Metachronous multiple primary malignancies: a case report of colon and thyroid cancer

Cancer remains a challenging disease for our profession despite the medical and technological advances achieved in recent years. This challenge increases when we encounter multiple primary tumors that significantly modify the prognosis of our patients.

Research progress on the mechanism of metachronous gastric cancer after endoscopic submucosal dissection and Helicobacter pylori eradication in early gastric cancer / 解放军医学杂志

Helicobacter pylori(HP)infection is a Class Ⅰ carcinogen in gastric cancer,closely related to the occurrence of gastric cancer.Many studies have shown that HP eradication has a preventive effect on gastric cancer.However,2.7%-6.1%of patients with early gastric cancer who have been eradicated after endoscopic submucosal dissection(ESD)can still develop metachronous gastric cancer(MGC),and the mechanism of its occurrence is still unclear.In this review,the atrophy of gastric mucosa and intestinal metaplasia cannot be completely reversed after HP eradication,the excessive proliferation of gastric mucosa epithelial cells,the accumulation of genetic abnormalities,the homeostasis imbalance of the epigenetic group,changes in immune microenvironment,the abnormality of stem cells in gastric mucosa,chromatin accessibility,and changes in chromosome remodeling were discussed in the mechanism of carcinogenesis caused by the above molecular changes after ESD and HP eradication in early gastric cancer.

Unusual sites of delayed metachronous metastases from renal cell carcinoma: a case series of five cases and review of literature

Renal cell carcinoma (RCC) is the most common malignant tumour of the kidney, representing 3% of all adult malignancies. Among men it is the sixth most common cancer while among women it is the ninth most common cancer. The mainstay of treatment for localized RCC is surgical resection with curative intent. The aggressive and often insidious nature of RCC is reflected by high recurrence rates of upto 20-40% after nephrectomy. Most commonly encountered sites of recurrent metastases include the lung, followed by bone, liver, brain, and local recurrence. Atypical sites of delayed metastases of RCC, although rare, have been reported in literature. We present our series of five cases where delayed metastasis has occurred at atypical sites including right sartorius muscle, right atrium and ventricle, urinary bladder, shaft of tibia and distal phalanx of hand upto six years later from the time of initial curative treatment of primary. The metastatic lesions in sartorius muscle, right atrium and ventricle, urinary bladder and distal phalanx were primarily managed by metastatectomy while that in the tibial shaft was managed by palliative targeted therapy with tyrosine kinase inhibitors. The key takeaway from this case series is that any primary neoplastic lesion in a patient with history of RCC should be evaluated with histopathology before definitive intervention is undertaken keeping in mind the notorious tendency of RCC to cause delayed metachronous metastases at unusual sites. In presence of solitary metastatic lesions at resectable locations, curative treatment can be offered by metastatectomy.

A case of Constitutional Mismatch Repair Deficiency (CMMRD)

@#Constitutionalmismatch repair deficiency(CMMRD) is a hereditary predisposition of malignancy evident in childhood leukemias, lymphomas, and malignant tumors of the brain, GI tract. It is a very rare condition that affects 1 per 1 million patients. Patients with CMMRD syndrome may also manifest with Neurofibromatosis Type 1 (NF1) phenotypic features, and benign masses, particularly in the gastrointestinal tract. This is a case of a 12-year old male who presented with phenotypic features of NF1, developed Acute Lymphoblastic Leukemia at 7 years old and went into remission. He subsequently developed synchronous Glioblastoma and Poorly differentiated Adenocarcinoma of the rectum.This report aims to raise awareness regarding the possibility of a CMMRD syndrome in pediatric patients who present with phenotypic features of NF1, and in those patients who present with two or more malignancies in their lifetime.

