Multinucleated giant cells of bladder mucosa are modified telocytes:Diagnostic and immunohistochemistry algorithm and relation to PDL1 expression score

BACKGROUND Multinucleated giant cells(MGCs)in bladder carcinomas are poorly studied.AIM To describe the function,morphogenesis,and origin of mononuclear and MGCs in urothelial carcinoma(UC)of the bladder in Bulgarian and French patients.METHODS Urothelial bladder carcinomas(n=104)from 2016-2020 were analyzed retrospectively using immunohistochemical(IHC)and histochemical stain examination.Giant cells in the bladder stroma were found in 35.6%of cases,more often in highgrades.RESULTS We confirm that MGCs in the mucosa in UC of the bladder were positive for both mesenchymal and myofibroblast markers(vimentin,smooth muscle actin,Desmin,and CD34)and the macrophage marker CD68.Furthermore,IHC studies revealed the following profile of these cells:Positive for p16;negative for epithelial(CK AE1/AE3 and GATA-3),vascular(CD31),neural(PS100 and CKIT),cambial,blastic(CD34-blasts and C-KIT),and immune markers(IG G,immunoglobulin G4,and PD-L1);no proliferative activity,possess no specific immune function,and cannot be used to calculate the Combined Positive Score scale.CONCLUSION In conclusion,the giant stromal cells in non-tumor and tumor bladder can be used as a characteristic and relatively constant,although nonspecific,histological marker for chronic bladder damage,reflecting the chronic irritation or inflammation.Likewise,according to the morphological and IHC of the mono-and multinucleated giant cells in the bladder,they are most likely represent telocytes capable of adapting their morphology to the pathology of the organ.

Invasive breast carcinoma with osteoclast-like stromal giant cells:A case report

BACKGROUND Invasive breast carcinoma with osteoclast-like stromal giant cells(OGCs) is an extremely rare morphology of breast carcinomas.To the best of our knowledge,the most recent case report describing this rare pathology was published six years ago.The mechanism controlling the development of this unique histological formation is still unknown.Further,the prognosis of patients with OGC involvement is also controversial.CASE SUMMARY We report the case of a 48-year-old woman,who presented to the outpatient department with a palpable,growing,painless mass in her left breast for about one year.Sonography and mammography revealed a 26.5 mm ×18.8 mm asymmetric,lobular mass with circumscribed margin and the Breast Imaging Reporting and Data System was category 4C.Sono-guided aspiration biopsy revealed invasive ductal carcinoma.The patient underwent breast conserving surgery and was diagnosed with invasive breast carcinoma with OGCs,grade Ⅱ,with intermediate grade of ductal carcinoma in situ(ER:80%,3+,PR:80%,3+,HER-2:negative,Ki 67:30%).Adjuvant chemotherapy and post-operation radiotherapy were initiated thereafter.CONCLUSION As a rare morphology of breast cancer,breast carcinoma with OGC occurs most often in relatively young women,has less lymph node involvement,and its occurrence is not racedependent.

Huge undifferentiated carcinoma of the pancreas with osteoclast-like giant cells

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells(OGCs)is very rare,less than1%of all pancreatic malignancies,and shows worse prognosis than that of invasive ductal adenocarcinoma of the pancreas.We present a case of en bloc resection for a huge undifferentiated carcinoma with OGCs that invaded the stomach and transverse mesocolon.A 67-year female was admitted for left upper quadrant pain and computed tomography demonstrated a mass occupying the lesser sac and abutting the stomach and pancreas.There were no distant metastases and the patient underwent subtotal pancreatectomy with splenectomy,total gastrectomy,and segmental resection of the transverse colon.Histopathological examination confirmed an 11 cm-sized undifferentiated carcinoma of the pancreas with OGCs.Immunohistochemical staining revealed reactivity with pan-cytokeratin in adenocarcinoma component,with vimentin in neoplastic multinucleated cells,with CD45/CD68 in OGCs,and with p53 in tumor cells,respectively.The patient had suffered from multiple bone metastases and survived9 mo after surgery.This case supports the ductal epithelial origin of undifferentiated carcinoma with OGCs and early diagnosis could result in favorable surgical outcomes.Investigations on the surgical role and prog-nostic factors need to be warranted in this tumor.

