Papaverine Effect on Superficial Vein in Thumb Replantation Procedure: A Case Study

An unusual case of ventral spontaneous thoracic epidural hematomaJunge ZhouDepartment of Neurosurgery, General Hospital of The Yangtze River Shipping, Wuhan Brain Hospital, Wuhan, Hubei 430010, ChinaE-mail: 43494830@qq.comTel: 15827617486Fax Number: +86-027 -82451001Patient consent: Written informed consent was obtained from the patient for the publication of this manuscript.Ethics approval: This research was approved by the ethics committee of General Hospital of The Yangtze River Shipping.Acknowledgments: We would like to thank Editage (www.editage.cn) for English language editing.Funding source: None.Conflicts of interest: None.Data access statement:  The data used to support the findings of this study have been included in this article.

Introduction:Invasive cribriform carcinoma of the breast, initially described by Page et al in 1983 due to its predominant cribriform growth pattern in the invasive component and relatively favourable prognosis, is a rare type of breast carcinoma, accounting for 0.3 to 3.5% of primary breast carcinomas [1, 2]. ICC patients typically have a small tumour size, few axillary lymph node invasion, low distant metastasis rate, tumour with a high frequency of well differentiation, high ER and PR positive rates with rarely-observed human epidermal growth factor receptor 2 (HER2) amplification and a low proliferation index [3, 4, 5]. To date, studies of skin manifestations of invasive cribriform breast of the breast are notably scarce. We herein report a patient of ICC with a presentation as an erythematous papule on the nipple that no one has reported before.Case history / examination:A 71-year-old Asian woman visited our Department of Dermatology with a chief complaint of a reddish protruding skin lesion on the tip of her right nipple that had appeared for 6 months. Upon physical examination, the skin lesion was a solitary, well-demarcated papule, 0.2 by 0.2 cm in size, appearing centrally erythematous with violaceous in the periphery, fairly dome-shaped and firm [Figure 1a-c]. Besides, the papule was completely asymptomatic. The patient did not report any other abnormal symptoms. Her medical history was also unremarkable.Differential diagnosis and investigations:With these clues, a benign skin lesion had been impressed. Therefore, a local excision was performed to obtain a specimen of 0.7 by 0.5 by 0.3 cm in size. Biopsy results turned out to be pure invasive cribriform carcinoma of the breast (pure ICC), characterized by the invasive cribriform pattern comprising >90% of the lesion, in addition to mammary Paget’s disease (MPD) in the epidermis [Figure 2a-c]. Immunohistochemical tests showed positive expressions of both oestrogen and progesterone receptors [ER >95%, PgR >95%]. The reaction to HER2 (human epidermal growth factor receptor type 2) protein was negative [HER 2 (-)] [Figure 3a-c]. The Ki-67 labelling index was 5 %.Treatment, outcome and follow-up:In the diagnosis of pure ICC with MPD, she was referred to the Breast Surgery Department for further survey and treatment. Results on both CEA and CA15-3 levels were normal. Bilateral breast mammography (CC and MLO view) revealed segmental fine pleomorphic microcalcifications in the lower-inner quadrant of her right breast. These findings raise high suspicion for malignancy and are consistent with a classification of 4C in the BIRADS-US system. Breast ultrasound revealed two oval hypoechoic lesions with tiny calcifications which were 7.8 mm and 24.5 mm in size at the right breast near the areola. Whole body bone scan found no evidence of bone metastasis. With a previous biopsy pathology report revealing ICC and MPD, a full discussion was carried out with the patient. Finally, a simple mastectomy and sentinel lymph node biopsy were performed on her right breast.With the right side simple mastectomy, pathology of the surgical specimen showed residual multifocal ductal carcinomas in situ. Both frozen sections of sentinel lymph nodes revealed no evidence of metastasis. The pathological TNM stage was pT1aN0 according to AJCC eighth edition. Further treatment plans for this patient included a five-year Tamoxifen therapy and regular follow-up at the Breast Surgery Department.Discussion:Based on the clinical features of the papule on her nipple, our initial impressions were benign skin lesions such as pyogenic granuloma, nipple adenoma, Spitz nevus and intradermal nevus. However, the pathologic diagnosis was pure ICC with MPD in the epidermis. Although ICC usually presents as an asymptomatic mass or may even be clinically occult[1, 3], the chance of ICC presenting as skin lesions cannot be ignored. The case reported by Katarzyna et al, in which ICC mimicked a breast abscess [6], along with our case of ICC presenting as a nipple papule, collectively demonstrates ICC’s potential to primarily manifest through skin lesions. To the best of our knowledge, ICC is a tumour having a more favourable prognosis than invasive breast carcinoma with less cribriform pattern and low grade invasive ductal carcinoma [11]. Despite favourable prognosis of ICC, there are still chances of aggressive behaviour or development into an advanced stage if left untreated long enough. Mishra et al reported a case of ICC with