeks,which were reversed by an SGK1 inhibitor,EMD638683.Conclusions We identified a somatic GJA4 mutation that presents in over one-third of ECH lesions and proposed that ECHs are vascular malformations due to GJA4-induced activation of the SGK1 signalling pathway in brain endothelial cells.