Comparison of Clinicopathological Characteristics Between Primary and Contralateral Cancers in BRCA1/2 Carriers with Metachronous Bilateral Breast Cancers / 肿瘤防治研究

Objective To compare the clinicopathological characteristics between primary and contralateral cancers in patients with metachronous bilateral breast cancer (MBBC) who carried a BRCA1/2 germline pathogenic variant. Methods A total of 496 BRCA1/2 carriers with primary unilateral breast cancer were included (196 with BRCA1 and 300 with BRCA2). Clinicopathological information of patients was collected, and the median follow-up for the entire cohort was 10.4 years (0.4-20.8 years). Results Among all patients, 31 (15.8%) of the 196 BRCA1 carriers and 49 (16.3%) of the 300 BRCA2 carriers had MBBC, respectively. Among the 31 BRCA1 carriers who developed MBBC, the proportion of triple-negative breast cancer (TNBC) in primary cancer and contralateral cancer was 61.3% and 67.7%, respectively. If the primary cancer of BRCA1-mutated MBBC was TNBC, the probability of the contralateral breast cancer with TNBC was 89.5% (17/19), which was significantly higher than that if the primary cancer was non-TNBC (33.3%, 4/12) (P=0.004). Among the 49 BRCA2 carriers who developed MBBC, the predominant molecular phenotype of the primary and contralateral cancers was HR+ & HER2- (77.6% and 67.3%, respectively; P=0.53). Conclusion Approximately 60% of BRCA1 carriers exhibit TNBC. If a BRCA1 carrier with a TNBC primary breast cancer had an MBBC, the probability of the contralateral breast cancer being TNBC phenotype is almost 89.5%.

The effect of Helicobacter pylori eradication on development of metachronous gastric cancer after endoscopic submucosal dissection of elderly patients with early gastric cancer / 中华老年医学杂志

Objective:To explore the effect of Helicobacter pylori(HP)eradication on development of metachronous gastric cancer(MGC)after endoscopic submucosal dissection(ESD)in elderly patients with early gastric cancer.Methods:From January 2014 to December 2019, 748 early gastric cancer patients aged 60 years or older, receiving ESD in Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, were included.According to the situation of HP infection and eradication efficacy within 1 year postoperatively, patients were divided into three groups.The patients with HP infection and successful HP-eradication were enrolled into successful eradication group, those without eradicating or with eradication failure were enrolled into eradication failure group, those with HP negative were enrolled into HP-negative group.And then the occurrence and risk factors of MGC after ESD among the three groups were statistically analyzed.Results:MGC were detected in 58 cases(7.7%)in elderly patients with early gastric cancer after ESD.The median follow-up time was 39 months.The multivariate regression analysis results of MGC showed that no HP-eradication or HP eradication of failure( HR=2.231, 95% CI: 1.054-4.722, P=0.036)and multiple lesions( HR=1.857, 95% CI: 1.076-3.204, P=0.026)were independent risk factors.Non-smoking was a protective factor for the occurrence of MGC( HR=0.409, 95% CI: 0.234-0.716, P=0.002). After adjusting for confounding factors, Cox proportional risk regression analysis showed that the incidence of MGC was significantly higher in group of no HP-eradicating or HP-eradicating of failure than in group of successful HP-eradicating group( χ2=37.877, P<0.001). Conclusions:HP eradication can effectively prevent MGC in elderly patients with early gastric cancer after ESD.Multiple lesions and smoking are independent risk factors for MGC.

Colonoscopy follow-up in patients with simultaneous multiple primary colorectal cancer and patients with sporadic colorectal cancer: a matched-pair study / 中华消化杂志

Objective:To investigate the incidences of metachronous advanced adenoma (MAA) in patients with simultaneous multiple primary colorectal cancer (CRC) and patients with sporadic CRC.Methods:From January 1, 2008 to September 30, 2022, at Beijing Shijitan Hospital, Capital Medical University, CRC patients who underwent surgery and 3 years follow-up with endoscopy were enrolled. The patients completed colonoscopy at least 2 times during follow-up in 6 to 36 months after surgery, and the interval between the 2 times colonoscopies was over 6 months. Clinical data including age, gender, and tumor location, stage, pathological features, combined underlying diseases, preoperative carcinoembryonic antigen, hemoglobin and other laboratory results, baseline colonoscopy results, and detection of MAA were collected. According to age (±2 years old), gender, location of primary lesion and stage of tumor, patients with simultaneous CRC or sporadic CRC were matched at 1∶1 ratio by propensity score matching. The cumulative risks of MAA in patients with simultaneous multiple primary CRC and patients with sporadic CRC were calculated. Cox proportional hazard regression was used to analyze the influencing factors in the occurrence of MAA.Results:A total of 814 CRC patients were enrolled and matched. After paired matching, there were 36 cases of simultaneous multiple primary CRC (78 lesions) and 78 cases of sporadic CRC (78 lesions). The cumulative incidences of MAA at 1, 2 and 3 years of simultaneous CRC group were 11.1%(4/36), 22.2%(8/36) and 33.3%(12/36), respectively. The cumulative incidences of MAA at 1-, 2- and 3-year of sporadic CRC group were 3.8%(3/78), 12.8%(10/78) and 20.5%(16/78), respectively.Simultaneous CRC was correlated with an increase in the 3-year cumulative incidence of MAA ( HR=4.163, 95% confidence interval(95% CI) 1.032 to 4.721, P=0.047). Especially in left-sided CRC, the risk of MAA in simultaneous CRC increased ( HR=7.186, 95% CI 1.602 to 20.787, P=0.010). The results of multivariate cox-regression analysis indicated that detection of simultaneous advanced adenoma at baseline endoscopy was an independent risk factor of MAA ( HR=3.175, 95% CI 1.411 to 7.142, P=0.005). Conclusion:Colouoscopy follow-up should be strengthened in patients with simultaneous multiple primary CRC and simultaneous advanced adenomas.

