Drug-induced sarcoidosis-like reaction three months after BNT162b2 mRNA COVID-19 vaccination: A case report and review of literature.

BACKGROUND: A 70-year-old man with hepatitis C virus-related recurrent hepatocellular carcinoma was admitted for further diagnosis of a 1 cm iso-hyperechoic nodule in segment (S) 5. CASE SUMMARY: Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) revealed the nodule in S5 with a defect at the hepatobiliary phase, hyperintensity on diffusion weighted imaging (DWI) and hypointensity on apparent diffusion coefficient (ADC) map. Contrast-enhanced computed tomography revealed hypervascularity at the early phase, and delayed contrast-enhancement was observed at the late phase. Contrast-enhanced ultrasound (US) revealed incomplete defect at the late vascular phase. Inflammatory liver tumor, lymphoproliferative disease, intrahepatic cholangiocarcinoma (small duct type) and bile duct adenoma were suspected through the imaging studies. US guided biopsy, however, showed a noncaseating hepatic sarcoid-like epithelioid granuloma (HSEG), and histopathological analysis disclosed spindle shaped epithelioid cells harboring Langhans-type multinucleated giant cells. One month after admission, EOB-MRI signaled the disappearance of the defect at the hepatobiliary phase, of hyperintensity on DWI, of hypointensity on ADC map, and no stain at the early phase. CONCLUSION: That the patient had received BNT162b2 messenger RNA (mRNA) coronavirus disease 2019 vaccination 3 mo before the occurrence of HSEG, and that its disappearance was confirmed 4 mo after mRNA vaccination suggested that the drug-induced sarcoidosis-like reaction (DISR) might be induced by the mRNA vaccination. Fortunately, rechallenge of drug-induced DISR with the third mRNA vaccination was not confirmed.

Distant metastasis of hepatocellular carcinoma to Meckel's cave and cranial nerves: A case report and review of literature.

BACKGROUND: Metastasis occurs as a late event in the natural history of hepatocellular carcinoma (HCC), and most patients die of liver failure attributed to the tumor supplanting the liver. Conversely, the brain is a less common metastatic site. CASE SUMMARY: We describe a rare case of hepatitis C virus-related multiple HCC metastasizing to the cavernous sinus, Meckel's cave, and the petrous bone involving multiple cranial nerves in an 82-year-old woman. At admission imaging studies including Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (MRI) revealed multiple HCC nodules in both right and left lobes. Ultrasound guided biopsy of the left lobe revealed moderately differentiated HCC. Molecular targeted therapy with Lenvatinib (8 mg/d for 94 d, per os) and Ramucirumab (340 mg/d and 320 mg/d, two times by intravenous injection) were administered for 4 mo, resulting in progression of the disease. Three months after the start of molecular target therapy, the patient presented with symptoms of hyperalgesia of the right face and limited abduction of the right eye, indicating disturbances in the right trigeminal and abducens nerves. Brain MRI disclosed a mass involving the cavernous sinus, Meckel's cave and the petrous bone. Contrast-enhanced MRI with gadolinium-chelated contrast medium revealed a well-defined mass with abnormal enhancement around the right cavernous sinus and the right Meckel's cave. CONCLUSION: The diagnosis of metastatic HCC to the cavernous sinus, Meckel's cave, and the petrous bone was made based on neurological findings and imaging studies including MRI, but not on histological examinations. Further studies may provide insights into various methods for diagnosing HCC metastasizing to the craniospinal area.

[A case of gastric carcinoma with peritoneal metastasis successfully treated by combination chemotherapy of S-1 and cisplatin].

