This tutorial defines the concepts of disease progression in the context of clinical pharmacology. Disease progression describes the natural history of disease, such as pain, or biomarker of drug response, such as blood pressure. The action of a drug, such as inhibiting an enzyme or activating a receptor, leads to a change in disease status over time. Two main types of drug response can be defined based on the pattern of the time course of disease status. The most common is a symptomatic effect equivalent to a shift up or down of the natural history curve. Less common but quite clinically important is a disease-modifying effect equivalent to a change in the rate of disease progression.
Blood Pressure ; Disease Progression ; Natural History ; Pharmacology, Clinical

Multiple studies have shown that oral antiviral therapies reduced the incidence of hepatocellular carcinoma (HCC) and improved the survival of patients with chronic hepatitis B when compared with that of untreated patients. In particular, entecavir and tenofovir share the qualities of high efficacy in reducing the HBV DNA levels, and they have excellent tolerability and safety. These drugs modified the natural history of liver fibrosis, improve liver function, decrease the incidence of HCC, decrease the need for liver transplantation, and improve survival. Many studies have suggested that long-term antiviral therapy reduces the risk of HCC and liver cirrhosis in patients with chronic hepatitis. The mechanism of these drugs in reducing the risk of HCC is not clear. This article reviews the mechanisms of carcinogenic HBV by conducting a review of the literature on the efficacy of therapy for reducing the risk of HCC. A few recent articles have suggested that tenofovir offers advantages over entecavir in terms of HCC prevention, but these articles have the inherent limitations of observational data. No other head-to-head randomized trials exist. Further randomized studies would help provide stronger evidence of the association between the type of antiviral agent and the HCC outcomes. Only achieving complete viral eradication from the liver will truly decrease the mortality and incidence of HCC.
Antiviral Agents ; Carcinoma, Hepatocellular ; DNA ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Incidence ; Liver ; Liver Cirrhosis ; Liver Transplantation ; Mortality ; Natural History ; Tenofovir

HBV is the most common etiology of both liver cirrhosis and hepatocellular carcinoma in Korea. Despite much progress made, the currently available antiviral therapies cannot eradicate or eliminate this virus. Hence, the benefits and risks of antiviral therapy should be carefully evaluated on an individual basis and within the context of the clinical situation. The ultimate goals of treatment are to decrease the mortality from liver disease. The benefits of antiviral therapy come from prevention of progression of liver disease. Understanding the natural history of chronic HBV infection is a key step in the decision making process to treat patients with chronic HBV infection. Generally, chronic hepatitis B patients in the immune tolerant phase and immune inactive phase are not recommended to undergo antiviral treatment, except for those patients in special conditions (e.g., immunosuppression or anticancer chemotherapy). Chronic hepatitis B patients in the immune active phase are recommended for antiviral therapy. For patients with liver cirrhosis, treatment should be considered when serum HBV DNA is detectable regardless of the serum level of ALT.
Carcinoma, Hepatocellular ; Decision Making ; DNA ; Hepatitis B virus ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Immunosuppression ; Korea ; Liver Cirrhosis ; Liver Diseases ; Mortality ; Natural History ; Risk Assessment

OBJECTIVE: Pituitary adenomas (PAs) are often detected as incidental findings. However, the natural history remains unclear. The objective of this study was to evaluate the natural history and growth pattern of untreated PAs.METHODS: Between 2003 and 2014, 59 PAs were managed with clinico-radiological follow up for longer than 12 months without any kind of therapeutic intervention. Tumor volumes were calculated at initial and last follow-up visit, and tumor growth during the observation period was determined. Data were analyzed according to clinical and imaging characteristics.RESULTS: The mean initial and last tumor volume and diameter were 1.83±2.97 mL and 13.77±6.45 mm, 2.85±4.47 mL and 15.75±8.08 mm, respectively. The mean annual tumor growth rate was 0.33±0.68 mL/year during a mean observation period of 46.8±32.1 months. Sixteen (27%) PAs showed tumor growth. The initial tumor size (HR, 1.140; 95% confidence interval, 1.003–1.295; p=0.045) was the independent predictive factor that determined the tumor growth. Six patients (11%) of 56 conservatively managed non-symptomatic PAs underwent resection for aggravating visual symptoms with mean interval of 34.5 months from diagnosis. By Cox regression analysis, PAs of last longest diameter over 21.75 mm were a significant prognostic factor for eventual treatment.CONCLUSION: The initial tumor size of PAs was independently associated with the tumor growth. Six patients (11%) of conservatively managed PAs were likely to be treated eventually. PAs of last follow-up longest diameter over 21.75 mm were a significant prognostic factor for treatment. Further studies with a large series are required to determine treatment strategy.
Diagnosis ; Follow-Up Studies ; Humans ; Incidental Findings ; Natural History ; Pituitary Neoplasms ; Prognosis ; Tumor Burden

