Primary malignant melanoma of the esophagus combined with squamous cell carcinoma:A case report

BACKGROUND Primary malignant melanoma of the esophagus is a rare malignant tumor of the esophagus,and its combination with squamous cell carcinoma is also rare.Here,we report the diagnosis and treatment of a case of primary esophageal malignant melanoma combined with squamous cell carcinoma.CASE SUMMARY A middle-aged man underwent gastroscopy for dysphagia.Gastroscopy revealed multiple bulging esophageal lesions,and after pathologic and immunohistochemical analyses,the patient was finally diagnosed with"malignant melanoma with squamous cell carcinoma".This patient received comprehensive treatment.After one year of follow-up,the patient was in good condition,and the esophageal lesions seen on gastroscopy were controlled,but unfortunately,liver metastasis occurred.CONCLUSION When multiple esophageal lesions are present,the possibility of multiple pathological sources should be considered.This patient was diagnosed with primary esophageal malignant melanoma combined with squamous cell carcinoma.

Cetuximab combined with chemotherapy for simultaneous esophageal squamous cell carcinoma and colon adenocarcinoma:A case report

BACKGROUND Multiple primary carcinomas(MPCs)are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual.Synchronous MPCs are rarer than solitary cancers or metachronous MPCs.Accurate diagnoses of synchronous MPCs and the choice of treatment are critical for successful outcomes in these cases.CASE SUMMARY A 64-year-old patient presented with dysphagia,without obvious cause.A diagnosis of synchronous esophageal squamous cell carcinoma and colon adenocarcinoma with liver metastasis was confirmed based on examination and laboratory results.After multi-disciplinary consultations,combination chemotherapy(a 3-wk cycle with oxaliplatin 212 mg administered on day 1 and capecitabine 1.5 g twice daily on days 1-14)and esophageal cancer radiotherapy were initiated.Based on the results of genetic testing,we switched to a regimen of leucovorin+fluorouracil+oxaliplatin and cetuximab regimen for 8 cycles.Subsequently,capecitabine and bevacizumab were administered until the most recent follow-up,at which the tumor remained stable.CONCLUSION Successful cetuximab chemotherapy treatment provides a reference for the nonoperative and homogeneous treatment of different pathological types of synchronous MCPs.

Primary pulmonary lymphoepithelioma-like carcinoma misdiagnosed as lung squamous cell carcinoma:A case report

BACKGROUND Primary pulmonary lymphoepithelioma-like carcinoma(PPLELC)is an uncommon subtype of squamous cell carcinoma(SCC)of the lung,closely associated with Epstein-Barr virus(EBV)infection.The pathological features of PPLELC closely resemble those of SCC,which makes it prone to misdiagnosis.Surgical intervention constitutes the primary treatment approach for PPLELC.CASE SUMMARY This report describes a 44-year-old woman who was hospitalized for 1 mo due to left chest pain.Computed tomography revealed a mass shadow in the anterior basal segment of the left lower lobe,and a subsequent needle biopsy suggested SCC.The patient underwent radical tumor resection in the lower left lobe of the lung,and postoperative pathological examination indicated lymphoepithelial carcinoma,and the test for EBV encoded small RNA was positive.Following surgery,the patient was scheduled to receive four cycles of adjuvant chemotherapy,using the paclitaxel+carboplatin regimen,but the patient refused further treatment.CONCLUSION PPLELC is an exceptionally rare subtype of lung SCC and is prone to misdiagnosis.

Primary pure squamous cell carcinoma of the duodenum: a case report and review of literature

Primary pure squamous cell carcinomas(SCC) of the duodenum are very uncommon. To the best of our knowledge, only a few cases of SCC of the duodenum exist in the reported literature. Here, we report a case of SCC of the duodenum in northern China. A 45-year-old Chinese Han male patient presented with abdominal pain and weight loss. CT, endoscopic examinations, X-rays, and immunohistochemical markers were used to confirm this rare diagnosis of SCC. We performed a pancreaticoduodenectomy with a curative intention. However, histological examination revealed SCC of the duodenum. Postoperative chemotherapy was started after surgery. To the best of our knowledge, pancreaticoduodenectomy is the preferred form of treatment for carcinoma of the duodenum. This is supplemented with chemotherapy, which can further prolong survival.