extensive perineural infiltration and lymphovascular invasion in a 58-year-old female; and Zhang et al also reported a case of pure ICC with bone metastasis when left untreated for 13 years[7, 8]. Therefore, such manifestation of a papule on the nipple, as in our case, may result in delayed diagnosis and treatment to ICC. It is crucial for dermatologists to have early awareness about skin manifestation of ICC and to avoid misdiagnosis.Mammary Paget’s disease (MPD), first described by Sir Paget in 1874 as eczematous nipple and areola skin lesions, is a rare form of breast carcinoma comprising 1 to 3% of all breast cancers. Nearly all cases of MPD are affiliated with underlying breast carcinomas, typically located near the areola, and >90% are either ductal carcinomas in situ (DCIS) or invasive ductal carcinomas (IDC). Pathophysiologically, there are two main hypotheses proposed for the origin of MPD: the epidermotropic theory and the malignant transformation theory. The epidermotropic theory states that Paget cells originate from underlying breast carcinoma, and they migrate via the lactiferous ducts to the epidermis of the nipple. On the other hand, the malignant transformation theory states that Paget cells are malignant transformation of pluripotent keratinocyte stem cells or cells of apocrine gland ducts[9]. Although remains controversial, it is currently widely accepted that MPD is associated with underlying breast carcinoma, forming the concept based on the epidermotropic theory. In our case, ICC and MPD were diagnosed within the papular lesion on the nipple. This case stands out from >90% of cases in which mammary Paget’s disease was diagnosed exclusively with underlying DCIS or IDC. Furthermore, to the best of knowledge, only one publication focusing on radiologic characteristics of 52 MPD cases mentioned a case of invasive lobular and invasive cribriform carcinoma being diagnosed with mammary Paget’s disease presenting as a mass on mammography[10], but details or images were not provided. As to our case, it is worth knowing that the patient was diagnosed with multifocal DCIS at 1 cm near the right areola in the surgical specimen from simple mastectomy. In our opinion, it was the invasive cribriform carcinoma of the breast but not DCIS resulting in the mammary Paget’s disease in the epidermis of the papule [Figure 2c] as consistent with the epidermotropic theory. Although DCIS has been diagnosed near the areola, we believe that the chance of mammary Paget’s disease originating from the DCIS was slim. That is because malignant Paget cells were not seen at other parts of the nipple nor at the areola, but merely in the epidermis of the papule on the nipple. Furthermore, based on pathologic images, the gross pictures and the clinical manifestations of ICC and MPD, we believe that the invasive cribriform carcinoma of breast had caused the dome-shaped violaceous papule on the nipple, and mammary Paget’s disease contributed to the central erythematous part of the papular lesion [Figure 1a]. Undoubtedly, more studies are needed to bring attention to the skin manifestation of invasive cribriform carcinoma of the breast. As far as we know, no publication has ever reported on ICC with skin manifestation as a papule on the nipple. Also, no case has been reported with detailed images and descriptions regarding a pure ICC being diagnosed with MPD. In this case report, we aim to bring awareness to skin manifestation of ICC.References:1. Cong Y, Qiao G, Zou H, Lin J, Wang X, Li X, et al. Invasive cribriform carcinoma of the breast: A report of nine cases and a review of the literature. Oncol Lett. 2015;9: 1753-1758.2. Page DL, Dixon JM, Anderson TJ, Lee D, Stewart HJ. Invasive cribriform carcinoma of the breast. Histopathology. 1983;7: 525-36.3. Zhang W, Zhang T, Lin Z, Zhang X, Liu F, Wang Y, et al. Invasive cribriform carcinoma in a Chinese population: comparison with low-grade invasive ductal carcinoma-not otherwise specified. Int J Clin Exp Pathol. 2013;6: 445-57.4. Mo CH, Ackbarkhan Z, Gu YY, Chen G, Pang YY, Dang YW, et al. Invasive cribriform carcinoma of the breast: a clinicopathological analysis of 12 cases with review of literature. Int J Clin Exp Pathol. 2017;10: 9917-9924.5. Liu J, Zheng X, Han Z, Lin S, Han H, Xu C. Clinical characteristics and overall survival prognostic nomogram for invasive cribriform carcinoma of breast: a SEER population-based analysis. BMC Cancer. 2021;21: 168.6. Dobruch-Sobczak K, Roszkowska-Purska K, Chrapowicki E. Cribriform carcinoma mimicking breast abscess - case report. Diagnostic and therapeutic management. J Ultrason. 2013;13: 222-9.7. Zhang W, Lin Z, Zhang T, Liu F, Niu Y. A pure invasive cribriform carcinoma of the breast with bone metastasis if untreated for thirteen years: a case report and literature review. World J Surg Oncol. 2012;10: 251.8. Mishra S, Yadav K, Singh Anshul, Misra Vatsala, Chaudhary Kuldeep. Unusual case of Invasive Cribriform Carcinoma of Breast (ICC). JCR [serial online] 20219. Lopes Filho LL, Lopes IM, Lopes LR, Enokihara MM, Michalany AO, Matsunaga N. Mammary and extramammary Paget’s disease. An Bras Dermatol. 2015;90: 225-31.10. Günhan-Bilgen I, Oktay A. Paget’s disease of the breast: clinical, mammographic, sonographic and pathologic findings in 52 cases. Eur J Radiol. 2006;60: 256-63.

