Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019.In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virusinfected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

PURPOSE: The purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers. MATERIALS AND METHODS: Patients with advanced solid tumors received standard therapy were given the study drug at escalating doses, using a 3+3 design. The study drug was orally administered on days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel was escalated from 60 to 420 mg/m2, and the dose of HM30181A was escalated from 30-210 mg/m2. RESULTS: A total of twenty-four patients were enrolled. Only one patient experienced a dose-limiting toxicity-a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained at a dose level of 300 mg/m2 and the area under the curve of plasma concentration-time from 0 to the most recent plasma concentration measurement of paclitaxel was reached at a dose level of 420 mg/m2. The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m2. The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease. CONCLUSION: The study drug appears to be well tolerated, and the effective plasma concentration of paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300 mg/m2.
Absorption ; Humans ; Maximum Tolerated Dose ; Neutropenia ; P-Glycoprotein* ; Paclitaxel* ; Pharmacokinetics ; Plasma

BACKGROUND: Necrotizing fasciitis is a life-threatening infectious disease with rapidly progressive involvement of the affected site. Because of the high mortality rate of this disease, early diagnosis, surgical exploration, and administration of appropriate antibiotics are necessary. The present study aimed to further review the changes in the clinical and microbiological characteristics of necrotizing fasciitis using patients' medical records from consecutive databases of 3 hospitals in Korea. MATERIALS AND METHODS: In this study, we retrospectively reviewed the medical records of patients with necrotizing fasciitis who were clinically diagnosed between May 2001 and February 2012 in 3 university hospitals in Korea. In total, the data of 83 patients were analyzed, including those of 20 patients from our previous study in 2006. An organism found in a blood culture or surgical specimen was regarded as a causative organism. RESULTS: Of the 83 patients, 68(81.9%) had community-acquired infections. Ninety microorganism species were indentifed by culture. Streptococcus was the most commonly identified pathogen. Non-fermentative gram-negative bacteria and Candida species have recently emerged, especially in immunocompromised hosts. CONCLUSIONS: Gram-positive organisms are still the most common pathogens of necrotizing fasciitis. However in our study, various gram-negative bacteria with different levels of susceptibility to antibiotics, as well as Candida species, were responsible for the necrotizing fasciitis. Initial empirical antimicrobial agents for necrotizing fasciitis should be considered depending on the individual patient's condition.
Anti-Bacterial Agents ; Anti-Infective Agents ; Candida ; Communicable Diseases ; Community-Acquired Infections ; Early Diagnosis ; Fasciitis, Necrotizing* ; Gram-Negative Bacteria ; Hospitals, University* ; Humans ; Immunocompromised Host ; Korea* ; Medical Records ; Mortality* ; Retrospective Studies ; Risk Factors* ; Streptococcus

Classic causes of fever of unknown origin (FUO) are infections, neoplasms, collagen vascular diseases and drugs. However, large studies of FUO have consistently reported that a considerable proportion of patients with FUO remain undiagnosed. We report a patient with a prolonged course of FUO and progressive pulmonary nodules in whom extensive clinical and laboratory evaluation did not reveal specific diagnosis. The patient had recurrent episodes of fever for more than three years, and the pulmonary nodules gradually progressed in size and number despite administration of antibiotics including antifungal and antituberculosis agents. Several pathologic examinations demonstrated an organizing pneumonia or non-neoplastic lung parenchyma with lymphoplasmacytic infiltration only. After a protracted course of disease, we thought that this patient might have lymphoproliferative disorder, possibly EBV-associated, and started anti-cancer chemotherapy. He was successfully treated with eight cycles of chemotherapy including cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP).
Anti-Bacterial Agents ; Collagen ; Cyclophosphamide ; Diagnosis ; Doxorubicin ; Drug Therapy* ; Fever of Unknown Origin* ; Fever* ; Humans ; Lung ; Lymphoproliferative Disorders ; Pneumonia ; Prednisolone ; Vascular Diseases ; Vincristine

Retroperitoneal Schwannoma is relatively rare and benign tumor originating from Schwann cell. Schwannomas arising in the retroperitoneum are infrequently reported. The majority of Schwannoma is found incidentally and misdiagnosed for other benign conditions both clinically and radiologically. We report a case of a benign retroperitoneal pelvic Schwannoma which was preoperatively misdiagnosed as an ovarian tumor with brief review of literatures.
Neurilemmoma*