Squamous cell carcinoma metastatic to cervical lymph nodes from unknown primary origin:the impact of chemoradiotherapy

The management of cervical lymph node metastases of squamous cell carcinoma from an unknown primary site is still a therapeutic challenge.We report here our experience in treating these patients with chemoradiotherapy as a curative approach.Data from 40 patients were reviewed.In total,20(50%) patients underwent excisional biopsy.All patients underwent radiotherapy,which was delivered to both sides of the neck and pharyngeal mucosa(extensive field),and concurrent chemotherapy consisting of weekly cisplatin at a dose of 40 mg/m2.The clinical stage of the cervical nodes at presentation was N1 in 25%,N2 in 60%,and N3 in 15%.Most patients(75%) developed at least grade 3 mucositis.Eight patients(20%) had grade 3 xerostomia and 18 patients(45%) required esophageal dilation for stricture.The 5-year overall survival(OS) rate of all patients was 67.5%.The 5-year OS rates of patients with N1,N2,and N3 lesions were 100%,67%,and 41%,respectively(P = 0.046).The 5-year progression-free survival rate was 62.5%.In multivariate analysis,only N stage significantly affected OS(P = 0.022).Emergence of the occult primary was very limited(1 patient only).Our results suggest that extensive irradiation of both sides of the neck and pharyngeal mucosa with concurrent chemotherapy results in a lower emergence of primary tumor.Because the survival of patients with unknown primary is comparable to that of patients with known primary,an attempt at cure should always be made.

Long-term survivor of metastatic squamous-cell head and neck carcinoma with occult primary after cetuximab-based chemotherapy:A case report

BACKGROUND Cancer of unknown primary(CUP)is a histological proven malignant tumor whose origin cannot be detected despite careful examination.Most cervical lymph node metastases in CUP(80%)will originate from head and neck sites,and 15%show infiltration of squamous carcinoma cells.The survival rates of CUP are poor:The 5-year-survival rate ranges from 10%to 15%.First-line treatment recommendation for advanced,inoperable squamous cell carcinoma of head/neck(HNSCC)was cetuximab plus platinum-fluorouracil chemotherapy until recently,when checkpoint inhibitors proved clinically beneficial therapies.CASE SUMMARY Here,we report a case of a 42-year-old female patient with cervical and abdominal lymph node and distant bone metastases of an occult primary of the head and neck(squamous cell carcinoma,human papillomavirus positive).The cancer was diagnosed during pregnancy 10 years ago,and after giving birth,the patient was treated with cetuximab plus platinum-fluorouracil chemotherapy achieving complete remission(CR).CR lasted 26 mo when new metastases(abdominal lymph node,lumbar vertebral body)emerged.Both manifestations were irradiated.From then on,the patient has not received any further treatment,and her disease has remained controlled.Ten years after the initial cancer diagnosis,the patient is still alive and in good health,representing an exceptional case of HNSCC.CONCLUSION This case illustrates the exceptional clinical course and benefits of combined therapy approaches in advanced metastatic HNSCC with occult primary.

Early Age of Onset, Multiple Primary Malignancies and Poor Prognosis Are Indicative of an Inherited Predisposition to Esophageal Squamous Cell Carcinoma in Familial Rather Than Sporadic Disease- An Update Based on 14- to 23-year Follow-up

<正> OBJECTIVE To demonstrate the effects of an inheritedpredisposition to familial esophageal squamous cellcarcinoma (ESCC) through the comparison and analysis of theclinicopathologic differences between familial and sporadic ESCCcases.METHODS Differences in age of onset, prevalence rates ofdouble primary ESCC, and survival rates between familial ESCC (n= 476) and sporadic ESCC cases (n = 1226) were analyzed.RESULTS Overall, familial ESCC cases showed a significantlyyounger age of onset (51.9 ± 8.2 vs. 53.4 ± 8.0, P_(t-test) = 0.00), asignificantly higher prevalence rate for double ESCC (2.73 % vs.1.22%, adjusted with TNM:χ_(MH)~2= 4.029, P = 0.045), and a lowersurvival rate than in sporadic cases (P_(wald) = 0.04). The familial casesshowed both a younger age of onset and poorer survival in mostsubgroups, and the differences were more marked in early-stagerather than in the late-stage disease groups.CONCLUSION Theses findings confirm the existence of familialas opposed to sporadic ESCC. By the theory of the 'two-hit' originof cancer, these findings also suggest that the 'first hit', a geneticpredisposition, can affect the age of onset, number of primarycarcinomas, and the prognosis for familial ESCC patients.