OBJECTIVE: To analyze the angiographic features and clinical course, including treatment outcomes and the natural course, of fusiform middle cerebral artery aneurysms (FMCAAs) according to their location, size, and configuration.METHODS: We reviewed the literature on adult cases of FMCAAs published from 1980 to 2018; from 25 papers, 112 FMCAA cases, for which the location, size, and configuration could be identified, were included in this study. Additionally, 33 FMCAA cases in our hospital were included, from which 16 were assigned to the observation group. Thus, a total of 145 adult FMCAA cases were included. We classified the FMCAAs according to their location (l-type 1, beginning from prebifurcation; l-type 2, beginning from bifurcation; l-type 3, beginning from postbifurcation), size (small, <10 mm; large, ≥10 mm; giant, ≥25 mm), and configuration (c-type 1, classic dissecting aneurysm; c-type 2, segmental ectasia; c-type 3, dolichoectatic dissecting aneurysm).RESULTS: The c-type 3 was more commonly diagnosed with ischemic symptoms (31.8%) than hemorrhage (13.6%), while 40.9% were found accidentally. In contrast, c-type 2 was more commonly diagnosed with hemorrhagic symptoms (14.9%) than ischemic symptoms (10.6%), and 72.3% were accidentally discovered. According to location, ischemic symptoms and hemorrhage were the most frequent symptoms in l-type 1 (28.6%) and l-type 3 (34.6%), respectively. Most of l-type 2 FMCAAs were found incidentally (68.4%). Based on the size of FMCAAs, only 11.1% of small aneurysms were found to be hemorrhagic, while 18.9% and 26.0% of large and giant aneurysms were hemorrhagic, respectively. Although four aneurysms of the 16 FMCAAs in the observation group increased in size and one aneurysm decreased in size during the observation period, no rupture was seen in any case and there were no significant predictors of aneurysm enlargement. Of 104 FMCAAs treated, 14 cases (13.5%) were aggravated than before surgery and all the aggravated cases were l-type 1.CONCLUSION: While ischemic symptoms occurred more frequently in l-type 1 and c-type 3, hemorrhagic rather than ischemic symptoms occurred more frequently in l-type 3 and c-type 2. In case of l-type 1 FMCAAs, more caution is required in determining the treatment due to the relatively high complication rate.
Adult ; Aneurysm ; Aneurysm, Dissecting ; Dilatation, Pathologic ; Hemorrhage ; Humans ; Intracranial Aneurysm ; Middle Cerebral Artery ; Natural History ; Rupture

Multiple studies have shown that oral antiviral therapies reduced the incidence of hepatocellular carcinoma (HCC) and improved the survival of patients with chronic hepatitis B when compared with that of untreated patients. In particular, entecavir and tenofovir share the qualities of high efficacy in reducing the HBV DNA levels, and they have excellent tolerability and safety. These drugs modified the natural history of liver fibrosis, improve liver function, decrease the incidence of HCC, decrease the need for liver transplantation, and improve survival. Many studies have suggested that long-term antiviral therapy reduces the risk of HCC and liver cirrhosis in patients with chronic hepatitis. The mechanism of these drugs in reducing the risk of HCC is not clear. This article reviews the mechanisms of carcinogenic HBV by conducting a review of the literature on the efficacy of therapy for reducing the risk of HCC. A few recent articles have suggested that tenofovir offers advantages over entecavir in terms of HCC prevention, but these articles have the inherent limitations of observational data. No other head-to-head randomized trials exist. Further randomized studies would help provide stronger evidence of the association between the type of antiviral agent and the HCC outcomes. Only achieving complete viral eradication from the liver will truly decrease the mortality and incidence of HCC.
Antiviral Agents ; Carcinoma, Hepatocellular ; DNA ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Incidence ; Liver ; Liver Cirrhosis ; Liver Transplantation ; Mortality ; Natural History ; Tenofovir

HBV is the most common etiology of both liver cirrhosis and hepatocellular carcinoma in Korea. Despite much progress made, the currently available antiviral therapies cannot eradicate or eliminate this virus. Hence, the benefits and risks of antiviral therapy should be carefully evaluated on an individual basis and within the context of the clinical situation. The ultimate goals of treatment are to decrease the mortality from liver disease. The benefits of antiviral therapy come from prevention of progression of liver disease. Understanding the natural history of chronic HBV infection is a key step in the decision making process to treat patients with chronic HBV infection. Generally, chronic hepatitis B patients in the immune tolerant phase and immune inactive phase are not recommended to undergo antiviral treatment, except for those patients in special conditions (e.g., immunosuppression or anticancer chemotherapy). Chronic hepatitis B patients in the immune active phase are recommended for antiviral therapy. For patients with liver cirrhosis, treatment should be considered when serum HBV DNA is detectable regardless of the serum level of ALT.
Carcinoma, Hepatocellular ; Decision Making ; DNA ; Hepatitis B virus ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Immunosuppression ; Korea ; Liver Cirrhosis ; Liver Diseases ; Mortality ; Natural History ; Risk Assessment