Surgical roles in the management of metachronus para-aortic lymph node recurrence and synchronous para-aortic lymph node metastasis in colorectal cancer patients

Background: The relative rarity of synchronous para-aortic lymph node (PALN) metastasis (SPM) and metachronous PALN recurrence (MPR) in colorectal carcinoma (CRC) patients leads to a limited number of studies on patient management, and no treatment guidelines have been established to date. Objective: To assess the prognostic, predictive roles, and long-term outcomes of different management strategies for isolated MPR and SPM in CRC patients to establish the best one. Materials and Methods: We included 35 CRC patients with isolated MPR and 25 patients with isolated SPM who underwent curative R0 resection. We performed PALN dissection (PALND) in 15 cases in MPR group and in 10 cases in the SPM group; all remaining patients in both groups underwent chemoradiotherapy (CRT) without further surgical intervention. During the study period of about 5 years, we compared the patients who underwent PALND and those who underwent CRT. Results: The overall survival and recurrence-free survival rates were significantly longer in patients who underwent PALND (p = 0.049 and 0.036 respectively). (AU)

Analysis of Clinical Characteristics of Lung Cancer Combined with Multiple Primary Malignancies in Other Organs / 中国肺癌杂志

BACKGROUND@#With the popularization of chest computed tomography (CT) early screening for lung cancer, the detection rate of lung cancer combined with multiple primary malignancies (MPM) in other organs has been increasing. In this paper, the incidence, pathological characteristics, diagnosis and treatment characteristics and prognosis were discussed and analyzed to provide research basis for improving the clinical diagnosis and treatment of this disease.@*METHODS@#From September 2011 to September 2015, a total of 5,570 patients with lung cancer were treated in Jiangsu Cancer Hospital. The clinicopathological characteristics of 61 patients with lung cancer combined with MPM in other organs were retrospectively analyzed.@*RESULTS@#The incidence rate of lung cancer combined with MPM in other organs in this group was 1.1%, of which 15 cases were synchronous MPM (SMPM), 46 cases were metachronous MPM (MMPM). Colorectal cancer, breast cancer and thyroid cancer accounted for the top three of lung cancer combined with MPM in other organs. The overall 5-year survival rate was 39.3% and 71.4% of patients died from metastasis or recurrence of lung cancer. Multivariate analysis showed that the clinical stage of lung cancer patients, the order of occurrence of lung cancer and other tumors, the treatment status of patients with other organ tumors and the presence of epidermal growth factor receptor (EGFR) gene mutation were important factors for the survival of the patients.@*CONCLUSIONS@#The incidence rate of lung cancer combined with MPM in other organs is not uncommon. Lung cancer is the main cause of death compared with other organs tumors. Patients with advanced lung cancer, SMPM, lung cancer first, combined with tumor only receiving palliative treatment and without EGFR gene mutation had a poor prognosis.