PRIMARY SQUAMOUS CELL CARCINOMA OF THE BREAST-3 CASES REPORT

Primary squamous cell carcinoma of thebreast is very rare and 3 cases of this disease weredetected at our hospital.

Primary nonkeratinizing squamous cell carcinoma of the scapular bone:A case report

BACKGROUND Squamous cell carcinoma(SCC)of bone is usually caused by metastasis from the lungs,bladder,or other sites.Primary SCC of bone most frequently involves the skull bones,and primary involvement of other sites in the skeletal system is extremely rare.To date,only three such cases have been reported,which makes the diagnosis,treatment,and prognosis of this disease a challenge.CASE SUMMARY A 76-year-old Chinese man presented to our hospital with nonspecific pain and limited mobility in the right shoulder for 4 mo.He underwent three-dimensional computed tomography reconstruction and magnetic resonance imaging of the right shoulder,which revealed an osteolytic destructive lesion in the right scapula with invasion into the surrounding muscles and soft tissues.Ultrasound-guided core needle biopsy detected a malignant tumor,and immunohistochemical analysis revealed a poorly differentiated SCC.Wide excision of the right scapular bone was performed,and pathological examination of the surgical specimen confirmed the diagnosis.At the last follow-up examination within 2 years,the patient was doing well with the pain significantly relieved in the right shoulder.CONCLUSION Primary SCC of bone is extremely rare at sites other than the skull.Clinicians must exhaust all available means for the diagnosis of primary SCC of the bone,so greater attention can be paid to its timely and effective management.Regular and adequate follow-up is essential to help rule out metastasis and judge the prognosis.

Primary Pure Squamous Cell Carcinoma of the Gallbladder: Case Report

Squamous cell carcinoma of the gallbladder is rare and accounts for about 12.7% of all cases of gallbladder cancer. Pure squamous cell carcinoma is even less common with a reported incidence of 3.3%. We present a case of 72 year-old African-American woman with decreased appetite, fatigue, and weight loss associated with intermittent right upper quadrant pain for two months. Computed tomography of the abdomen revealed a mass in the gallbladder and the hepatic flexure of the colon with involvement of adjacent small bowel. On exploratory laparotomy, a mass at the dome of the gallbladder was found with local invasion of the hepatic flexure, and the proximal transverse colon. There was no obvious involvement of the duodenum, common bile duct, or the extra-hepatic biliary tree. An extended right hemicolectomy, distal small bowel resection, cholecystectomy, a wedge resection of the liver and a feeding jejunostomy, were performed. Pathologic evaluation demonstrated well to moderately differentiated squamous cell carcinoma of gallbladder without evidence of distant metastasis. The patient improved clinically and was discharged home in good condition.

Determination of esophageal squamous cell carcinoma and gastric adenocarcinoma on raw tissue using Raman spectroscopy

BACKGROUND Cancer detection is a global research focus,and novel,rapid,and label-free techniques are being developed for routine clinical practice.This has led to the development of new tools and techniques from the bench side to routine clinical practice.In this study,we present a method that uses Raman spectroscopy(RS)to detect cancer in unstained formalin-fixed,resected specimens of the esophagus and stomach.Our method can record a clear Raman-scattered light spectrum in these specimens,confirming that the Raman-scattered light spectrum changes because of the histological differences in the mucosal tissue.AIM To evaluate the use of Raman-scattered light spectrum for detecting endoscopically resected specimens of esophageal squamous cell carcinoma(SCC)and gastric adenocarcinoma(AC).METHODS We created a Raman device that is suitable for observing living tissues,and attempted to acquire Raman-scattered light spectra in endoscopically resected specimens of six esophageal tissues and 12 gastric tissues.We evaluated formalin-fixed tissues using this technique and captured shifts at multiple locations based on feasibility,ranging from six to 19 locations 200 microns apart in the vertical and horizontal directions.Furthermore,a correlation between the obtained Raman scattered light spectra and histopathological diagnosis was performed.RESULTS We successfully obtained Raman scattered light spectra from all six esophageal and 12 gastric specimens.After data capture,the tissue specimens were sent for histopathological analysis for further processing because RS is a label-free methodology that does not cause tissue destruction or alterations.Based on data analysis of molecular-level substrates,we established cut-off values for the diagnosis of esophageal SCC and gastric AC.By analyzing specific Raman shifts,we developed an algorithm to identify the range of esophageal SCC and gastric AC with an accuracy close to that of histopathological diagnoses.CONCLUSION Our technique provides qualitative information for real-time morphological diagnosis.However,further in vivo evaluations require an excitation light source with low human toxicity and large amounts of data for validation.