Thoracic giant cell tumor after two total en bloc spondylectomies including one emergency surgery:A case report

BACKGROUND For patients with acute paraplegia caused by spinal giant cell tumor(GCT)who require emergency decompressive surgery,there is still a lack of relevant reports on surgical options.This study is the first to present the case of an acute paraplegic patient with a thoracic spinal GCT who underwent an emergency total en bloc spondylectomy(TES).Despite tumor recurrence,three-level TES was repeated after denosumab therapy.CASE SUMMARY A 27-year-old female patient who underwent single-level TES in an emergency presented with sudden severe back pain and acute paraplegia due to a thoracic spinal tumor.After emergency TES,the patient's spinal cord function recovered,and permanent paralysis was avoided.The postoperative histopathological examination revealed that the excised neoplasm was a rare GCT.Unfortunately,the tumor recurred 9 months after the first surgery.After 12 months of denosumab therapy,the tumor size was reduced,and tumor calcification.To prevent recurrent tumor progression and provide a possible cure,a three-level TES was performed again.The patient returned to an active lifestyle 1 month after the second surgery,and no recurrence of GCT was found at the last follow-up.CONCLUSION This patient with acute paraplegia underwent TES twice,including once in an emergency,and achieved good therapeutic results.TES in emergency surgery is feasible and safe when conditions permit;however,it may increase the risk of tumor recurrence.

Multimodal imaging in the diagnosis of bone giant cell tumors:A retrospective study

BACKGROUND Giant cell tumor of bone is a locally aggressive and rarely metastasizing tumor,and also a potential malignant tumor that may develop into a primary malignant giant cell tumor.AIM To evaluate the role of multimodal imaging in the diagnosis of giant cell tumors of bone.METHODS The data of 32 patients with giant cell tumor of bone confirmed by core-needle biopsy or surgical pathology at our hospital between March 2018 and March 2023 were retrospectively selected.All the patients with giant cell tumors of the bone were examined by X-ray,computed tomography(CT)and magnetic resonance imaging(MRI),and 7 of them were examined by positron emission tomography(PET)-CT.RESULTS X-ray imaging can provide overall information on giant cell tumor lesions.CT and MRI can reveal the characteristics of the internal structure of the tumor as well as the adjacent relationships of the tumor,and these methods have unique advantages for diagnosing tumors and determining the scope of surgery.PET-CT can detect small lesions and is highly valuable for identifying benign and malignant tumors to aid in the early diagnosis of metastasis.CONCLUSION Multimodal imaging plays an important role in the diagnosis of giant cell tumor of bone and can provide a reference for the treatment of giant cell tumors.

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas diagnosed by endoscopic ultrasonography-guided fine-needle aspiration

Undifferentiated carcinoma with osteoclast-like giant cells, also formerly known as osteoclast-like giant cell tumor, is a rare neoplasm of the pancreas and usually diagnosed after pancreatectomy. The presence of non-neoplastic osteoclast-like giant cells is the histological hallmark of this tumor and the diagnosis is usually not difficult on tissue sections. However there have been relatively few reports regarding the cytological features of this type of tumor in literatures. Here we present a case of undifferentiated pancreatic carcinoma with osteoclast-like giant cells coexisting with ductal adenocarcinoma diagnosed by endoscopic ultrasonography （EUS）-guided fine-needle aspiration （FNA） and liquid-based cytology test. To our knowledge,

Gastric carcinoma with osteoclast-like giant cells:a case report and review of the literature

Gastric carcinoma with osteoclast-like giant cells （OGCs） is an extremely rare tumor. So far, only six cases have been reported in the literature. Here we report an additional case of this tumor in a Chinese 78-year-old man presented with abdominal pain, vomiting, and hematemesis. Physical examination and gastroscopy revealed a tumor in the gastric antrum. The biopsy and pathological findings indicated a gastric adenocarcinoma with OGCs, which were present in both the tumor and the metastatic lymph nodes. Further immunohistochemical staining indicated that OGCs were reactive with CD68, CD45, and vimentin protein, but not with pancytokeratin, carcinoembryonic antigen, or epithelial membrane antigen, suggesting the monocytic/histiocytic derivation of these OGCs. In situ hybridization for Epstein-Burr virus showed no nuclear positivity in either adenocarcinoma or OGCs. Postoperative follow-up showed that the patient had survived for at least 6 months without recurrence. Further investigation is warranted to clearly define the prognostic significance of OGCs in gastric carcinoma.

