Sclerosing epithelioid fibrosarcoma of the pancreas:A case report

BACKGROUND A sclerosing epithelioid fibrosarcoma(SEF)is a rare malignant fibroblastic soft tissue tumor that rarely occurs in intra-abdominal organs.A case of a SEF in the pancreatic head is reported herein,including its clinical manifestations,preoperative imaging features,gross specimen and pathological findings.CASE SUMMARY A 33-year-old male patient was admitted to Peking Union Medical College Hospital in December 2023 due to a one-year history of intermittent upper abdominal pain and the discovery of a pancreatic mass.The patient underwent an enhanced computed tomography scan of the abdomen,which revealed a welldefined,round mass with clear borders and calcifications in the pancreatic head.The mass exhibited progressive,uneven mild enhancement,measuring approximately 6.6 cm×6.3 cm.The patient underwent laparoscopic pylorus-preserving pancreaticoduodenectomy.Postoperative pathological examination revealed that the lesion was consistent with a SEF.At the 3-month postoperative follow-up,the patient did not report any short-term complications,and there were no signs of tumor recurrence.CONCLUSION SEFs are rare malignant fibrous soft tissue tumors.SEFs rarely develop in the pancreas,and its preoperative diagnosis depends on imaging findings,with confirmation depending on pathological examination and immunohistochemistry.Currently,only four cases of pancreatic SEF have been reported in studies written in English.This case is the first reported case of a pancreatic SEF by a clinical physician.

Solid-pseudopapillary tumor of the pancreas: Clinical experience and literature review

AIM: To evaluate the clinical presentations of solidpseudopapillary tumor of the pancreas (SPT) and examine the diagnosis, treatment, low grade malignant potential of this rare disease.METHODS: We retrospectively reviewed a series of seven patients with SPT managed in our hospital between July 1990 and October 2003. Six females and one male with mean age of 31 years (range 13 to 50 years) were diagnosed with SPT at our institution.RESULTS: Clinical presentation included a palpable abdominal mass in two patients and vague abdominal discomfort in another two. Two patients were asymptomatic;their tumors were found incidentally on abdominal sonographic examination for other reasons. The final patient was admitted with hemoperitoneum secondary to tumor rupture. The mean diameter of the tumors in the seven patients was 10.5 cm (range 5 to 20 cm). The lesions were located in the body and tail in five cases and in the head of the pancreas in two. Surgical procedures included distal pancreatectomy (3), distal pancreatectomy with splenectomy (2), pancreaticoduodenectomy (1) and a pylorus-preserving Whipple procedure (1). There were gross adhesions or histological evidence of infiltration to the adjacent pancreas and/or splenic capsule in four cases. None of the patients received adjuvant therapy.The mean follow up was 7 years (range 0.5 to 14 years).One patient developed multiple liver metastases after 14 years of follow up.CONCLUSION: SPT is a rare tumor that behaves less aggressively than other pancreatic tumor. However, in cases with local invasion, long-term follow up is advisable.

Surgical outcome of adenosquamous carcinoma of the pancreas

Adenosquamous carcinoma is rare,accounting for 3%-4% of all pancreatic carcinoma cases. These tumors are characterized by the presence of variable proportions of mucin-producing glandular elements and squamous components,the latter of which should account for at least 30% of the tumor tissue. Recently,several reports have described cases of adenosquamous carcinoma of the pancreas. However,as the number of patients who undergo resection at a single institute is limited,large studies describing the clinicopathological features,therapeutic management,and surgical outcome for adenosquamous carcinoma of the pancreas are lacking. We performed a literature review of English articles retrieved from Medline using the keywords 'pancreas' and 'adenosquamous carcinoma'. Additional articles were obtained from references within the papers identif ied by the Medline search. Our subsequent review of the literature revealed that optimal adjuvant chemotherapy and/or radiotherapy regimens for adenosquamous carcinoma of the pancreas have not been established,and that curative surgical resection offers the only chance for long-term survival. Unfortunately,the prognosis of the 39 patients who underwent pancreatic resection for adenosquamous carcinoma was very poor,with a 3-year overall survival rate of 14.0% and a median survival time of 6.8 mo. Since the postoperative prognosis of adenosquamous carcinoma of the pancreas is currently worse than that of pancreatic adenocarcinoma,new adjuvant chemotherapies and/or radiation techniques should be investigated as they may prove indispensible to the improvement of surgical outcomes.