PURPOSE: Perianal adenocarcinoma arising from a chronic anorectal fistula is a rare condition for which the natural history and optimal management are not well established. For that reason, we conducted a retrospective analysis of 5 consecutive patients with a perianal adenocarcinoma arising from a chronic anorectal fistula managed at our institution from January 2014 to December 2015. METHODS: The patients were identified from a prospectively collected colorectal cancer database that included all patients managed for colorectal cancer at our institution. RESULTS: The median age at diagnosis was 64 years (range, 55–72 years). Magnetic resonance imaging (MRI) was the initial investigation for all patients and showed a hyperintense T2-weighted image. One patient underwent an abdominoperineal resection following neoadjuvant chemoradiotherapy and remained disease free during the 12-month follow-up. Three patients received neoadjuvant therapy with intent for surgery, but did not undergo surgery due to either worsening health or metastatic spread. One patient declined intervention. The median overall survival was 10.5 months (range, 2–19 months). CONCLUSION: A high index of suspicion is required to make a clinical diagnosis of an anal adenocarcinoma arising from a chronic fistula. Histologic diagnosis must be achieved to confirm the diagnosis. Multimodal therapy with neoadjuvant chemoradiotherapy followed by abdominoperineal resection is the treatment of choice.
Adenocarcinoma ; Asian Continental Ancestry Group ; Chemoradiotherapy ; Colorectal Neoplasms ; Diagnosis ; Fistula ; Follow-Up Studies ; Humans ; Magnetic Resonance Imaging ; Natural History ; Neoadjuvant Therapy ; Prospective Studies ; Rectal Fistula ; Retrospective Studies

BACKGROUND: Epidemic thunderstorm asthma (ETSA) severely affected Melbourne, Australia in November 2016. There is scant literature on the natural history of individuals affected by ETSA. OBJECTIVE: A multicentre 12-month prospective observational study was conducted assessing symptomatology and behaviors of ETSA-affected individuals. METHODS: We used a structured phone questionnaire to assess asthma symptom frequency, inhaled preventer use, asthma action plan ownership and healthcare utilization over 12 months since the ETSA. Analysis of results included subgroup analyses of the “current,” “past,” “probable,“ and “no asthma” subgroups defined according to their original 2016 survey responses. RESULTS: Four hundred forty-two questionnaires were analyzed. Eighty percent of individuals reported ongoing asthma symptoms at follow-up, of which 28% were affected by asthma symptoms at least once a week. Risk of persistent asthma symptoms was significantly higher in those with prior asthma diagnosis, current asthma, and probable undiagnosed asthma (all p < 0.01). Of 442 respondents, 53% were prescribed inhaled preventers, of which 51% were adherent at least 5 days a week. Forty-two percent had a written asthma action plan and 16% had sought urgent medical attention for asthma in the preceding year. CONCLUSIONS: Following an episode of ETSA, patients experience a pivotal change in asthma trajectory with both loss of asthma control and persistence of de novo asthma. Suboptimal rates of inhaled preventer adherence and asthma action plan ownership may contribute to asthma exacerbation risk and susceptibility to future ETSA episodes. Longer-term follow-up is needed to determine the extent and severity of this apparent change.
Asthma ; Australia ; Delivery of Health Care ; Diagnosis ; Environmental Exposure ; Follow-Up Studies ; Humans ; Natural History ; Observational Study ; Ownership ; Prospective Studies ; Public Health ; Surveys and Questionnaires ; Weather

BACKGROUND: Immune thrombocytopenic purpura (ITP) in children less than one year of age is less well characterized compared to ITP in toddlers and school-age children. Since children of different ages may have differing clinical courses, better delineation of the natural history of ITP in infants is needed. METHODS: We retrospectively reviewed the admission records of 248 consecutive pediatric patients between 1 month and 15 years of age who were admitted and treated for acute ITP at Pusan National University Children's Hospital from 2009 through 2017. All patients less than 1 year of age were identified and enrolled in this study. We investigated their demographics, clinical features, laboratory examinations, response to treatment, and long-term outcomes and made a comparison to those of children aged 1 to 10 years of age. RESULTS: Ninety nine infants were identified. Male to female ratio was highest in infants and decreased with age. Seventy nine (79.8%) of the 99 infant were found to be under 6 months old. The median platelet counts at diagnosis was 6×10⁹/L. Minor bleeding (bleeding score 0–2) was significantly dominant in infant compared to older subjects. Eighty two (96.5%) out of 85 patients achieved complete remission after initial intravenous immunoglobulin (IVIG) treatment. The relapse rate after initial CR was significantly lower than older ages (P=0.003). The platelet count after IVIG treatment in infant showed more rapid response compared to older subjects (P=0.04). Follow up information at 12 months was available for 70 infants. Chronic ITP at 12 month was seen less frequently in infants than in children 1 to 10 years of age (1.4% vs. 20.2%, P<0.001). CONCLUSION: Infants with acute ITP respond more favorably to IVIG treatment and are less likely to develop chronic ITP compared to children 1 to 10 years of age.
Busan ; Child ; Demography ; Diagnosis ; Female ; Follow-Up Studies ; Hemorrhage ; Humans ; Immunoglobulins ; Immunoglobulins, Intravenous ; Infant ; Male ; Natural History ; Platelet Count ; Purpura, Thrombocytopenic, Idiopathic ; Recurrence ; Retrospective Studies