This case is a 69-year-old woman. We diagnosed gastric cancer and cholecystolithiasis by close inspection of abdominal pain. Because preoperative diagnosis was T2N0M0, Stage I B, we performed an operation. Many lesser tubercles were shown, and were diagnosed as peritoneal metastases pathologically. The tumor in corpus ventriculi infiltrated out of gastric serosa. We judged that curative resection was impossible and finished the operation after giving an intra-abdominal dosage of cisplatin(CDDP)at 85mg. After operation, 3 courses of performed S-1/CDDP combination chemotherapy were performed. Because we observed contraction of the main lesion and could not point out the peritoneal metastases and ascitis, we performed a second look operation. All the nodules found with peritoneal and rectouterine excavation had disappeared and we performed distal gastrectomy. The postoperative diagnosis was pT2(MP), pN0CY0, Stage I B, Cur A, therapy grade 1a. Chemotherapy does succeed, and this is a valuable case in which a radical operation could be performed.

[S-1-based chemotherapy for recurrent gastric cancer with peritoneal dissemination resulting in long-term survival--report of a case].

A 52-year-old man underwent distal gastrectomy for gastric cancer in July 2000. In July 2005, abdominal CT and barium study of the colon revealed peritoneal recurrence, and chemotherapy of S-1 was started. Within 2 courses, the serum CEA level increased, so combination chemotherapy of S-1 and cisplatin (CDDP) was begun. After 7 courses, the regimen was switched to S-1+paclitaxel (PTX). However, the patient developed digital numbness within 8 courses and single-agent chemotherapy with S-1 was restarted. In July 2007, he developed abdominal distension, and abdominal CT showed a large amount of ascites. S-1+CDDP was administered again, however, and we had to change the regimen within 3 courses due to fatigue and appetite loss. S-1 was restarted, but soon severe fatigue and appetite loss restricted the use of chemotherapeutic agents, and he died in December. This patient had been alive for 2 years and 5 months since peritoneal recurrence was diagnosed. We concluded that S-1-based sequential chemotherapy was effective for recurrent gastric cancer.

[A case of gastric carcinoma with lung and liver metastasis successfully treated by mFOLFOX6].

The case is a 66-year-old woman. CT showed multiple metastasis of the liver and lung after operation by colectomy for ascending colon carcinoma. A close inspection showed progressive stomach cancer with lymph node metastasis. Metastasis was considered an effect when it was of colon cancer origin, and treatment by mFOLFOX6 was started. In the results, we confirmed contraction of the liver and lung metastasis and contraction of the regional lymph node metastasis of the stomach by CT. The gastric cancer lesion became only a cicatrix with endoscopic examination. For gastric cancer, the availability of mFOLFOX6 was suggested.

[Resection of cancer of the cardia enabled by combined treatment with S-1 and paclitaxel after esophageal stenting for impaired patency complicating stage IV gastric cancer - a case report].

The patient was a 47-year-old man who was discovered to have Borrmann type 4 cancer of the cardiac region of the stomach associated with esophageal invasion during upper GI endoscopy and was histopathologically diagnosed with poorly-differentiated adenocarcinoma. Invasion of the aorta was suspected based on a CT examination, and resection was judged to be impossible. Since the tumor was associated with impaired patency, after first inserting a metallic stent, the patient was treated with 4 cycles of S-1 100 mg/body for 2 weeks and paclitaxel (PTX) 120 mg/body by intravenous drip infusion on days 1 and 15 for 2 weeks followed by a 2-week rest period. The tumor regressed considerably, and total gastrectomy and lower esophagectomy with D1+ a lymph node resection through a left thoracolaparotomy became possible. A bypass operation or palliative resection is sometimes performed when complicated by impaired patency. In our patient, after achieving an improvement in QOL by stenting, resection became possible as a result of a response to chemotherapy with S-1. However, when considering resection after chemotherapy it seemed necessary to be careful to insert the stent as close as possible to the proximal margin of the tumor so as not to broaden the extent of the esophageal resection.

Comparative analysis of the fate of donor dendritic cells and B cells and their influence on alloreactive T cell responses under tacrolimus immunosuppression.