Pancreatic endometrial cyst mimics mucinous cystic neoplasm of the pancreas

Pancreatic cysts include a variety of benign, premalignant, and malignant lesions. Endometrial cysts in the pancreas are exceedingly rare lesions that are difficult to diagnose pre-operatively. This report describes the findings in a 43-year-old patient with a recent episode of acute pancreatitis who presented with a large cyst in the tail of the pancreas. Imaging demonstrated a loculated pancreatic cyst, and cyst fluid aspiration revealed an elevated amylase and carcinoembryonic antigen. The patient experienced an interval worsening of abdominal pain, fatigue, diarrhea, and a 15-pound weight loss 3 mo after the initial episode of pancreatitis. With concern for a possible pre-malignant lesion, the patient underwent a laparoscopic distal pancreatectomy with splenectomy, which revealed a 16cm×12cm×4cm lesion. Final histopathology was consistent with an intra-pancreatic endometrial cyst. Here we discuss the overlapping imaging and laboratory features of pancreatic endometrial cysts and mucinous cystic neoplasms of the pancreas.

Solid pseudopapillary neoplasm of the pancreas

Solid pseudopapillary neoplasms are rare.This article reviews the clinical and pathologic features of solid pseudopapillary neoplasm of the pancreas,including the epidemiology,cytology,molecular pathology,differential diagnosis,treatment,and prognosis.Solid pseudopapillary neoplasms are low-grade malignant tumours of the pancreas characterized by poorly cohesive epithelial cells with solid and pseudopapillary patterns.Solid pseudopapillary neoplasms occur predominantly in young women.Although solid pseudopapillary neoplasms can occur throughout the pancreas,they arise slightly more frequently in the tail of the pancreas.The aetiology is unknown.Extremely rare cases have been reported in the setting of familial adenomatous polyposis.There are no symptoms unique to solid pseudopapillary neoplasms,however,the most common symptom is abdominal pain or discomfort.The features of solid pseudopapillary neoplasms on computed tomography imaging are indicative of the pathologic changes within the tumour.Typically,well-demarcated masses with variably solid and cystic appearances.Microscopically,these tumours are composed of epithelial cells forming solid and pseudopapillary structures,frequently undergoing haemorrhagic cystic degeneration.Typically,these tumours express nuclear and/or cytoplasmicβ-catenin.Almost all solid pseudopapillary neoplasms harbour mutations in exon 3 of CTNNB1,the gene encodingβ-catenin.The overall prognosis is excellent,and most patients are cured by complete surgical resection.

Prognosis of cancer with branch duct type IPMN of the pancreas

AIM:To examine the coexistence of metachronous and synchronous cancer in branch duct intraductal papillary mucinous neoplasms of the pancreas (IPMN).METHODS: We reviewed the records of 145 patients with branch duct IPMN between January 1991 and April 2008 and assessed the relationship between IPMN and intraor extra-pancreatic carcinoma and the outcome of IPMN.RESULTS: The mean observation period was 55.9 ± 45.3 mo. Among the 145 patients, the frequency of extra-pancreatic cancer was 29.0%. The frequency of gastric cancer, colon cancer, breast cancer, and pan-creatic cancer were 25.5%, 15.7%, 13.7%, and 9.8%, respectively. Twenty (13.8%) of the patients died. The cause of death was extra-pancreatic carcinoma in 40%,pancreatic cancer in 25%, IPMN per se in 20%, and benign disease in 15% of the patients.CONCLUSION: The prognosis for IPMN depends not on the IPMN per se, but on the presence of intraor extra-pancreatic cancer.

Laparoscopic distal pancreatectomy for adenocarcinoma of the pancreas

Since the first report on laparoscopic distal pancreatectomy (LDP) appeared in the 1990s, the procedure has been performed increasingly frequently to treat both benign and malignant lesions of the pancreas. Many earlier publications have shown LDP to be a good alternative to open distal pancreatectomy for benign lesions, although this has never been studied in a prospective, randomized manner. The evidence for the use of LDP to treat adenocarcinoma of the pancreas is not as well established. The purpose of this review is to evaluate the current evidence for LDP in cases of pancreatic adenocarcinoma. We conducted a review of English language publications reporting LDP results between 1990 and 2013. All studies reporting results in patients with histologically proven pancreatic adenocarcinoma were included. Thirty-nine publications were found and included in the results for a total of 309 cases of pancreatic adenocarcinoma (potential double publications were not eliminated). Most LDP procedures are performed in selected cases and generally involve smaller tumors than open distal pancreatectomy (ODP) procedures. Some of the papers report unselected cases and include procedures on larger tumors. The number of lymph nodes harvested using LDP is comparable to the number obtained with ODP, as is the frequency of R0 resections. Current data suggest that similar short term oncological results can be obtained using LDP as those obtained using ODP.