ABSTRACT.Squamous cell carcinoma (SCC) of the bladder is a rare urologic malignancy, estimated to affect 3% to 5% of the bladder. Squamous cell carcinoma (SCC) of the bladder remains the most common subtype throughout Africa. Most literatures focused on management of Transitional cell carcinoma(TCC) with fewer discussion in SCC management. TCC typically presents with painless hematuria, whereas SCC presents with painful hematuria, bladder mass, and necroturia. SCC is mostly radioresistant and does not respond to chemotherapy. The mainstay treatment is Partial Cystectomy or radical cystectomy, which can be performed through open surgery, laparoscopic or robot-assisted approach, all techniques with acceptable results. We report a case with favourable outcome following partial cystectomy which was managed by open surgery. In a 12months follow up the patient remained asymptomatic with good surgical outcome.

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INTRODUCTION:The posterior reversible encephalopathy syndrome (PRES) presents as focal neurological symptoms associated with neuroimaging of brain edema, frequently evolving toward remission. It typically manifests as a transient episode of encephalopathy, seizures, and visual disturbances within specific patient populations. Originally described in patients with autoimmune conditions, it also occurs in solid organ transplant (SOT) recipients, possibly due to the effect of immunosuppressive drugs (ISDs). [1] In these conditions, presumed damage to the blood-brain barrier results from endothelial dysfunction caused by exposure to the toxic effects of these agents, or is precipitated by cerebrovascular dysregulation following acute hypertension. [2]Common brain magnetic resonance image (MRI) patterns associated with PRES include vasogenic brain edema in the white matter, with a dominant parieto-occipital pattern, bilateral watershed pattern, or superior frontal sulcus pattern. However, atypical localizations such as frontal, temporal, basal ganglia, brainstem, or cerebellar involvement can also occur. Recently, a bilateral occurrence of basal vasogenic brain edema outlining the lentiform nucleus, known as the ’lentiform fork sign’ (typically described as a reliable sign of uremic encephalopathy), has been identified in patients experiencing PRES without metabolic disturbances. [4-7]In this report, we present a case of a recent bilateral lung and liver transplant recipient with a diagnosis of cystic fibrosis who experienced his first-ever seizure episode, reflecting PRES with an atypical neuroimaging pattern, including the lentiform fork sign.

IgG4 Related Disease: case report and 6-year follow up of an elusive diagnosis mimicking malignancySara Melo Oliveira1, Inês Trigo1, Ana Sofia Oliveira1, Isabel Gomes1, Rita Neto Lopes11Family Health Unit of Barrinha, Esmoriz, ACeS Baixo-Vouga, Aveiro, PortugalCorrespondence: Sara Melo Oliveira, Family Health Unit of Barrinha, ACeS Baixo-Vouga, Aveiro, Portugal. Email:sara.portu@gmail.comKey Clinical Message: IgG4-related disease is a rare and emerging pathology, characterized by the appearance of pseudotumors. Due to the ability to mimic other pathologies, it is essential to consider it as a differential diagnosis in multisystemic processes. The diagnosis is challenging, requiring a multidisciplinary approach, to minimize the associated morbidity and mortality.Abstract: IgG4-related disease (IgG4-RD) is a rare, emerging, systemic and chronic pathology,characterized by the appearance of pseudotumors resulting from tissue infiltration by IgG4-positive plasmablasts that promote eosinophilic inflammation of the tissue with subsequent fibrosis. We present the case of a male, 45-year-old patient, who consulted his Family Health Unit with complaints of postprandial discomfort in the left hypochondrium with a feeling of fullness, weight loss, chronic fatigue and hyperhidrosis that had lasted for a month. During physical examination, he was pale, and had pain at palpation of the left hypochondrium. Laboratory data showed increased inflammation markers, abdominal ultrasound and CT demonstrated numerous enlarged lymph nodes in the upper quadrants, raising concern for a malignant lymphoproliferative process. Laparoscopic excisional biopsy revealed features of IgG4-related lymphadenopathy and excluded malignant lymphoproliferative disease. The increase in serum IgG4 supported the final diagnosis of IgG4-RD.Keywords: IgG4-related disease; Pseudotumor; Immune-mediated; Systemic; Chronic.FUNDING INFORMATION: This work did not receive any type of financial support from any entity in the public or private domain.CONFLICT OF INTEREST STATEMENT: The authors have no conflicts of interest to declare.DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available from the corresponding author upon reasonable request.ETHICS STATEMENT: All procedures performed in this case were in accordance with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.CONSENT: Written informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policy.PATIENT PERSPECTIVE: The patient was anxious and worried about his health condition, mainly due to the possibility of a neoplastic disease. However, he felt calmer as soon as he was informed about the diagnosis and experienced symptomatic improvement after starting treatment. During the follow-up, he remained cooperative and assiduous in regular consultations.ORCID: Sara Melo Oliveira:https://orcid.org/0000-0003-0649-2694