Three-dimensional collagen-based scaffold model to study the microenvironment and drug-resistance mechanisms of oropharyngeal squamous cell carcinomas

Objective:Squamous cell carcinoma(SCC)represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma(OSCC),a tumor associated with different clinical outcomes and linked to human papilloma virus(HPV)status.Translational research has few available in vitro models with which to study the different pathophysiological behavior of OSCCs.The present study proposes a 3-dimensional(3 D)biomimetic collagen-based scaffold to mimic the tumor microenvironment and the crosstalk between the extracellular matrix(ECM)and cancer cells.Methods:We compared the phenotypic and genetic features of HPV-positive and HPV-negative OSCC cell lines cultured on common monolayer supports and on scaffolds.We also explored cancer cell adaptation to the 3 D microenvironment and its impact on the efficacy of drugs tested on cell lines and primary cultures.Results:HPV-positive and HPV-negative cell lines were successfully grown in the 3 D model and displayed different collagen fiber organization.The 3 D cultures induced an increased expression of markers related to epithelial–mesenchymal transition(EMT)and to matrix interactions and showed different migration behavior,as confirmed by zebrafish embryo xenografts.The expression of hypoxia-inducible factor 1α(1α)and glycolysis markers were indicative of the development of a hypoxic microenvironment inside the scaffold area.Furthermore,the 3 D cultures activated drug-resistance signaling pathways in both cell lines and primary cultures.Conclusions:Our results suggest that collagen-based scaffolds could be a suitable model for the reproduction of the pathophysiological features of OSCCs.Moreover,3 D architecture appears capable of inducing drug-resistance processes that can be studied to better our understanding of the different clinical outcomes of HPV-positive and HPV-negative patients with OSCCs.

Primary rectal squamous cell carcinoma treated with surgery and radiotherapy

Primary squamous cell carcinoma of the rectum is a rare malignancy,and the discrete dual lesions of rectum are even rarer.There is currently no effective and satisfactory treatment for this disease.Here we report a case of an elderly female with bi-primary squamous cell carcinoma of the rectum treated with radical resection and radiotherapy.The patient is still alive 43mo after the initial curative resection of the tumor.We suggest that surgery as the primary treatment followed by concomitant radiotherapy may be an effective protocol for elderly patients with rectal squamous cell carcinoma.

Metachronous squamous cell carcinoma of pancreas and stomach in an elderly female patient:A case report

BACKGROUND Squamous cell carcinoma(SCC)in pancreas and stomach is a rare histologic subtype with aggressive behavior,poor prognosis,and no standardized therapy.Pancreatic SCC or gastric SCC has been previously reported.However,case of SCC occurring in both the pancreas and the stomach has not been reported yet.CASE SUMMARY A 75-year-old female with prior history of hypertension and diabetes mellitus visited our hospital with complaint of abdominal pain that started three months ago.Computed tomography(CT)scan of the abdomen showed 3.3 cm mass at the distal pancreas.She received surgical resection which was histologically found to be SCC of the pancreas with clear resection margins.After she was discharged,she no longer visited the hospital.Three years later,she was referred to our hospital after showing abnormal findings on a gastroscopy performed at another hospital.Gastroscopy revealed a single,2cm sized,ill-defined irregular flat and hyperemic mass at high body.Histologic finding of the mass was SCC.CT scan and positive emission tomography CT showed metastatic lesions to the liver and the peritoneum.She received combination chemotherapy with capecitabine and oxaliplatin.However,she passed away 6 mo after diagnosis of gastric SCC.CONCLUSION To the best of our knowledge,this is the first case of metachronous SCC of stomach occurring after diagnosis of pancreatic SCC.