Reoperation for heterochronic intraductal papillary mucinous neoplasm of the pancreas after bile duct neoplasm resection:A case report

BACKGROUND Intraductal papillary neoplasm of the bile duct(IPNB)and intraductal papillary mucinous neoplasm(IPMN)of the pancreas have similar pathological manifestations.However,they often develop separately and it is rare for both to occur together.Patients presenting with heterochronic IPMN after IPNB are prone to be misdiagnosed with tumor recurrence.CASE SUMMARY A 67-year-old male patient was admitted 8.5 years after IPNB carcinoma and 4 years after the discovery of a pancreatic tumor.A left hepatic bile duct tumor with distal bile duct dilatation was found 8.5 years ago by the computed tomography;therefore,a left hepatectomy was performed.The postoperative pathological diagnosis was malignant IPNB with negative cutting edge and pathological stage T1N0M0.Magnetic resonance imaging 4 years ago showed cystic lesions in the pancreatic head with pancreatic duct dilatation,and carcinoembryonic antigen continued to increase.Positron emission tomography showed a maximum standard uptake value of 11.8 in the soft tissue mass in the pancreatic head,and a malignant tumor was considered.Radical pancreatoduodenectomy was performed.Postoperative pathological diagnosis was pancreatic head IPMN with negative cutting edge,pancreaticobiliary type,stage T3N0M0.He was discharged 15 d after the operation.Follow-up for 6 mo showed no tumor recurrence,and quality of life was good.CONCLUSION IPNB and IPMN are precancerous lesions with similar pathological characteristics and require active surgery and long-term follow-up.

Large-duct pattern invasive adenocarcinoma of the pancreas–a variant mimicking pancreatic cystic neoplasms: A minireview

Pancreatic cancer currently has no subtypes that inform clinical decisions;hence,there exists an opportunity to rearrange the morphological and molecular taxonomy that guides a better understanding of tumor characteristics.Nonetheless,accumulating studies to date have revealed the large-duct type variant,a unique subtype of pancreatic ductal adenocarcinoma(PDA)with cystic features.This subtype often radiographically mimics intraductal papillary mucinous neoplasms(IPMNs)and involves multiple small cysts occasionally associated with solid masses.The“bunch-of-grapes”sign,an imaging characteristic of IPMNs,is absent in large-duct PDA.Large-duct PDA defines the mucin profile,and genetic alterations are useful in distinguishing large-duct PDA from IPMNs.Histologically,neoplastic ducts measure over 0.5 mm,forming large ductal elements.Similar to classic PDAs,this subtype is frequently accompanied by perineural invasion and abundant desmoplastic reactions,and KRAS mutations in codon 12 are nearly ubiquitous.Despite such morphological similarities with IPMNs,the prognosis of large-duct PDA is equivalent to that of classic PDA.Differential diagnosis is therefore essential.

MSCT and MRCP features of intraductal papillary mucinous tumor of the pancreas

Objective:To study the multi-slice CT(MSCT) and magnetic resonance cholangio-pancreatography(MRCP) features of intraductal papillary mucinous tumor(IPMT) of the pancreas.Methods:The clinical information,laboratory val-ues,imaging features and pathological findings of 8 cases were reviewed.Results:There were 6 males and 2 females with average 71.3 years old in this series.These lesions involved pancreatic branch ducts or main duct.Among them,2 cases were involved in the pancreatic uncinate process,1 case in the pancreatic head,1 in the pancreatic body,2 in the pancreatic tail and 2 cases involved multiple pancreatic duct.The common complaint was chronic upper abdominal pain.The imaging features included cystic lesion and it's association with the dilated pancreatic main duct,and bulging of the duodenal papilla.Mucin plug,septa or mural nodule were found in these cystic lesions.5 cases were confirmed with endoscopic retrograde cholangio-pancreatography(ERCP).3 cases had undergone surgery.Pathological findings of the 3 cases were adenoma,adenocarcinoma and borderline tumor,respectively.Conclusion:The MSCT and MRCP features of IPMT are somewhat characteristic,and the correct diagnosis can be made with the combination of clinical features.Diameter of branch duct ≥ 3 cm with multiple or large mural nodules,or severe dilated main duct indicates the probability of malignant IPMT.