TITLENeuroendocrine tumor mimicking a recalcitrant vocal fold granuloma: appearances can be deceiving

Introduction: Pulse field ablation (PFA) is a new technology that has been approved for the isolation of pulmonary veins in paroxysmal and persistent atrial fibrillation. Using PFA for targetting extra pulmonary sites combined with ultrahigh density 3D electroanatomic mapping (EAM) is an innovative approach that has been reported as single center

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Massive malignant phyllodes tumor accompanied by anemia and ulceration in the breast: A case reportAttention:Written informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policy.[Abstract] Large malignant breast phyllodes tumors are uncommon in clinical settings. Here, we report such a case to provide a reference for clinical work. A 48-year-old woman discovered a lump in her right breast, which eventually grew to 25 cm by 10 cm and began to rapidly bleed and ulcerate within 3 months. The patient had visible signs of anemia and significant emaciation as a result of the tumor’s wasting effect and the protracted course of the disease. The patient underwent modified radical mastectomy on the right breast. The pathology results obtained after surgery revealed a malignant phyllodes tumor. No adjuvant therapy, such as chemotherapy or radiation, was administered. The patient had no symptoms of tumor recurrence and complications from the surgery after a follow-up of 9 months.[Keywords] Breast cancer; Malignant phyllodes tumor; Diagnosis; Complications; Pathology1.IntroductionPhyllodes tumors of the breast (PTB), formerly known as ”cystosarcoma phyllodes,” are relatively rare in clinical practice, and they account for 0.3%–1% of breast tumors[1]. According to the histological features, the World Health Organization currently divides PTB into three categories, namely benign, borderline (also known as low-grade malignant PTB), and malignant (also known as high-grade malignant PTB)[2]. PTB rarely affects men, and typically affects women between 40 and 50 years of age[3]. In most cases, the clinical signs are unilateral, typically exhibited as a painless mass, and there may be a history of quick growth.The high-risk factors and pathogenesis of PTB are currently unclear. There are hypotheses suggesting that PTB originates from fibroadenomas, but there is still a significant debate[4]. High estrogen status may also be an independent pathogenic factor for PTB[5]. This tumor is a fibroepithelial tumor that contains both stromal and epithelial components. Reduction of the epithelial component is associated with greater malignancy. The characteristics of phyllodes tumors are composed of proliferative stroma accompanied by elongated fissure-like gaps, with the surface of the gaps covered by epithelium. Chromosomal changes are associated with the malignant phenotype of PTB. In borderline and malignant PTB, chromosome 1q amplification is common, and as the degree of amplification increases, malignant behavior increases[6, 7].Phyllodial breast tumors are generally rare, however, their incidence rates have increased in recent years. The clinical manifestations of phyllodial tumors lack specific characteristics but include insidious onset, slow progression, a long medical history, and the main manifestation being rapid growth of painless masses in the affected breast. These characteristics make it difficult to determine the nature of phyllodial tumors without surgery. In the present study, we report a case of a giant malignant phyllodial tumor and emphasize the importance of ”detect, diagnose, and treat early” to avoid serious complications.Case presentation 2.1 Background of the caseA 48-year-old woman with a right breast tumor was admitted to the hospital on February 2, 2023. Six years ago, the patient discovered the tumor in her right breast by chance. The tumor was left untreated and showed no signs of redness, swelling, pain, or ulceration. Three months ago, following a COVID-19 infection, the right breast’s lump rapidly grew, accompanied by bleeding and ulceration but without purulent secretion.2.2 Physical examination and laboratory testsPhysical examination of the patient revealed pale nail beds on both hands, pale eyes, and an anemic face. The skin in the right breast’s lateral quadrant was pigmented, with surface ulceration and bleeding, and the right breast was noticeably bigger than the left one. The left breast showed no signs of skin redness, swelling, nipple depression, dimples, or orange peel sign. The right breast was noticeably enlarged, and the tumor measuring roughly 25 cm by 10 cm protruded from the skin (Figures 1 and 2). The left breast did not have any discernible bulk. There were no swollen lymph nodes palpable in the bilateral supraclavicular area or left armpit, but there was a lymph node measuring roughly 2 cm by 1 cm in the right armpit. Ultrasound examination revealed a mixed echogenic mass of approximately 20 cm by 5.2 cm in the right breast. Blood flow signals were present within the bulk, and the boundary was clearly defined despite the uneven shape. In addition, ultrasound indicated hyperplastic alterations in the left breast. The left axillary region did not appear to have any noticeable anomalous lymph