Hydroxyurea-induced cutaneous squamous cell carcinoma: A case report

BACKGROUND Hydroxyurea(HU)is a non-alkylating antineoplastic agent that is active in the Sphase of the cell cycle and inhibits the enzyme ribonucleoside reductase.HU is currently used to treat leukemia,sickle cell anemia,psoriasis,and chronic myeloproliferative disorders.Although HU is easy to use and effective and has high tolerance,there have been numerous reports of cutaneous complications during long-term therapy with HU.CASE SUMMARY We report a 67-year-old woman on long-term HU therapy for primary myelofibrosis who developed concurrent skin lesions during treatment.The first skin lesion appeared on the dorsum of her right hand in 2015.Despite continuous use of HU,her cutaneous changes were neglected.Approximately 3 years ago,she had multiple nodular and keratotic lesions on both hands with sharp margins,branny desquamation,and dotted hyperpigmentation.Furthermore,she developed acutely numerous ulcerative lesions on her hands and legs.Topical wound therapy with dressing changes and parenteral antibiotics was applied for management of the lesions.Most of the wounds healed after HU withdrawal.Lesions on both hands were replaced by scabs.Nevertheless,the wound on her left ankle reached 9 cm×7 cm in size in January 2018.Pathology confirmed welldifferentiated squamous cell carcinoma at the ulcer area.In addition,her left foot was severely affected and radical surgery with a below-the-knee amputation was suggested followed by preventive right groin nodal dissection.CONCLUSION In patients receiving continuous HU therapy,close dermatologic follow-up is critical for the early diagnosis and selection of appropriate treatment for cutaneous lesions.

Younger age of onset and multiple primary lesions associated with esophageal squamous cell carcinoma cases with a positive family history of the cancer suggests genetic predisposition

Background Previous epidemiological studies have consistently found a positive family history of esophageal cancer is associated with a significantly increased risk of the cancer.However,whether the elevated risk could be attributed to common household exposure or inherited susceptibility is uncertain.This study aimed to highlight the effect of genetic predisposition by noting the significant differences in onset age and multiple primary cancers between esophageal squamous cell carcinoma （ESCC） cases with or without a positive family history of the cancer.Methods Age at onset and the percentage of multiple primary cancers were compared between ESCCs with （n=766） or without （n=1 776） a positive family history of the cancer in a consecutive surgery cohort at the Department of Thoracic Surgery of Hebei Tumor Hospital and the Fourth Hospital of Hebei Medical University.Results Overall,ESCCs with a positive family history of the cancer featured both a significantly younger age of onset and significantly more multiple primary cancers than those with a negative family history （onset age 51.83 vs.53.49 years old,P 〈0.01; percent of multiple primary cancers 5.50% vs.1.70%,x2=25.42,P 〈0.01）.Both the differences were evident in subgroup analyses,but did not correlate.While age at onset differed significantly by family history among the male,smoking,and drinking groups,the difference of multiple primary cancers was significant among the otherwise nonsmoking,nondrinking,and younger onset age groups.Conclusions Younger age of onset and multiple primary cancers associated with ESCCs with a positive,as opposed to a negative family history of the cancer,suggest a genetic predisposition.The results of subgroup analyses indicate a younger age of ESCC development results from the interaction of environmental and genetic risk factors,but multiple primary cancers may be related only to genetic predisposition.

Primary Squamous Cell Carcinoma of the Small Intestine： Pathogenesis and Clinical Features

Relative to the length and surface area of the gastrointestinal tract, malignant tumors of the small intestine are remarkably rare, with a global incidence of〈1 per 100,000 population. Among the forty different histological subtypes of small intestinal cancers, primary squamous cell carcinoma （SCC） is exceptionally rare with only occasional case reports in literature. The present study reported a case of primary SCC of the small intestine and reviewed all cases reported in English literature to provide a systematic overview of this rare disease.