Analysis of bilateral breast carcinomas: a profile of patients at a reference service

Objective: To select cases of bilateral breast carcinoma (BBC) of patients seen at Hospital de Clínicas of Paraná, besides recognizing clinical and family characteristics, histological and immunohistochemical pattern, and incidences of synchronic/metachronic tumor in these patients. Method: Observational and analytical study of BBC cases of patients treated at Hospital de Clínicas of Paraná, from 2003 to 2019, developed from the analysis of medical records. Result: A total of 42 patients with BBC were selected. The incidence of BBC was 3.64%. All patients were women, mostly of white skin color and postmenopausal, with an average age of 51.82 years. Half patients showed a positive family history for cancer, with breast cancer present in 46%, ovarian cancer in 16%, and other topographies in 68%. In this sample, the synchronous tumor was present in 55% of patients, and the metachronous tumor, in 45%. Regarding patients' initial clinical staging, 61% had a locally advanced tumor at diagnosis. Both in the group of synchronic and metachronic tumors, the ductal subtype was the most frequent. Regarding the immunohistochemical subtype, patients in both groups had Luminal B tumors more frequently. In the group of metachronic tumors, the average time between the diagnosis of the first tumor and the second tumor was 5.68 years. Conclusion: In this sample, BBC is associated with a relevant family history, with a synchronic presentation pattern, from histology to ductal and immunohistochemistry to Luminal B as the most frequent.

Percutaneous Radiofrequency Ablation for Metachronous Hepatic Metastases after Curative Resection of Pancreatic Adenocarcinoma

OBJECTIVE: To retrospectively evaluate the safety and efficacy of percutaneous radiofrequency ablation (RFA) in patients with metachronous hepatic metastases arising from pancreatic adenocarcinoma who had previously received curative surgery.MATERIALS AND METHODS: Between 2002 and 2017, percutaneous RFA was performed on 94 metachronous hepatic metastases (median diameter, 1.5 cm) arising from pancreatic cancer in 60 patients (mean age, 60.5 years). Patients were included if they had fewer than five metastases, a maximum tumor diameter of ≤ 5 cm, and disease confined to the liver or stable extrahepatic disease. For comparisons during the same period, we included 66 patients who received chemotherapy only and met the same eligibility criteria described.RESULTS: Technical success was achieved in all hepatic metastasis without any procedure-related mortality. During follow-up, local tumor progression of treated lesions was observed in 38.3% of the tumors. Overall median survival and 3-year survival rates were 12 months and 0%, respectively from initial RFA, and 14.7 months and 2.1%, respectively from the first diagnosis of liver metastasis. Multivariate analysis showed that a large tumor diameter of > 1.5 cm, a late TNM stage (≥ IIB) before curative surgery, a time from surgery to recurrence of < 1 year, and the presence of extrahepatic metastasis, were all prognostic of reduced overall survival after RFA. Median overall (12 months vs. 9.1 months, p = 0.094) and progression-free survival (5 months vs. 3.3 months, p = 0.068) were higher in the RFA group than in the chemotherapy group with borderline statistical difference.CONCLUSION: RFA is safe and may offer successful local tumor control in patients with metachronous hepatic metastases arising from pancreatic adenocarcinoma. Patients with a small diameter tumor, early TNM stage before curative surgery, late hepatic recurrence, and liver-only metastasis benefit most from RFA treatment. RFA provided better survival outcomes than chemotherapy for this specific group with borderline statistical difference.

Papillary squamous carcinoma of the cervix with metachronous clear cell renal cell carcinoma / Philippine Journal of Obstetrics and Gynecology

@#Multiple primary tumors can be classified as synchronous or metachronous. Cases have been reported, with a prevalence, in gynecologic malignancies, of 1.9 to 4.3%, and commonly occurring in endometrial and ovarian malignancies. Renal tumors coexisting with primary cervical cancer are mostly metastatic tumors, and at present, no case of cervical carcinoma metachronous with renal cell carcinoma has been reported on literature. This is a case of Papillary Squamous Cell Carcinoma of the cervix who developed a metachronous Clear Cell Renal Cell Carcinoma. Several months after the diagnosis of cervical cancer, she presented with an abdominal mass and signs of uremia secondary to obstructive uropathy. She underwent radical nephrectomy with contralateral percutaneous nephrostomy. Definitive plan for the cervical mass is concurrent chemotherapy and radiation, depending on the improvement in renal function. Currently, there are no clearly established guidelines in managing metachronous cervical and renal masses, and this presents a unique opportunity to document this case, and study its implications on management and prognosis.