nodes. The right armpit revealed many lymph nodes, and the largest one was 1.6 cm by 0.6 cm in size and had a thicker cortex compared with the normal cortex. Ultrasonography of the right breast tumor indicated that the lesion was BI-RADS4 class 4b (Figure 3). Positron emission tomography–computed tomography (PET-CT) was also performed, and the right breast mass could not be ruled out as a phyllodes tumor with malignant transformation due to (1) its heterogeneous metabolism and mixed density; (2) elevated metabolism of lymph nodes situated in the right axilla and behind the pectoralis major and minor muscles, possibly suggesting the presence of metastasis; (3) slight inflammation in the upper and lower lobes of both lungs; an inflammatory small nodule in the upper lobe of the right lung; localized emphysema in the upper lobe of the right lung; and anemia. Puncture pathology of the right breast fibroepithelial tumor did not show any conclusive indications of malignancy. Because fibroepithelial tumors are heterogeneous and biopsy tissue is limited, it is important to integrate clinical information and, if necessary, perform full lesion resection. Owing to the tumor’s massive size and ulceration, the patient’s blood routine test revealed mild anemia (hemoglobin, 75 g/L) and infection (white blood cell count, 13.68×109/L). Hemoglobin level reached 99 g/L following a 400 mL leukocyte-free suspended red blood cell transfusion and using cephalosporin drugs to treat inflammation.2.3 TreatmentPreoperative diagnosis was a right breast phyllodes tumor (high likelihood of malignancy), and right axillary lymph node metastasis was highly probable. A modified radical mastectomy of the right breast was carried out (Figure 4). About 40 mL of blood was lost during the successful procedure.General morphology of surgical specimens: There was a large lobulated mass in the breast tissue (22 cm × 21 cm × 7.5 cm), with a solid and tough cut surface. The total volume of the breast and axilla measured 24 cm × 23 cm × 8 cm; the area of the spindle skin measured 24 cm × 17 cm; and the diameter of the nipple was 1.8 cm. The breast did not contain any normal glands. The tumor was located 0.1 cm from the superficial fascia. Locally, the tumor affected the skin. A single adipose tissue mass of 8 cm × 7 cm × 2 cm was discovered, and 25 lymph nodes with a diameter of 0.3–2 cm were palpable inside the mass. Microscopic examination (Figure 5) showed a 22 cm × 21 cm × 7.5 cm malignant phyllodes tumor in the right breast. Low-grade fibrosarcoma, characterized by localized ossification, intrusion into the duct to generate papilloma-like morphology, and myofibroblastic differentiation, constituted the sarcoma component. The tumor lacked a distinct capsule, most of which exhibit expansion and progressive growth, local skin invasion, and formation of skin ulcers. The tumor cells showed a wide range of morphologies, including myxoid, sparse, dense, and collagenized cells, and presented mild to severe atypia. Mitotic figures were found in 1–7/10 HPFs. No tumor metastases were found in the axillary lymph nodes, and there was no tumor infiltration of the papillary or superficial fascia (0/25). The postoperative pathological(Figure 6) diagnosis was a malignant breast phyllodes tumor. Immunohistochemistry: -3: CK5/6(−), CKpan(−), SATB2(+), ER(−); -8: Ki-67 (+20%), β-catenin (membrane +), CKpan (−), CD34 (+), CD31 (blood vessels +); -11: Ki-67 (+10% to 20%), Desmin (−), Calponin (foci+), S-100 (−), β-catenin (membrane +).2.4 Outcome and follow-upAfter surgery, the patient made a full recovery. Half a month after the operation, hemoglobin level improved (92 g/L), and no adjuvant therapy, such as chemotherapy or radiation, was administered. At a follow-up 9 months after surgery, the patient has not experienced any associated problems or indications of tumor recurrence thus far.

Introduction Choriocarcinoma is a rare form of gestational trophoblastic neoplasia, which occurs in approximately 1 in 20,000-40,000 pregnancies. About half of choriocarcinomas occur after molar pregnancies, rest can occur after a spontaneous abortion, ectopic pregnancy, or a term pregnancy.1Choriocarcinoma arises from villous trophoblast and placental-site trophoblastic tumors from the interstitial trophoblast. In addition to the uterus, choriocarcinoma may also develop in the fallopian tubes, liver, lungs, spleen, kidneys, colon, and brain.1It is characterized by a propensity to metastasize rapidly to various distant sites, particularly the lungs (94%), vagina (44%), and liver (28%). Intracranial metastases from choriocarcinoma are uncommon and cerebral intratumoral haemorrhage resulting from metastatic choriocarcinoma is an even rarer entity, especially in the young.2, 3, 4 Structural lesions such as arteriovenous malformations and aneurysms are typically the cause of lobar intracerebral hemorrhage (ICH), whereas hypertension is typically the cause of non-lobar ICH in young people.5Even though choriocarcinoma is highly aggressive, it is very responsive to chemotherapy.1, 6 Therefore, the importance of early detection cannot be over-emphasized.3 We present three cases of choriocarcinoma with brain metastases who presented with intracranial hemorrhage. The case series is to draw attention to metastatic choriocarcinoma as a cause of unexplained intracerebral hemorrhage in women of childbearing age.