Night blindness due to vitamin A deficiency associated with resected adenocarcinoma of the pancreas

【正】Dear Sir,W e write to present a rare case of night blindness caused by vitamin A deficiency secondary to resected adenocarcinoma of the pancreas.To our knowledge this is the first reported case of this association.A 62 year-old man presented to the eye clinic with a 12mo history of worsening nyctalopia and colour perception.

Primary non-Hodgkin' s lymphoma of the pancreas:report of six cases

Objective To evaluate the diagnosis and treatment of primary non-hodgkin’ s lymphoma (PNHL) of the pancreas. Methods The therapeutic result of 6 cases admitted from January 1980 to March 2000 was reviewed retrospectively. Results The lesion was located in the head of the pancreas in 2 cases and the body and/or tail in 4, respectively. Clinical manifestations included epigastric discomfort, loss of weight, abdominal mass and jaundice. Two cases underwent Whipple’ s procedure and distal pancreatectomy respectively, the other 4 underwent laparotomy and biopsy. B cell non-Hodgkin’ s lymphoma of 5 cases and T cell non-Hodgkin’s lymphoma of one were verified by pathology. One patient lost follow-up, the other 5 patients survived 58, 49, 22, 13 and 4 months respectively. Conclusion The clinical manifestation and radiological features of PNHL of the pancreas are not specific. Comprehensive therapy including surgery is beneficial to the long-term survival of patients with PNHL of the pancreas. 4 refs.

Synchronous intraoperative radiofrequency ablation for multiple liver metastasis and resection of giant solid pseudopapillary tumors of the pancreas

The solid pseudopapillary tumors of the pancreas （SPTP） are rare tumors, which are commonly found in adolescent women. Radical surgical resection of the primary tumor or metastases is the standard treatment for SPTP and could achieve long-term survival. We reported a case of a 20-year-old female with multiple liver metastases of SPTP, and performed surgical resection for primary tumor 14 cm in diameter and 2 major liver metastases （both 5 cm in diameter）, radiofrequency ablation （RFA） for small lesions and one major liver metastase 6 cm in diameter successfully. No evidence of recurrence in situ or in the liver was found by computed tomography （CT） scan 3 months after the operation. RFA is a safe and effective treatment for unresectable multiple liver metastases of SPTP.

Loss of chromosome 9p21 is associated with a poor prognosis in adenosquamous carcinoma of the pancreas

Adenosquamous carcinoma of the pancreas(ASCP)is a rare histological subtype of pancreatic cancer with a poor prognosis and a high metastasis rate.However,little is known about its genomic landscape and prognostic biomarkers.A total of 48 ASCP specimens and 98 pancreatic ductal adenocarcinoma(PDAC)tumour specimens were sequenced to explore the genomic landscape and prognostic biomarkers.The homozygous deletion of the 9p21.3 region(including CDKN2A,CDKN2B,and MTAP)(9p21 loss)occurred in both ASCP and PDAC,and a higher frequency of 9p21 loss was observed in ASCP(12.5%vs 2.0%,P=0.022).Notably,9p21 loss was significantly associated with poor disease-free survival(DFS)in ASCP patients(mDFS(Median DFS)=4.17 vs 7.33 months,HR(Hazard Ratio)=3.70,P=0.009).The most common gene alterations in patients with ASCP were KRAS(96%),TP53(81%),CDKN2A(42%),SMAD4(21%),CDKN2B(13%),and FAT3(13%).The mutation rates of ACVR2A(6.25%vs 0%),FANCA(6.25%vs 0%),RBM10(6.25%vs 0%),and SPTA1(8.33%vs 1.02%)were significantly higher in ASCP than in PDAC.In conclusion,we have comprehensively described the genomic landscape of the largest cohort of ASCP patients to date and highlight that 9p21 loss may be a promising prognostic biomarker for ASCP,which provides a molecular basis for prognosis prediction and new therapeutic strategies for ASCP.