We have shown that tacrolimus (TAC)-induced liver allograft acceptance is associated with migration and persistence of donor B cells and dendritic cells (DC). To clarify whether these MHC class II+ leukocytes have favorable roles in inducing tolerance, we analyzed recipient T cell reactions after allogeneic B or DC infusion. LEW rat B cells localized exclusively in BN host B cell follicles without any direct contact with host T cells. While few donor DC migrated to T cell areas and marginal zones, they were captured by host APC, suggesting that allogeneic MHC class II+ cells may induce immune reactions via the indirect pathway. Although DC-infused non-immunosuppressed recipients showed enhanced ex vivo anti-donor responses, persistent in vitro donor-specific hyporeactivity was seen equally with donor DC or B cell infusion under TAC. The results indicate that donor MHC class II+ APC are capable of regulating recipient immune reactions under TAC. Possible involvement of the indirect pathway of allorecognition is discussed.

FK778 and FK506 combination therapy to control acute rejection after rat liver allotransplantation.

BACKGROUND: In organ transplantation, several immunosuppressants are currently used to control graft rejection. Clinically, no single immunosuppressive agent can completely prevent posttransplantation immunoreaction; thus, combination therapy is usually performed. Novel agents with more powerful immunosuppressive activity and less toxicity need to be developed. METHODS: Lewis rat livers were orthotopically transplanted into Brown-Norway recipients. FK778 was administered orally from day 0 to day 6 to prevent acute rejection and from day 7 to day 13 to rescue ongoing rejection. To assess the combined effects, recipients were treated with intramuscular injection of FK506 and oral administration of FK778 from day 0 to day 6. Blood chemistry and histopathologic findings were measured to determine the patient's general condition and the graft condition. Allospecific antibodies were measured using enzyme-linked immunosorbent assays. The FK778 trough concentration was examined by using high-performance liquid chromatography. RESULTS: The acute immune response was suppressed by FK778 alone in a dose-dependent manner. The optimal FK778 dosage was determined to be 20 mg/kg per day, because adverse effects (weight loss and intestinal bleeding) occurred at 30 mg/kg per day. FK778 treatment from day 7 to day 13 rescued liver grafts from ongoing rejection. The intramuscular FK506 (0.125 mg/kg per day) injection and the oral FK778 (20 mg/kg per day) gavages suppressed acute liver graft rejection effectively and maintained better graft condition compared with monotherapy. CONCLUSIONS.: FK778 treatment effectively prevented acute rejection and rescued ongoing rejection after liver transplantation. The optimal dosage was determined to be 20 mg/kg per day. Combination therapy with FK506 was more beneficial than FK778 monotherapy.

Long-term function and morphology of intestinal autografts and allografts in outbred dogs.

Although small bowel transplantation (SBTx) has become a clinical option, there have been few studies of long-term function and histopathology of intestinal grafts. Unrelated mongrel dogs received autologous (n = 4) or allogeneic (n = 11) orthotopic SBTx under oral cyclosporine. Intestinal graft function and routine/immunohistopathology of full-thickness intestine were studied. Six allograft and all isograft recipients had comparable body weight gain and are currently alive (> 420 days). Five allograft recipients were sacrificed because of significant body weight loss and malnutrition at a median of 119 days. Analyses of intestinal function in long-surviving recipients revealed marginal reduction of D-xylose/cyclosporine absorption, intestinal transit time, in vitro muscle contractility, and mucosal enzyme activity compared with normal dogs. However, these changes were insignificant and no statistical difference was seen between auto and long-surviving allografts. In histopathological analysis, long-surviving allografts had normal mucosa with submucosal, muscularis propria, and perineural (Auerbach's plexus) inflammation. Five allorecipients with malnutrition had mucosal atrophy/erosion and significantly reduced intestinal absorption and motility. Thus, denervated intestinal allografts are able to efficiently digest and absorb nutrients to support life. Results also indicate that these allografts experienced low-grade chronic rejection as evidenced in the submucosa and muscle layers, despite the lack of clinical symptoms.

Morphology and function of canine small intestinal autografts: with particular interest in the influence of ex vivo graft irradiation.