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A rare case of Non-lupus full house nephropathy in a transplanted kidney, case report:Ahmad Matarneh(1), Omar Salameh(2), Sundus Sardar(1), Amanda Karasinski(1), Theja Channapragada(2), Muhammad Abdulbasit(1), Erik Washburn(3), , Nasrollah Ghahramani(1)Affiliations: 1. Department of nephrology, Penn state Milton S Hershey Medical Center, United States of America2. Department of Internal Medicine, Penn state Milton S Hershey Medical Center, United States of America3. Department of pathology, Penn state Milton S Hershey Medical Center, United States of AmericaCorresponding authorAhmad MatarnehAffiliation: Penn State health , Milton S.hershey medical centerContact: Email ahmadmatarneh99@gmail.comPhone # 717-708-6754Keywords:Autoimmune disorders, Systemic lupus erythematosus, Transplant rejection. Full house nephropathyAbstract:Non lupus full house nephropathy is a rare entity with an unclear incidence. It describes the kidney biopsy findings of positive deposits for IgG, IgA, IgM, C3, C1q on immunofluorescence in the absence of the classical diagnostic features of systemic lupus nephritis. This disease entity is becoming more recognised but further studies are still needed to evaluate the incidence, etiologies and management of this condition. Transplant glomerulopathy is a major cause for renal graft loss. It can present with a wide variety of manifestations; It can cause AKI, CKD or glomerular inflammations through an immune complex or autoimmune mediated damage.Introduction:Non lupus full house nephropathy is defined as having the classical findings of lupus nephritis which are positive deposits for IgG, IgA, IgM, C3, C1q on immunofluorescence but without the other extra-renal or seologic manifestations needed for SLE diagnosis i.e ACR criteria.(1) Systemic lupus erythematosus is a multi-system autoimmune disorder. It can involve several organs with variable presentations. The diagnosis of SLE is mainly based on establishing the presence of >= 4 points of the American College of Rheumatology criteria. (2) Lupus nephritis is the renal manifestation of SLE, it can have a wide range of manifestations which can include AKI, nephrotic or nephritic syndrome secondary to glomerulonephritis or it can ultimately lead to ESRD. Kidney biopsy remains the gold standard test to diagnose and to guide the treatment of lupus nephritis. Classical kidney involvement in SLE is based mainly on the pattern of histological involvement and it is divided into several classes according to the international society of nephrology. (3) Transplant rejection remains a huge challenge to both patients and treating physicians, it can result in variable degree of kidney dysfunction and ultimately it might lead to graft loss.(4) Several risk factors for transplant rejection have been described in literature and certainly, autoimmune diseases remain high on the list.(5) We hereby report a patient who presented with nephrotic syndrome and was found to have de-novo non lupus full house nephropathy in the transplanted kidney.Case presentation: Patient is a 57-year-old female with a past medical history of End-Stage Renal Disease that was managed with a living unrelated kidney transplant in 2016, Hypothyroidism, and Type 1 Diabetes Mellitus (T1DM) managed with an insulin pump. The patient underwent a living unrelated kidney transplant in 2016 with significant post-transplant complications with ureteral strictures. Initially, she was managed by nephrostomy followed by multiple indwelling stent exchanges. However, stents were repeatedly colonized with multiple bacterial and candida infections, requiring antibiotic and antifungal therapy. Due to recurrent acute infections mycophenolate mofetil was held and she had a stent removal in an attempt to decrease her risk of UTI’s.She presented to an outside hospital with a 1-week history of progressively worsening generalized headaches, nausea/vomiting, and elevated home blood pressures. Her blood pressure was noted to be 200/120. Initial labs were notable for hemoglobin of 8.5g/dl, blood urea nitrogen (BUN) of 82 mg/dL, and creatinine of 3.35mg/dL, with baseline creatinine 2.2-2.5mg/dL.Physical exam on presentation was significant for +1 lower extremity edema, with the remainder of the physical exam within normal limits, Patient was afebrile and BP was noted to be 171/81 mmHg.Investigations:Labs notable for potassium 6.1 mEq/L, chloride 116 mEq/L, bicarbonate 18 mmol/L, blood urea nitrogen (BUN) 82 mg/dL, creatinine 3.64 mg/dL, phosphorus 6.0 mg/dL, hemoglobin 8.7 g/dl, and platelets 148. VBG showed pH 7.240, PCO2 41, PO2 42, bicarbonate 17.6. Blood, urine, and fungal cultures were normal. A urine protein/creatinine (PCR) ratio was 12.74, consistent with nephrotic range proteinuria. (Table 1)Table 1. Laboratory investigations.Ultrasound retroperitoneal revealed hydronephrosis in the right lower quadrant, transplant kidney with urothelial and collecting system thickening, stable from the previous ultrasound one month prior. Given the patient’s history of prior urethral stricture, however, she had a right ureteral stent placed with the urology team. Following stent placement, however, the patient’s urine output was less than 200cc, and her creatinine rose to 3.9.An additional renal ultrasound with doppler was done to evaluate blood flow through the transplanted kidney, revealing increased renal artery resistive indices of 0.93 and associated high resistance arterial waveform, concerning for chronic rejection. While CMV/BK and donor-specific antibiotics were negative, Further immunological workup was done revealing positive Antinuclear Antibody (ANA) but negative anti-double stranded DNA (anti-dsDNA) and anti-smith antibody (Sm). C3 was borderline low and C4 was normal. Additional workup for membranoproliferative glomerulonephritis, including hepatitis B and C serologies, were negative. there were still concerns about