Metachronous primary cerebral rhabdomyosarcoma after treatment of Oral Primitive Neuroectodermal Tumor/Ewing’s Sarcoma in a school-aged girl: A case report

@#Multiple primary malignancies are defined as two or three malignant neoplasms arising in different organ systems. Several cases of multiple primary malignancies are emerging in recent years due to the advancement in medical therapy and diagnostics. Multiple primary malignancies are not uncommon occurring at 0.7-16% of cancer patients, however, reported cases of multiple primary sarcomas are sparse. Presented in this report is a pediatric patient diagnosed with primary metachronous cerebral rhabdomyosarcoma after being treated for primitive neuroectodermal tumor/Ewing’s sarcoma of the oral cavity. Despite limited cases addressing multiple primary sarcomas, this entity must not be overlooked as it is associated with a meager outcome compared to an index case of sarcoma alone.

Double malignancies: a clinicopathological and outcomes retrospective analysis from a tertiary cancer referral centre in South India

Background: The presence of second synchronous or metachronous primary malignancies in a cancer patient is not a rare phenomenon. Our study is an endeavour to present data on the frequency, types, and outcomes of double primary malignancies in Indian cancer patients.Methods: This was a retrospective study conducted in 28 cancer patients diagnosed with histologically confirmed double malignancy. Retrospective data of the cancer site, patient’s age at the presentation, gender, type of cancer (synchronous/metachronous), treatment, and outcome were recorded from patients presented with double malignancies from January 2012 to January 2019.Results: Among 28 patients (18 females; 10 males) with multiple primary malignancies, 10 (35.7%) and 18 patients (64.3%), respectively, had synchronous and metachronous primary malignancies. Overall, breast, gynecological, head, and neck cancer were the most common primary malignancies. Gastrointestinal tract, breast, and lung cancer emerged to be the most common second primary malignancy sites. Squamous cell carcinoma (SCC) and invasive ductal carcinoma (IDC) were the most common histopathological types of double malignancies. The majority of the patients received appropriate treatment for both the malignancies.Conclusions: Data from the present study clearly suggest that the occurrence of second primary malignancy is not rare in Indian cancer patients. The double malignancies can occur at any stage and for any type of cancer. Hence, we wish to highlight that the clinician should always be aware of the possibility of developing second malignancy either during evaluation or in follow up of a patient with malignancy.

Metachronous nasopharyngeal carcinoma masquerading as a base of skull metastasis in a case of primary extraskeletal vulvar Ewing’s sarcoma

Ewing’s sarcoma (ES) and primitive neuroectodermal tumor (PNET) resemble each other and commonly affect the skeletal system. Extraskeletal ES/PNET is a rare neoplasm. Here, we report a case of primary vulvar ES in an 18-year-old adolescent girl confirmed by histopathology and immunohistochemistry, who underwent surgery followed by adjuvant chemotherapy. Following 1 year of chemotherapy, she presented with multiple cranial nerve palsies (VI, IX, X, and XII). Contrast tomography of the base of the skull and nasopharynx showed a heterogeneous mass lesion involving the base of skull, sphenoid sinus, and left nasopharynx. Biopsy from the left nasopharyngeal mass revealed it to be well-differentiated squamous cell carcinoma, which was initially thought of metastasis to the base of the skull. In spite of its aggressive nature, a patient of primary sarcoma presenting with a second lesion should be adequately investigated before considering it as a metastatic lesion.

Risk Factors for Metachronous Recurrence after Endoscopic Submucosal Dissection of a Gastric Neoplasm

BACKGROUND/AIMS: Although endoscopic submucosal dissection (ESD) is an accepted treatment method for gastric neoplasm worldwide, metachronous recurrence often occurs. Here, we evaluated the risk factors for metachronous recurrence after ESD of gastric dysplasia or adenocarcinoma and also examined the effects of Helicobacter pylori (H. pylori) eradication. MATERIALS AND METHODS: Among 400 patients who underwent endoscopic resection from February 2005 to December 2014 at Ewha Womans University Hospital, the medical records of 180 patients were retrospectively reviewed. RESULTS: The enrolled patients included 118 men and 62 women, and their median age was 61.7±10.3 years. During a median follow-up period of 34.5 months, metachronous recurrence occurred in 21 (11.7%) patients. Multivariate analyses revealed that H. pylori eradication did not have any preventive effects on metachronous recurrence. A family history of gastric cancer was the only risk factor for metachronous recurrence after ESD of the gastric neoplasm. CONCLUSIONS: Metachronous recurrence was found to be related to family history of gastric cancer. However, H. pylori eradication had no preventive effects on metachronous recurrence after ESD of a gastric neoplasm. Therefore, intensive surveillance is required for patients who undergo ESD of a gastric neoplasm and have a family history of gastric cancer.