ANTI-HUMAN LUNG GIANT CELL CANCER (PG) EFFECT OF HUMAN LAK CELLS IN VITRO AND IN NUDE MICE

Human LAK cells were prepared by culturing normal human peripheral blood mononuclear cells (PBMC) with or without rIL-2 and assayed for T cell surface markers as well as anti-tumor activity against PC in vitro and in nude mice. Although the percentages of T3, T4, and T8 positive cells in rIL-2-activated cells did not differ significantly from those of control cells in vitro, the former showed stronger cytotoxicity than control cells to PG tumor cells in vitro. In vivo, LAK cells completely inhibited the growth of PG tumor in nude mice, whereas PBMC control cells were to be of no effect. The anti-tumor effect of human LAK cells in nude mice may offer a useful model to study the role of human LAK cells against human tumor in vivo.

Cellular signaling pathways of T cells in giant cell arteritis

Giant cell arteritis(GCA)is a commonly occurring large vacuities characterized by angiopathy of medium and large-sized vessels.GCA granulomatous formation plays an important role in the pathogenesis of GCA.Analysis of T cell lineages and signaling pathways in GCA have revealed the essential role of T cells in the pathology of GCA.T cells are the dominant population present in GCA lesions.CD4+T cell subtypes that are present include Th1,Th2,Th9,Th17,follicular helper T(Tfh)cells,and regulatory T(Treg)cells.CD8 T cells can primarily differentiate into cytotoxic CD8+T lymphocytes and Treg cells.The instrumental part of GCA is the interplay between dendritic cells,macrophages and endothelial cells,which can result in the vascular injury and the characteristics granulomatous infiltrates formation.During the inflammatory loop of GCA,several signaling pathways have been reported to play an essential role in recruiting,activating and differentiating T cells,including T-cell receptor(TCR)signaling,vascular endothelial growth factor(VEGF)-Jagged-Notch signaling and the Janus kinase and signal transducer and activator of transcription(STAT)pathway(JAK-STAT)pathway.In this review,we have focused on the role of T cells and their potential signaling mechanism(s)that are involved in the pathogenesis of GCA.A better understanding of the role of T cells mediated complicated orchestration during the homeostasis and the changes could possibly favor developments of novel treatment strategies against immunological disorders associated with GCA.

Management of a rare giant cell tumor of the distal fibula: A case report

BACKGROUND Aggressive giant cell tumor of the distal fibula is so rare that no consensus on a surgical strategy has been reached.Thus,an appropriate treatment strategy is still important to discuss.CASE SUMMARY A 61-year-old man who had been experiencing progressive swelling of the left lateral malleolus accompanied by pain for half a year was presented at our hospital.He had never been treated prior to coming to our hospital.Preoperative imaging revealed a 10 cm×6 cm mass located in the body of the distal fibula.Pathological biopsies confirmed it was a giant cell tumor.Preoperative examination revealed he had dilated cardiomyopathy with class 3 cardiac function.The cardiologist and anesthesiologist determined that he could tolerate the operation,but the operation should be as short and minimally invasive as possible.With the patient’s consent,we performed a tibiotalar fusion and followed up with him for 2years,finding no recurrence and a satisfactory recovery.CONCLUSION Tibial talus fusion is an effective method for the treatment of distal fibula tumors.

Tamoxifen induced multinucleated cells (symplasts) and distortion of seminiferous tubules in rat testis

Aim: To evaluate the effect of tamoxifen citrate on male reproductive system of rat. Methods: Groups of male rats were gavaged with tamoxifen at doses of 200 mg·kg-1·d-1, 400 mg·kg-1·d-1 or 800 mg·kg-1·d-1 in 0.1 mL olive oil for 10 consecutive days. Controls were treated with 0.1 mL olive oil. Rats were anesthetized and killed on d 3, d 15 or d 35 after the last dose. Testes were collected, processed for paraffin embedding, sectioned at 5 μm thickness, stained with H&E and analyzed microscopically. Results: There was a dose-dependent increase in the occurrence of seminiferous tubular distortion with germinal cell sloughing. The highest dose increased the number of multinucleated giant cells on d 3 and d 15. Conclusion: Tamoxifen citrate induces multinucleated giant cells and germinal epithelial sloughing in a dose-dependent manner and these changes are detrimental to male fertility.