rejection, and the patient underwent a renal biopsy with interventional radiology. The preliminary read from the biopsy was concerning T-cell kidney transplant rejection versus membranoproliferative glomerulonephritis versus lupus nephritis.The final read of the biopsy demonstrated membranoproliferative glomerulopathy, immune complex-mediated with rare cellular crescents, and foci of fibrinoid necrosis. The full-house immunofluorescence staining suggests lupus nephritis as a possible etiology. Mild tubulitis and interstitial mononuclear inflammation meet the criteria for borderline/suspicious for acute T-cell mediated rejection. (Figures 1-5)She was diagnosed as a case of chronic rejection with immune complex deposition disease. She was treated with 1 gram of intravenous methylprednisolone once and transitioned to 60 mg oral prednisone once daily throughout the remainder of the course and at discharge. Her BUN continued to rise in the setting of steroid use, as high as 178 mg/dL at discharge.. In addition, patient developed hypoalbuminemia with associated anasarca. Her anasarca was managed with a bumetanide drip that was transitioned to intermittent dosing of 2 mg bumetanide on discharge. The patient’s urine output increased to over 1L with diuretics, with creatinine levels down trending. On discharge, the patient’s creatinine was 2.98 mg/dL.Outcome:The patient was followed up in the transplant nephrology clinic two weeks after discharge. Creatinine improved to 2.63 mg/dL. Proteinuria decreased to 5.7 with a 50% reduction from hospital admission. Patient’s lower extremity swelling decreased significantly. She was maintained on tacrolimus 2 mg twice daily, MMF 500 mg twice daily. Given the biopsy findings and her improvement of her creatinine and proteinuria degree it was decided to continue treatment as an underlying chronic rejection.Discussion: Glomerulonephritis remains one of the leading causes of renal graft loss following kidney transplant.(6) The incidence is widely variable and differs between studies. Recurrent and de-novo glomerulonephritis following kidney transplant are not uncommon and have been described as a cause of renal graft loss and/or dysfunction. Recurrence of GN is typically more common than de-novo processes.(7) GN is one of the main causes of renal graft loss after kidney transplant, according to one of the studies it was noted that recurrence of GN was the third most common cause of renal graft loss. (8) De-novo disease is defined as any new disease process that occurs in the kidney graft unrelated to the primary kidney disease. De-novo disease can have a variable presentation as it can manifest as acute, subacute to chronic with manifestations usually arising from glomerulonephritis, tubulointerstitial nephritis or vascular disease. The incidence of de-novo GN is unclear and has been hypothesized to be occurring in 4-20% of transplant recipients.(9) Most common patterns of GN are FSGS, MGN, MPGN. (10) Transplant glomerulopathy remains one of the major debilitating conditions that transplant patients deal with. It can present with a chronic or acute rejection picture in the form of steady rise in creatinine and GN pattern of injury. (11) Systemic lupus nephritis is a chronic inflammatory autoimmune condition that can affect multiple organs with variable presentations. Diagnosis is usually based on the classical serologic and extra renal criteria. (12)Lupus nephritis is one of the serious manifestations of SLE, it is defined as the presence of significant proteinuria and classical findings on kidney biopsy. Classical kidney biopsy findings of lupus nephritis under light microscopy are I. minimal mesangial, II. Proliferative mesangial, III. Focal proliferative, IV. Diffuse proliferative, V. membranous and VI. Sclerosing. One of the relatively specific findings on direct immunofluorescence on kidney biopsy is finding deposits positive for IgG, IgA, IgM, C3 and C1q, a pattern that is usually referred to as the full house pattern. (13) This finding is relatively specific for lupus nephritis however, in order to establish the diagnosis of SLE, the ACR criteria must be met.(14) Non lupus nephritis describes the classical IF findings of LN but without the clinical or serological evidence of lupus. It is a newly developing entity and that means further studies are still needed to better understand the incidence and its exact pathophysiology and presentations. (15)Kidney transplant remains the gold standard treatment for ESRD. It has shown to improve both quality of life and survival in comparison to renal replacement therapies. (16) Transplant rejection occurs as a result of the body’s own immune system creating antibodies against the alloantigen from the transplanted kidney. (17) The response can be variable in intensity and onset, it ranges from hyperacute which can happen within minutes of transplant and is usually related to preformed antibodies or ABO mismatch. Acute rejection occurs any time following transplant and is subclassified depending on the underlying factor and immune mechanism to antibody mediated rejection (ABMR), which usually happens as a result of donor specific alloantibodies damaging the kidney causing peritubulitis/capillaritis. And acute T-cell mediated rejection (TCMR_ which is characterized by lymphocytic infiltrate into tubules, interstitium and arterial intima. Chronic rejection on the other hand usually occurs after 3 months and can be as a result of chronic T cell mediated or chronic antibody mediated. (18)Risk factors for transplant rejection include: HLA mismatch, Positive B cell crossmatchAdvanced age of the donor type of transplant and inadequate immunosuppression. (19) Patients with rejection present differently, any increase in creatinine more than 25% of the baseline or the presence / worsening of proteinuria should raise the suspicion for rejection. Kidney biopsy might be warranted if transplant rejection is