HPV Related Retroperitoneal Squamous Cell Cancer: A Rare Presentation

Objective: To describe the primary carcinoma of the retroperitoneum that was positive for human papillomavirus (HPV), a surrogate molecular marker for high-risk HPV (p16) and p53. Methods: This is a case report. Results: We report a case of 50-year-old woman with a large retroperitoneal mass (squamous cell carcinoma on histology) that was treated in September of 2014 with radical concurrent chemotherapy with weekly cisplatin and pelvic radiation (4500 cGY) and additional right pelvic boost of 900 cGY. It was assumed she had FIGO stage IIIB local advanced cervical cancer. She initially presented with the right leg swelling, severe pain and difficulty in walking and was treated with antibiotics for presumed cellulitis. Several months later right leg extensive deep vein thrombosis (DVT) was diagnosed and was started on anticoagulation. CT scan and MRI reported a large right-sided retroperitoneal mass occluding the illiac vessels and ureter. The mass had invaded into the adjacent pelvic sidewall, with destruction of the iliacus muscle and underlying iliac wing. MRI showed that the cervix and uterus were both normal. On examination cervix appeared grossly normal and cervical punch biopsy revealed HSIL only. CT-guided biopsy of the mass revealed a moderately differentiated squamous cell carcinoma positive for p16 and p53. Conclusion: Primary squamous cell carcinoma of the retroperitoneum is a real entity that is unknown. It is unclear if primary neoplasia in the cervix was small from which a cell clone arose and migrated to the retroperitoneal space.

Treatment of 104 Cases of Chemotherapy-Induced Leukopenia by Injection of Drugs into Zusanli

From April 1992 to April 1998, 104 cases of chemotherapy-induced leukopenia were treated by injection into Zusanli (ST 36) with a mixture consisting of dexamethasone, 654-2, ATP and inosine. The therapeutic results were satisfactory as reported in the following. Clinical Data In this series, all the 127 cases were definitely diagnosed by pathological examination. Of them, 93 were male and 34 female, ranging in age from 12 to 75 years. 38 cases were carcinoma of esophagus, 22 carcinoma of cardia of stomach, 21 cancer of lung, 11 hepatic carcinoma, 8 lymphoma, 8 mammary cancer, 7 carcinoma of colon, and 12 other kinds of the tumors. Leukocyte count was below 4.0×109/L in all the patients after being treated by chemotherapy.

Despite shared susceptibility loci, esophageal squamous cell carcinoma embraces more familial cancer than gastric cardia adenocarcinoma in the Taihang Mountains high-risk region of northern central China

Background In China, esophageal squamous cell carcinoma （ESCC） and gastric cardia adenocarcinoma （GCA） share susceptibility loci, but different rates of multiple primary cancer and male/female ratio suggest the proportion of familial cancer is not equal. Methods The percent of cases with a positive family history, median onset age, rate of multiple primary cancer, and male/female ratio associated with upper, middle, lower third ESCC and GCA were compared to reveal the proportion of familial cancer. The 7267 subjects analyzed constituted all ESCC and GCA cases in whom the cancer was resected with cure intention between 1970 and 1994 at the 4th Hospital of Hebei Medical University. Results A positive family history for cancer was most often associated with the multiple primary ESCC and/or GCA cases, e.g. with 42% of the males and 59% of the females. For upper, middle, lower third ESCC and GCA, the percent of cases with a positive family history decreased by 38.5%, 26.3%, 26.5%, and 11.2% in males （P 〈0.000） and 25.0%, 22.3%, 23.9%, and 9.8% in females （P 〈0.0001）. Median onset age increased from 49, 52, 55, to 56 years old in males and from 50, 53, 55, to 56 years old in females （ both P 〈0.0001） for upper, middle, lower third ESCC and GCA. Male/female ratio increased from 2.2, 2.1, 2.2, to 6.2：1 for upper, middle, lower third ESCC and GCA （P〈0.0001）. For upper, middle, lower third ESCC and GCA, the percent of multiple primary cancers decreased from 21.2%, 2.3%, 2.2%, to 1.5% in males and from 14.3%, 2.4%, 3.4%, to 3.1% in females. The preponderance of males, smoking, drinking, or onset-age 〉50 years was significantly higher in GCA than in ESCC, and the difference in the rates of multiple primary cancers between the preponderant and the non-preponderant cases was significant in GCA, but not in ESCC, suggesting non-equal requirement for genetic susceptibility when environmental hazards did not exist. Conclusions The proportion of familial cancer in upper gastrointestinal carcinomas decreases by the priamry site of upper, middle, lower third esophagus and gastric cardia. Considering familial and sporadic cancers differ in preventability, screening strategy and recurrence, our findings have basic and clinical implications.