Expect the unexpected:Brown tumor of the mandible as the first manifestation of primary hyperparathyroidism

Hyperparathyroidism(HPT)is a condition in which one or more parathyroid glands produce increased levels of parathyroid hormone(PTH),causing disturbances in calcium homeostasis.Most commonly HPT presents with asymptomatic hypercalcemia but the clinical spectrum may include disturbances reflecting the combined effects of increased PTH secretion and hypercalcemia.Brown tumors are rare,benign,tumor-like bone lesions,occurring in 1.5%to 4.5%of patients with HPT,as a complication of an uncontrolled disease pathway,and are nowadays rarely seen in clinical practice.The tumor can appear either as a solitary or multifocal lesion and usually presents as an asymptomatic swelling or a painful exophytic mass.Furthermore,it can cause a pathological fracture or skeletal pain and be radiologically described as a lytic bone lesion.The diagnosis of a brown tumor in HPT is typically confirmed by assessing the levels of serum calcium,phosphorus,and PTH.Although when present,brown tumor is quite pathognomonic for HPT,the histologic finding often suggests a giant cell tumor,while clinical presentation might suggest other more frequent pathologies such as metastatic tumors.Treatment of brown tumors frequently focuses on managing the underlying HPT,which can often lead to regression and resolution of the lesion,without the need for surgical intervention.However,in refractory cases or when dealing with large symptomatic lesions,surgical treatment may be necessary.

Osteoclast-like giant cell tumors of the pancreas and liver

Osteoclast-like giant cell tumors （OGCT） are rare abdominal tumors, which mainly occur in the pancreas. The neoplasms are composed of two distinct cell populations and frequently show an inhomogenous appearance with cystic structures. However, due to the rarity of these tumors, only very limited clinical data are available. Imaging features and sonographic appearance have hardly been characterized. Here we report on two cases of osteoclast-like giant cell tumors, one located within the pancreas, the other within the liver, in which OGCTs are extremely rare. Both patients were investigated by contrast sonography, which demonstrated a complex, partly cystic and strongly vascularized tumor within the head of the pancreas in the first patient and a large, hypervascularized neoplasm with calcifications within the liver in the second patient. The liver OGCT responded well to a combination of carboplatin, etoposide and paclitaxel. With a combination of surgical resection, radiofrequency ablation and chemotherapy, the patient＇s survival is currently more than 15 too, making him the longest survivor with an OGCT of the liver to date.

Giant cell tumor of the pancreas:a pathological diagnosis with poor prognosis

BACKGROUND: Giant cell tumors are rare and highly malignant tumors of the pancreas. Based on two distinct cell populations, they have been divided into two subtypes corresponding to the osteoclast-like giant cell tumor and the pleomorphic giant cell carcinoma of the pancreas. Distinctive imaging features of the tumors remain uncharacterized. Surgical removal is the only appropriate treatment for them, but responses to chemotherapy or radiotherapy remain undocumented. METHODS: Clinical, radiological, histopathologic, and immuno- histochemical features of two cases of giant cell tumor of the pancreas are presented along with a brief review of the literature. RESULTS: En-bloc resection was done successfully in both cases. The patient with an osteoclast-like giant cell tumor remained disease-free with no clinical or radiological evidence of recurrence at 6 months after surgery. However, the patient with the pleomorphic type died 4 months later due to diffuse pulmonary metastasis. CONCLUSIONS: En-bloc surgical resection is the only appropriate treatment for giant cell tumors. The overall prognosis of these tumors is poorer than that of pancreatic ductal adenocarcinoma, especially the pleomorphic type. More studies are required to document the management and outcomes of the tumors.