The intestinal transplantation procedure obligates an early functional deficit in intestinal grafts. Graft irradiation has been used to modulate post-transplant immune reactions; however, irradiation may cause further deterioration of the function of the transplanted intestine. Using the canine model, we investigated the influence of the transplant procedures, with and without ex vivo graft irradiation, on early intestinal graft function and histopathology. Outbred hound dogs underwent autointestinal transplantation with (n=8) or without (n=5) 7.5 Gy ex vivo graft irradiation. Mucosal cytochrome P450 and P-glycoprotein, routine immunohistopathology, and intestinal absorptive function were studied. Weight gain was slow after surgery, but was comparable in the irradiated and nonirradiated groups. During the early post-transplant period, both groups showed defects in intestinal absorption, associated with decreased cytochrome P450 3A4 activity and reduced P-glycoprotein expression, regardless of graft irradiation. These changes returned to normal in both groups by day 28. Histopathologically, epithelial apoptosis showed a slight increase 1 hour after transplantation; however, there was no evidence of histopathologic abnormalities including arterial changes associated with irradiation. In addition, the frequency of T and B lymphocytes in the lamina propria were not significantly influenced by the transplant surgery or ex vivo irradiation. Thus, early after transplantation, intestinal function was impaired and effectiveness of orally administered immunosuppressive drugs was significantly altered. Graft irradiation did not induce further defects in intestinal function or cause histopathologic abnormalities.

Role of NF-kappaB on liver cold ischemia-reperfusion injury.

The role of NF-kappaB, the rapid-response transcription factor for multiple genes, in cold ischemia-reperfusion (I/R) injury was examined after syngeneic transplantation of liver grafts. Lewis rat recipients were killed 1-48 h after reperfusion of three different liver grafts: 1) uninfected control, 2) infected ex vivo with control adenoviral vector (AdEGFP), and 3) infected ex vivo with AdIkappaB. In uninfected control livers, NF-kappaB was activated biphasically at 1-3 and 12 h after reperfusion with aspartate transaminase (AST) levels of 4,244 +/- 691 IU/l. The first peak of NF-kappaB activation associated with an increase of mRNA for TNF-alpha, IL-1beta, and IL-10. AdEGFP transfection resulted in similar outcomes. Interestingly, AdIkappaB-transfected liver grafts suffered more severe I/R injury (AST >9,000 IU/l). Transfected IkappaB was detected in transplanted livers as early as 6 h, and this correlated with the abrogation of the second, but not the first, peak of NF-kappaB activation at 12-48 h and increased apoptosis. Thus inhibition of the second wave of NF-kappaB activation in IkappaB-transfected livers resulted in an increase of liver injury, suggesting that NF-kappaB may have a dual role during liver I/R injury.

Early passenger leukocyte migration and acute immune reactions in the rat recipient spleen during liver engraftment: with particular emphasis on donor major histocompatibility complex class II+ cells.

After a short course of tacrolimus, Lewis rat liver allografts induce donor-specific nonreactivity in Brown Norway recipients that is immunosuppression-independent after 28 days. To clarify the role of donor major histocompatibility complex (MHC) class II+ cells, we investigated the migration to the recipient splenic T- and B-cell compartments of different subsets of Lewis MHC class II+ passenger leukocytes. The rise and decline of immune activation were monitored in the hepatic allograft and in the host spleen by analyses of BrdU+ (proliferating) leukocytes, TUNEL+ (apoptotic) cells, apoptosis-associated molecules, TH1/TH2 cytokine profiles, and histoimmunocytochemical examination of graft and splenic tissues. Serial flow cytometry studies during the 28-day period of drug-assisted "hepatic tolerogenesis" showed that migratory MHC class II+ cells accounted for less than half of the donor cells in the host spleen. The class II+ cells consisted mostly of B cells that homed to splenic B-cell follicles with only a sparse representation of dendritic cells that were exclusively found in the splenic periarteriolar lymphoid sheath. In parallel studies, transplantation of the less tolerogenic heart produced a diminutive version of the same events, but with far fewer donor cells in the host spleen, evidence of sustained immune activation, and the development of chronic rejection by 100 days. The data are consistent with the paradigm that migration of donor leukocytes is the prime determinant of variable tolerance induction induced by transplantation of the liver and other organs, but without regard for donor MHC class II+ expression.