We here report two cases of combined liver-kidney transplantation in patients with both end stage renal disease and hepatitis B related liver cirrhosis. The first case was a 55-year-old man with hepatitis B related liver cirrhosis and chronic renal failure, who received cadaveric liver and kidney transplantation. Immunosuppressants were cyclosporine, prednisolone, and mycophenolate mofetil. Clinical course was uneventful except for hemolytic anemia due to alloimmunization that occurs after ABO-mismatched solid organ transplantation. Hemoglobin level became stable after plasmapheresis. His renal and hepatic function is maintained up to the present time. The second case was a 42-year-old man with nephrotic syndrome and liver cirrhosis. The patient underwent living related-combined liver-kidney transplantation. Donors were his son and brother. Blood type of the patient and donors were identical and the result of HLA crossmatch was negative. On the 14th postoperative day, stenosis at anastomotic site of hepatic artery was detected. After balloon angioplasty hepatic function was normalized. At 8 months after the transplantation, the patient is stable without adverse events.
Adult ; Anemia, Hemolytic ; Angioplasty, Balloon ; Cadaver ; Constriction, Pathologic ; Cyclosporine ; Hepatic Artery ; Hepatitis B* ; Hepatitis* ; Humans ; Immunosuppressive Agents ; Kidney Failure, Chronic ; Kidney Transplantation ; Liver Cirrhosis* ; Liver* ; Middle Aged ; Nephrotic Syndrome ; Organ Transplantation ; Plasmapheresis ; Prednisolone ; Siblings ; Tissue Donors ; Transplants

BACKGROUND/AIMS: Transforming growth factor alpha (TGFalpha) is an important autocrine growth factor of hepatocytes. We were to evaluate the roles of TGFalpha in chronic viral hepatitis (CVH) and hepatocellular carcinoma (HCC). METHODS: We measured the amounts of TGFalpha mRNA in liver tissues from 18 patients with HCC, 31 with CVH and 7 normal controls. 'Hot start' reverse transcription polymerase chain reaction (RT-PCR) using oligo-dT and specific primers detected TGFalpha mRNA in total cellular RNA extracted from liver tissues. The levels of TGFalpha mRNA were determined by the end point titers of serial two-fold dilutions of cDNA. The amounts of HBV-RNA in livers of patients with chronic hepatitis B were also measured by Northern blot hybridization. RESULTS: TGFalpha mRNA levels were significantly higher in HCC than CVH and normal controls; those of CVH were also elevated compared to normal controls. They were overexpressed in the nontumorous livers surrounding HCC compared to CVH, although lower than HCC tissues. They were higher in chronic hepatitis B than in chronic hepatitis C. They were not correlated with serum alanine aminotransferase (ALT) or HBV-RNA levels in liver tissues (in cases of chronic hepatitis B). However, the expression of TGFalpha mRNA tended to be higher in the livers of patients with serum AFP levels raised. CONCLUSION: Overexpression of TGFalpha mRNA in liver seems to be associated with the regeneration of hepatocytes rather than hepatic necrosis or viral replication. Also, it may be closely related to the development or growth of HCC, especially in the livers of chronic hepatitis B.
Alanine Transaminase ; Blotting, Northern ; Carcinoma, Hepatocellular* ; DNA, Complementary ; Hepatitis B, Chronic ; Hepatitis C, Chronic ; Hepatitis* ; Hepatitis, Chronic ; Hepatocytes ; Humans ; Liver* ; Necrosis ; Polymerase Chain Reaction ; Regeneration ; Reverse Transcription ; RNA ; RNA, Messenger ; Transforming Growth Factor alpha* ; Transforming Growth Factors*

Ovarian granulosa cell tumor is a uncommon low-grade feminizing malignancy. Its natural history shows slow growth without pain. It often reveals to be very large sized mass when diagnosed, and is confined to the involved ovary in many cases. Complete surgical removal is primary treatment and recurrences thereafter are relatively common. Postoperative adjuvant therapy including reoperation, chemotherapy, radiation therapy or a combination therapy has been used with various degrees of success. We experienced a case of huge ovarian granulosa cell tumor occupying whole abdominal cavity by rapid growth, which is presented with a brief review of corresponding literatures.
Abdominal Cavity ; Drug Therapy ; Female ; Granulosa Cell Tumor* ; Granulosa Cells* ; Natural History ; Ovary* ; Recurrence ; Reoperation