Three-dimensional-printed custom-made patellar endoprosthesis for recurrent giant cell tumor of the patella:A case report and review of the literature

BACKGROUND Giant cell tumor(GCT)is a benign lesion and rarely involves the patella.This disease is characterized by a relatively high recurrence rate after primary treatment.En bloc resection has been a predominant option for recurrent GCT.However,total patellectomy can lead to disruption of the knee.Therefore,exploration of functional reconstruction of the extensor mechanism is worthwhile.CASE SUMMARY A 54-year-old woman presented with right knee pain and swelling,and was diagnosed as having a GCT in the patella following curettage and autograft.Medical imaging revealed a lytic and expanded lesion involving the whole patella with focal cortical breaches and pathological fracture.Based on the combination of histological,radiological,and clinical features,a diagnosis of recurrent GCT in the patella was made(Campanacci grade III).After a multidisciplinary team discussion,three-dimensional(3D)-printed custom-made patellar endoprosthesis was performed following en bloc resection for reconstructing the extensor mechanism.The patient was followed for 35 mo postoperatively.No evidence of local recurrence,pulmonary metastasis,or osteoarthritis of the right knee was observed.The active flexion arc was 0°-120°,and no extension lag was detected.A favorable patellar tracking and height(Insall-Salvati ratio 0.93)were detected by radiography.CONCLUSION We depict a case of a GCT at the right patella,which was successfully treated by patellectomy and 3D-printed custom-made endoprosthetic replacement.The patella normal reconstruction,the precise-fit articular design,and gastrocnemius flap augmentation could lead to satisfactory knee function and a low rate of complications in the short-term follow-up.

Three-dimensional printed talar prosthesis with biological function for giant cell tumor of the talus:A case report and review of the literature

BACKGROUND Giant cell tumors(GCT)are most commonly seen in the distal femur.These tumors are uncommon in the small bones of the hand and feet,and a very few cases have been reported.A giant cell tumor of the talus is rarely seen clinically and could be a challenge to physicians.CASE SUMMARY We report a rare case of GCT of the talus in one patient who underwent a new reconstructive surgery technique using a three-dimensional(3D)printing talar prosthesis.The prosthesis shape was designed by tomographic image processing and segmentation using technology to match the intact side by mirror symmetry with 3D post-processing technologies.The patient recovered nearly full range of motion of the ankle after 6 mo.The visual analogue scale and American Orthopaedic Foot and Ankle Society scores were 1 and 89 points,respectively.CONCLUSION We demonstrated that 3D printing of a talar prosthesis is a beneficial option for GCT of the talus.

Post-infantile giant cell hepatitis:A single center’s experience over 25 years

BACKGROUND Giant cell hepatitis in the adult population remains very poorly defined with only 100 case reports published in the literature over the last three decades.AIM To present our center’s experience in an attempt to learn about the predisposing factors,outcomes and efficacy of proposed therapeutic interventions for giant cell hepatitis.METHODS A retrospective chart review was conducted through the electronic records of the University of Pittsburgh Medical Center.We queried 36726 liver biopsy reports from January 1,1991 to December 6,2016.Our search yielded 50 patients who were identified as carrying a definite diagnosis of post-infantile giant cell hepatitis(PIGCH)by pathology.The data collected included demographic information,laboratory data(liver function tests,autoimmune markers)and transplant status.In order to better analyze patient characteristics and outcomes,subjects were separated into a non-transplant(native)liver group and a post-liver transplant(allograft)group.RESULTS The incidence of PIGCH was approximately 0.14%of all biopsies queried in the 25-year period.The mean age was 48 years with 66%females.Liver function tests were classified as 38.2%cholestatic,35.3%hepatocellular and 26.5%mixed.Autoimmune hepatitis was found to be the most prevalent predisposing factor leading to PIGCH constituting 32%of cases.Management consisted mainly of immunosuppression,viral targeted therapy,supportive care and in six cases liver transplantations.CONCLUSION The diagnosis of PIGCH remains clinically challenging and requires a high index of suspicion as well as a thorough history,physical examination,serological workup and liver biopsy.Treatment of the underlying cause can result in clinical stability in a large number of cases.