suspected as it would guide the management and further prognosis. (20)There has been no cases in literature describing the presence of non-lupus-full house nephropathy in the setting of post kidney transplant, we hypothesize that it might be related to circulating immune complex mediated damage to the transplant kidney possibly in the setting of chronic rejection. The point of interest in this condition and in our case in particular is that the patient was treated mainly for the possible underlying rejection with resuming mycophenolate and optimizing tacrolimus with institution steroids which lead to improvement in her kidney parameters and more than 50% drop in the degree of proteinuria. This further suggests that the possible underlying mechanism is related to the rejection process causing the non lupus pattern and nephrotic syndrome.Conclusion: Non lupus full house nephropathy is rare and is poorly understood. It has been described in association to several conditions however, There has been no data describing the associated post kidney transplant and rejection. Non lupus full house nephropathy can occur in the setting of kidney transplant and it might be related to transplant rejection. We wanted to raise awareness about this condition and possible association in transplant recipients as it carried out a worse prognosis and can lead to loss of graft function, also, to describe the methods in the diagnosis and a proposed treatment regimen.References:• Silva MD, Oliveira PV, Vale PH, Cunha RD, Lages JS, Brito DJ, Salgado Filho N, Guedes FL, Silva GE, Santos RF. Non-lupus full-house nephropathy: a case series. Brazilian Journal of Nephrology. 2020 Nov 11;43:586-90. • Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. Journal of clinical pathology. 2003 Jul;56(7):481. • Ayoub I, Cassol C, Almaani S, Rovin B, Parikh SV. The kidney biopsy in systemic lupus erythematosus: a view of the past and a vision of the future. Advances in chronic kidney disease. 2019 Sep 1;26(5):360-8. • Vaillant AA, Mohseni M. Chronic Transplantation Rejection. InStatPearls [Internet] 2023 Jan 1. StatPearls Publishing. • Neuberger J. Incidence, timing, and risk factors for acute and chronic rejection. Liver transplantation and surgery: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 1999 Jul 1;5(4 Suppl 1):S30-6. •Allen PJ, Chadban SJ, Craig JC, Lim WH, Allen RD, Clayton PA, Teixeira-Pinto A, Wong G. Recurrent glomerulonephritis after kidney transplantation: risk factors and allograft outcomes. Kidney international. 2017 Aug 1;92(2):461-9.• • Jafari R, Mehrazma M, Vahedi M, Ossareh S. Prevalence and Prognosis of Post-transplant Glomerulonephritis in Kidney Transplant Biopsies, A Single-Center Report. Iranian Journal of Kidney Diseases. 2023 Mar 1;17(2):92. • Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonephritis. New England Journal of Medicine. 2002 Jul 11;347(2):103-9. • Abbas F, El Kossi M, Jin JK, Sharma A, Halawa A. De novo glomerular diseases after renal transplantation: How is it different from recurrent glomerular diseases?. World Journal of Transplantation. 2017 Dec 12;7(6):285. • Hariharan S, Adams MB, Brennan DC, Davis CL, First MR, Johnson CP, Ouseph R, Peddi VR, Pelz CJ, Roza AM, Vincenti F. RECURRENT AND DE NOVO GLOMERULAR DISEASE AFTER RENAL TRANSPLANTATION: A Report from Renal Allograft Disease Registry (RADR): 1, 2. Transplantation. 1999 Sep 15;68(5):635-41. • Filippone EJ, McCue PA, Farber JL. Transplant glomerulopathy. Modern Pathology. 2018 Feb 1;31(2):235-52. • Gill JM, Quisel AM, Rocca PV, Walters DT. Diagnosis of systemic lupus erythematosus. American family physician. 2003 Dec 1;68(11):2179-87. • Musa R, Brent LH, Qurie A. Lupus nephritis. • Anders HJ, Saxena R, Zhao MH, Parodis I, Salmon JE, Mohan C. Lupus nephritis. Nature reviews Disease primers. 2020 Jan 23;6(1):7. • Wani AS, Zahir Z, Gupta A, Agrawal V. Clinicopathological pattern of non-lupus full house nephropathy. Indian Journal of Nephrology. 2020 Sep;30(5):301. • Braun MM, Khayat M. Kidney Disease: End-Stage Renal Disease. FP essentials. 2021 Oct 1;509:26-32. • Halloran PF, Einecke G, Sikosana ML, Madill-Thomsen K. The biology and molecular basis of organ transplant rejection. InPharmacology of Immunosuppression 2022 Jan 29 (pp. 1-26). Cham: Springer International Publishing. • Wood KJ, Goto R. Mechanisms of rejection: current perspectives. Transplantation. 2012 Jan 15;93(1):1-0. • Oweira H, Ramouz A, Ghamarnejad O, Khajeh E, Ali-Hasan-Al-Saegh S, Nikbakhsh R, Reißfelder C, Rahbari N, Mehrabi A, Sadeghi M. Risk factors of rejection in renal transplant recipients: a narrative review. Journal of Clinical Medicine. 2022 Mar 3;11(5):1392. • Williams WW, Taheri D, Tolkoff-Rubin N, Colvin RB. Clinical role of the renal transplant biopsy. Nature Reviews Nephrology. 2012 Feb;8(2):110-21.Acknowledgments: We thank the nephrology department at penn state health for giving us the opportunity and support to conduct this workAuthor contribution: Ahmad Matarneh: Manuscript writing, literature review, Clinical careOmar salameh Manuscript writing, literature review, Clinical careSundus sardar Manuscript writing, literature review, Clinical careTheja Channapragada Manuscript writing, literature review, Clinical careMohammad Abdulbasit Manuscript writing, literature review, Clinical careAmanda Karasinsk iManuscript writing, literature review, Clinical careErik Washburn HistopathologyNasrollah ghahramani: Clinical care, literature review, manuscript write up, MentorConsent: Verbal informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policyConflict of interest The authors associated with the this case report have no actual or possible conflict of interest to declareDate availability statement: The data that support the findings of this study are available on request from the corresponding authorFunding: The funding process is solely done from the writing authors

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