Clinicopathological characteristics and treatment of multiple primary colorectal carcinoma / 中华消化内镜杂志

Objective To investigate clinicopathological characteristics,diagnosis and treatment of multiple primary colorectal carcinoma (MPCC). Methods From January 2008 to March 2017,42 patients diagnosed with MPCC underwent surgery at Beijing Shijitan Hospital,Capital Medical University. Their clinicopathological features,diagnosis and treatment were analyzed. Results These 42 MPCC patients accounted for 7. 1％ (42/ 592)colorectal cancer patients in the same period. There were 64 intestinal cancer lesions in 32 patients (76. 2％)with synchronous carcinoma (SC),and 20 intestinal cancer lesions in 10 patients (23. 8％)with metachronous carcinoma(MC),where the interval between the first and the recurrent was 18-105 months. The proportion of patients in the SC group with highly to moderately differentiated adenocarcinoma was significantly higher compared with that of the MC group (P<0. 05),while the incidence of mucinous carcinoma was lower than that of the MC group(P<0. 05). No significant differences were found with regard to tumor size,location,complications with adenoma,TNM stages,lymph nodes metastases or DNA mismatch repair between the SC group and the MC group(all P>0. 05). Among 42 patients undergoing radical operation,6 received colonic metallic stent implantation as a bridge to elective resection in 10 patients with colonic obstruction. Conclusion MPCC,mainly two-lesion cancer,is most commonly found in sigmoid colon and rectum. Those with poorly differentiated cancer, mucinous carcinoma and those complicated with adenoma should be closely followed up with colonoscopy. Colonic metallic stent implantation as a bridge to elective resection may improve the detection rate of SC.

Clinicopathological characteristics and treatment of multiple primary colorectal carcinoma / 中华消化内镜杂志

Objective@#To investigate clinicopathological characteristics, diagnosis and treatment of multiple primary colorectal carcinoma (MPCC).@*Methods@#From January 2008 to March 2017, 42 patients diagnosed with MPCC underwent surgery at Beijing Shijitan Hospital, Capital Medical University. Their clinicopathological features, diagnosis and treatment were analyzed.@*Results@#These 42 MPCC patients accounted for 7.1% (42/592) colorectal cancer patients in the same period. There were 64 intestinal cancer lesions in 32 patients (76.2%) with synchronous carcinoma (SC), and 20 intestinal cancer lesions in 10 patients (23.8%) with metachronous carcinoma(MC), where the interval between the first and the recurrent was 18-105 months. The proportion of patients in the SC group with highly to moderately differentiated adenocarcinoma was significantly higher compared with that of the MC group (P<0.05), while the incidence of mucinous carcinoma was lower than that of the MC group(P<0.05). No significant differences were found with regard to tumor size, location, complications with adenoma, TNM stages, lymph nodes metastases or DNA mismatch repair between the SC group and the MC group(all P>0.05). Among 42 patients undergoing radical operation, 6 received colonic metallic stent implantation as a bridge to elective resection in 10 patients with colonic obstruction.@*Conclusion@#MPCC, mainly two-lesion cancer, is most commonly found in sigmoid colon and rectum. Those with poorly differentiated cancer, mucinous carcinoma and those complicated with adenoma should be closely followed up with colonoscopy. Colonic metallic stent implantation as a bridge to elective resection may improve the detection rate of SC.

Multiple Metachronous Malignancies: One Patient with Five Primary Malignancies / 대한내과학회지

We report a case of a 73-year-old male with multiple, metachronous primary malignancies. He presented with adenocarcinoma of the stomach with transverse colon invasion followed by bladder cancer, hypopharyngeal cancer, urothelial cancer, and hepatocellular carcinoma, in that order, over 10 years. While these multiples malignancies were separate entities, they shared several etiologic factors, including smoking. To the best of our knowledge, this is the first description of five metachronous malignancies in a Korean patient.