Contrast-enhanced multidetector computed tomography features and histogram analysis can differentiate ameloblastomas from central giant cell granulomas

BACKGROUND No qualitative or quantitative analysis of contrast-enhanced computed tomography(CT)images has been reported for the differentiation between ameloblastomas and central giant cell granulomas(CGCGs).AIM To describe differentiating multidetector CT(MDCT)features in CGCGs and ameloblastomas and to compare differences in enhancement of these lesions qualitatively and using histogram analysis.METHODS MDCT of CGCGs and ameloblastomas was retrospectively reviewed to evaluate qualitative imaging descriptors.Histogram analysis was used to compare the extent of enhancement of the soft tissue.Fisher’s exact tests and Mann–Whitney U test were used for statistical analysis(P<0.05).RESULTS Twelve CGCGs and 33 ameloblastomas were reviewed.Ameloblastomas had a predilection for the posterior mandible with none of the CGCGs involving the angle.CGCGs were multilocular(58.3%),with a mixed lytic sclerotic appearance(75%).Soft tissue component was present in 91%of CGCGs,which showed hyperenhancement(compared to surrounding muscles)in 50%of cases,while the remaining showed isoenhancement.Matrix mineralization was present in 83.3%of cases.Ameloblastomas presented as a unilocular(66.7%),lytic(60.6%)masses with solid components present in 81.8%of cases.However,the solid component showed isoenhancement in 63%.No matrix mineralization was present in 69.7%of cases.Quantitatively,the enhancement of soft tissue in CGCG was significantly higher than in ameloblastoma on histogram analysis(P<0.05),with a minimum enhancement of>49.05 HU in the tumour providing 100%sensitivity and 85%specificity in identifying a CGCG.CONCLUSION A multilocular,lytic sclerotic lesion with significant hyperenhancement in soft tissue,which spares the angle of the mandible and has matrix mineralization,should indicate prospective diagnosis of CGCG.

Malignant giant cell tumors of the tendon sheath of the right hip:A case report

BACKGROUND Malignant giant cell tumor of the tendon sheath(MGCTTS)is an extremely rare malignant tumor originating from synovial and tendon sheath tissue with highly aggressive biological behavior and a high rate of local recurrence and distant metastasis which should be considered a highly malignant sarcoma and managed aggressively.How to systemically treat MGCTTS remains a challenge.In this case,a patient with MGCTTS suffered a recurrence after 2 surgical resections received adjuvant chemotherapy and radiation therapy,but the treatment outcome remained poor.More clinical trials and better understanding of the biology and molecular aspects of this subtype of sarcoma are needed while novel medicines should be developed to efficiently target particular pathways.CASE SUMMARY A 52-year-old man presented with persistent dull pain in the right groin accompanied by limited right hip motion starting 6 mo ago.Two months before his attending to hospital,the patient’s pain worsened,presenting as severe pain when standing or walking,limping,and inability to straighten or move the right lower extremity.Surgical excision was performed and MGCTTS was confirmed by pathology examination.Two recurrences occurred after surgical resection,moreover,the treatment outcome remained poor after adjuvant chemotherapy and radiation therapy.The patient died only 10 mo after the initial diagnosis.CONCLUSION MGCTTS is characterized by a joint mass with pain and limited motion.It typically grows along the tendons and infiltrated into the surrounding muscle and bone tissue,with a stubborn tendency to relapse,as well as pulmonary metastasis.Radically surgical resection provides a choice of treatment whereas post-operation care should be taken to preserve the function of the joint.Chemotherapy and radiotherapy can be used as alternative treatments when radical resection cannot be performed.

Spinal giant cell-rich osteosarcoma-diagnostic dilemma and treatment strategy:A case report

BACKGROUND Giant cell-rich osteosarcoma(GCRO) is a rare histological variant of osteosarcoma. Spinal GCROs are extremely rare, with challenging diagnosis and management. Herein, we present a case of spinal GCRO at T2, which was not diagnosed in initial biopsy but after T2 corpectomy. We detailed the clinical course, management strategy, and outcome after a 4-year follow-up.CASE SUMMARY A 17-year-old female patient presented with back pain followed by ascending paresthesia. Spinal computed tomography(CT) and magnetic resonance imaging(MRI) revealed a collapsed T2 vertebra with an enhancing osteolytic mass. CTguided biopsy showed inconclusive morphology. Pathology from T2 corpectomy revealed GCRO. The patient subsequently received neoadjuvant chemotherapy followed by salvage operation of T2 costotransversectomy with grossly-total resection adjuvant chemoradiation. Upon treatment completion, she had complete GCRO remission. The 4-year follow-up spinal MRI showed no tumor recurrence.CONCLUSION Spinal GCRO poses unique challenges in obtaining sufficient tissue diagnosis and complete surgical removal. However, long-term local control of spinal GCRO is possible following complete resection and adjuvant chemoradiation.