Case analysis of epithelioid hemangioendothelioma of pancreas with liver and lung involvement

Objective:To summarize the clinical manifestation,diagnosis and treatment of a case of epithelioid hemangioendothelioma of the pancreas(epithelioid hemangioendothelioma,EHE)with liver and right lung involvement.Methods:The clinical,imaging,histomorphological and immunohistochemical features of a patient with pancreatic epithelioid hemangioendothelioma with liver and right lung involvement diagnosed in Laizhou traditional Chinese Medicine Hospital in 2021 were analyzed retrospectively,and the related literatures were reviewed.Results:After 8 cycles of chemotherapy combined with hyperthermia and traditional Chinese medicine treatment,the clinical discomfort symptoms were significantly improved,the quality of life was improved,and the condition was stable,which is still in the process of treatment.Conclusion:Pancreatic EHE is rare in clinic.Imaging plays an important role in the diagnosis of pancreatic EHE,but the final diagnosis should be confirmed by pathological examination.The histological features of this case of EHE should be distinguished from metastatic carcinoma,epithelioid sarcoma,mesothelioma and other common tumors in the abdominal cavity,and its diagnosis is challenging.Surgical resection is the first choice for EHE,but its sensitivity to radiotherapy and chemotherapy is not accurate.The prognosis of EHE needs to collect more case data for in-depth and systematic study and analysis.

Endoscopic therapy in acute recurrent pancreatitis

Endoscopic retrograde cholangiopancreatography (ERCP) has evolved from a largely diagnostic to a largely therapeutic modality. Cross-sectional imaging, such as computed tomography (CT) and magnetic resonance imaging (MRI), and less invasive endoscopy, especially endoscopic ultrasound (EUS), have largely taken over from ERCP for diagnosis. However, ERCP remains the "first line" therapeutic tool in the management of mechanical causes of acute recurrent pancreatitis, including bile duct stones (choledocholithiasis), ampullary masses (benign and malignant), congenital variants of biliary and pancreatic anatomy (e.g. pancreas divisum, choledochoceles), sphincter of Oddi dysfunction (SOD), pancreatic stones and strictures, and parasitic disorders involving the biliary tree and/or pancreatic duct (e.g Ascariasis, Clonorchiasis).

Current status of diagnosis and therapy for intraductal papillary neoplasm of the bile duct

Bile duct epithelial tumours showing papillary neoplasm in the bile duct lumen are present in the intrahepatic and extrahepatic bile ducts.Clinicopathological images of these tumours are distinctive and diverse,including histological images with a low to high grade dysplasia,infiltrating and noninfiltrating characteristics,excessive mucus production,and similarity to intraductal papillary mucinous neoplasm(IPMN)of the pancreas.The World Health Organization Classification of Tumours of the Digestive System in 2010 named these features,intraductal papillary neoplasm of the bile duct(IPNB),as precancerous lesion of biliary carcinoma.IPNB is currently classified into type 1 that is similar to IPMN,and type 2 that is not similar to IPMN.Many of IPNB spreads superficially,and diagnosis with cholangioscopy is considered mandatory to identify accurate localization and progression.Prognosis of IPNB is said to be better than normal bile duct cancer.

Role of phosphorylated Smad3 signal components in intraductal papillary mucinous neoplasm of pancreas