BACKGROUND/AIMS: p53 mutations have been reported to be a poor prognostic indicator in patients with HCC treated by surgical resection because of the association with frequent recurrence and shorter survival periods. Although poor differentiation of tumor has been considered to be associated with p53 mutation more frequently, the exact causes of unfavorable prognosis have not been clarified. METHODS: To evaluate the relationship of p53 mutation and details of histological features, we examined 20 HCCs and surrounding liver tissues from the patients treated with surgical resection using direct sequencing of p53 gene at exons 5, 6, 7 and 8, and analyzed histopathologic features. We also analyzed the clinical, biochemical and radiological characteristics including the recurrences of tumor and survival periods in HCC patients with p53 mutant comparing to those with wild type p53 gene. RESULTS: p53 mutants were found in 9 (45%) out of 20 resected HCC tissues, none from any surrounding tissues. p53 mutations were all point substitutions of a base; 5 in exon 8, 4 in exon 5 and 1 in exon 7. Between patients with mutants and those with wild type of p53 gene, there were no differences in age, sex, serum ALT, albumin, bilirubin and AFP levels, and HBV-ositivity. HCCs with p53 mutants tended to be larger in size (14% in < 5 cm vs 67 % in > 5 cm; p=0.03) and multinodular in type (3/9 vs 0/11; p=0.07). p53 mutants tended to be found in poorly differentiated HCCs comparing to wild types. Even though there was no evidence of vascular or biliary invasion radiologically in all, 5 of 9 p53 mutant (+) (56%) and none of 11 p53-utant (- cases showed vascular invasions microscopically (p<0.01). However, there was no correlation between p53 mutations in tumor tissues and formation of capsules, biliary invasions or association with cirrhosis. During follow-p periods (median: 22;2 -8 mos) recurrences of HCC had been found in 6 of 9 patients with mutants (67%) in contrast to only 2 of 11 with wild types (18%)(p=0.07). Extrahepatic metastases were also common in patients with p53 mutant than those without it (56% vs 9%; p=0.05). Consequently, the 1 year cancer free survival rate of HCC patients with p53 mutant was significantly lower than that with wild type (44% vs 82%; p=0.02). CONCLUSIONS: Thus, it is suggested that p53 mutations tend to be commonly associated with microvascular invasions as well as poor differentiation microscopically, which may result in micrometastasis and frequent recurrences, and consequently shorter survival periods in HCC patents undergoing surgical resection.
Bilirubin ; Capsules ; Carcinoma, Hepatocellular* ; Exons ; Fibrosis ; Genes, p53 ; Humans ; Liver ; Neoplasm Metastasis ; Neoplasm Micrometastasis ; Prognosis* ; Recurrence ; Survival Rate

BACKGROUNDS: Living-donor liver transplantation (LDLT) has been established as an efficacious option to resolve the shortage of cadaveric donor organs for pediatric recipients. This surgical innovation has significantly reduced the pretransplantation mortality for children, but the crisis of increasing scarcity of donor organs in our hospital has led us to extend LDLT to adult recipients. However, the extension of LDLT from pediatric recipients to adult recipients has been made only with limited success largely because of the inability of a relatively small-size left-lobe graft to meet the metabolic demands of an adult recipient. It has been postulated that a left-lobe graft smaller than 40% of the recipient's standard liver volume will not result in a successful adult-to-adult LDLT in chronic parenchymal liver disease. METHODS: From February 1997 to October 1997, 10 LDLTs, using 9 extended left-lobe grafts and 1 right-lobe graft, were performed on patients with end-stage parenchymal liver diseases (9 cases of B-hepatitis-induced cirrhosis with or without an associated hepatocellular carcinoma and 1 case of alcoholic cirrhosis) at the Department of Surgery, Asan Medical Center. The ratios of the graft to the standard liver volume of the recipients were in the range of 30% to 55%. RESULTS: All grafts showed immediate function, but delayed normalization of the serum total bilirubin was demonstrated in all recipients receiving left-lobe grafts. There were no mortalities and serious complications in donors. Two recipients died of sepsis 21 days and 40 days after transplantation, and 8 recipients (80%) are alive with good liver function at a median follow-up of 5.1 months (range 2~10 months). CONCLUSIONS: The aim of this article is to report our experience with adult-to-adult LDLT shows that a graft size greater than 30% of the recipient's standard liver volume is able to meet the metabolic demands of adult recipients with chronic parenchymal liver disease and that LDLT might open a new donor pool for adult recipients when the supply of cadaveric organs is severely restricted.
Adult ; Alcoholics ; Bilirubin ; Cadaver ; Carcinoma, Hepatocellular ; Child ; Chungcheongnam-do ; Fibrosis ; Follow-Up Studies ; Humans ; Liver Diseases ; Liver Transplantation* ; Liver* ; Living Donors* ; Mortality ; Sepsis ; Tissue Donors ; Transplants