Background:Malignant intraductal papillary mucinous neoplasm(IPMN)has poor prognosis.The carcinogenesis of IPMN is not clear.The aim of this study was to clarify transitions in phosphorylated Smad3 signaling during IPMN carcinogenesis.Methods:By using immunohistochemistry,we examined the expression of pSmad3C and pSmad3L from 51 IPMN surgical specimens resected at our institution between 2010 and 2013.We also examined the expression of Ki-67,c-Myc and p-JNK.Results:The median immunostaining index of pSmad3C was 79.2%in low-grade dysplasia,74.9%in highgrade dysplasia,and 42.0%in invasive carcinoma(P<0.01),whereas that of pSmad3L was 3.4%,4.3%,and 42.4%,respectively(P<0.01).There was a negative relationship between the expression of pSmad3C and c-Myc(P<0.001,r=-0.615)and a positive relationship between the expression of pSmad3L and c-Myc(P<0.001,r=0.696).Negative relationship between the expression of pSmad3C and Ki-67(P<0.01,r=-0.610)and positive relationship between the expression of pSmad3L and Ki-67(P<0.01,r=0.731)were confirmed.p-JNK-positive cells were frequently observed among pSmad3L-positive cancer cells.The median of pSmad3L/pSmad3C ratio in the non-recurrence group and the recurrence group were 0.58(range,0.05–0.93),3.83(range,0.85–5.96),respectively(P=0.02).The median immunostaining index of c-Myc in the non-recurrence group and the recurrence group were 2.91(range,0–36.9)and 82.1(range,46.2–97.1),respectively(P=0.02).The median immunostaining index of Ki-67 in the non-recurrence group and the recurrence group were 12.9(range 5.7–30.8)and 90.9(range 52.9–98.5),respectively(P=0.02).Conclusions:pSmad3L was upregulated in malignant IPMN.pSmad3L/pSmad3C ratio may be a useful prognostic factor in IPMN.

Sequential therapy with combined trans-papillary endoscopic nasopancreatic and endoscopic retrograde pancreatic drainage for pancreatic pseudocysts

BACKGROUND Endoscopic retrograde pancreatic drainage(ERPD)and stent implantation has become the major treatment method for pancreatic pseudocysts.However,it is associated with a high recurrence rate and infection.AIM To manage pancreatic pseudocysts by sequential therapy with endoscopic nasopancreatic drainage(ENPD)combined with ERPD and evaluate the treatment outcome.METHODS One hundred and sixty-two cases of pancreatic pseudocyst confirmed by endoscopic examination at our hospital between January 2014 and January 2020 were retrospectively analyzed.There were 152 cases of intubation via the duodenal papilla,of which 92 involved pancreatic duct stent implantation and 60 involved sequential therapy with combined ENPD and ERPD(two-step procedure).The success rate of the procedure,incidence of complications(infection,bleeding,etc.),recurrence,and length and cost of hospitalization were compared between the two groups.RESULTS The incidence of infection was significantly higher in the ERPD group(12 cases)than in the two-step procedure group(2 cases).Twelve patients developed infection in the ERPD group,and anti-infection therapy was effective in five cases but not in the remaining seven cases.Infection presented as fever and chills in the two-step procedure group.The reoperation rate was significantly higher in the ERPD group with seven cases compared with zero cases in the two-step procedure group(P<0.05).Similarly,the recurrence rate was significantly higher in the ERPD group(19 cases)than in the two-step procedure group(0 cases).CONCLUSION Sequential therapy with combined ENPD and ERPD is safe and effective in patients with pancreatic pseudocysts.

Early detection and prevention of pancreatic cancer:Is it really possible today?

Pancreatic cancer is the 4th leading cause of cancer-related death in Western countries. Considering the low incidence of pancreatic cancer, population-based screening is not feasible. However, the existence of a group of individuals with an increased risk to develop pancreatic cancer has been well established. In particular, individuals suffering from a somatic or genetic condition associated with an increased relative risk of more than 5- to 10-fold seem to be suitable for enrollment in a surveillance program for prevention or early detection of pancreatic cancer. The aim of such a program is to reduce pancreatic cancer mortality through early or preemptive surgery. Considering the risk associated with pancreatic surgery, the concept of preemptive surgery cannot consist of a prophylactic removal of the pancreas in high-risk healthy individuals, but must instead aim at treating precancerous lesions such as intraductal papillary mucinous neoplasms or pancreatic intraepithelial neoplasms, or early cancer. Currently, results from clinical trials do not convincingly demonstrate the efficacy of this approach in terms of identification of precancerous lesions, nor do they define the outcome of the surgical treatment of these lesions. For this reason, surveillance programs for individuals at risk of pancreatic cancer are thus far generally limited to the setting of a clinical trial. However, the acquisition of a deeper understanding of this complex area, together with the increasing request for screening and treatment by individuals at risk, will usher pancreatologists into a new era of preemptive pancreatic surgery. Along with the growing demand to treat individuals with precancerous lesions, the need for low-risk investigation, low-morbidity operation and a minimally invasive approach becomes increasingly pressing. All of these considerations are reasons for preemptive pancreatic surgery programs to be undertaken in specialized centers only.