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P Lipponen

Publications and source records attributed to P Lipponen.

At least 55 records · Page 3Linked to original sources
PubMed1995

Expression of insulin-like growth factor I (IGF-I) in female breast cancer as related to established prognostic factors and long-term prognosis.

The expression of insulin-like growth factor I (IGF-I) was analysed immunohistochemically in a series of 211 breast cancers with special emphasis on its relationship to conventional prognostic factors and long-term prognosis. Altogether, IGF-I was expressed by the tumour cells in 91% of the breast carcinomas, and by stromal cells in 29%. The expression of IGF-I in cancer cells was weakly related to a high proportion of intraductal growth (P = 0.032), distinct tumour margins (P = 0.048) and high S-phase fraction (P = 0.074). In a univariate analysis, IGF-I expression in cancer cells was significantly related to a high survival probability in the entire cohort (P = 0.0144) as well as in the axillary lymph node positive tumours (P = 0.0286). Alternatively, expression of IGF-I in the stromal cells was related to metastasis at the time of diagnosis (P = 0.05), tumour diameter (P = 0.04), DNA ploidy (P = 0.07) and nuclear pleomorphism (P = 0.025), but it was without prognostic significance in a univariate analysis (P > 0.1). In a multivariate analysis, the conventional prognostic factors were superior to IGF-I expression in predicting the disease outcome, albeit expression of IGF-I in tumour stroma showed some independent prognostic significance in axillary lymph node negative tumours. The results suggest that IGF-I expression is related to malignant histopathological features in breast cancer, and expression of IGF-I has independent prognostic significance in the early phases of the disease.

Adult↗
PubMed1995

Expression of tumour-suppressor gene Rb, apoptosis-suppressing protein Bcl-2 and c-Myc have no independent prognostic value in renal adenocarcinoma.

The expression of retinoblastoma (Rb), c-Myc and Bcl-2 proteins was studied by immunohistochemical methods in 104 cases of renal adenocarcinoma. One tumour was completely negative for Rb protein and altered expression pattern was detected in 36% of cases. A low fraction of Rb-positive nuclei was related to high grade (P = 0.016) and high mitotic index (P = 0.012). Twenty-eight per cent of the tumours expressed c-Myc in cancer cell nuclei and 87% showed cytoplasmic positivity. Cytoplasmic expression of c-Myc was related to high grade (P = 0.002), while nuclear expression of c-Myc was related to small tumour diameter (P = 0.034), low T category (P = 0.04), low mitotic index (P = 0.019) and expression of c-ErbB-2 (P = 0.0007). Overexpression of c-myc predicted favourable outcome in M0 tumours (P = 0.0157). Bcl-2 was expressed in 20% of tumours and it was related to small tumour size (P < 0.0001), low T category (P < 0.0001), lack of venous invasion (P = 0.008), node negativity (P = 0.015) and absence of metastasis (P = 0.017). In multivariate analysis the expression of Rb, Bcl-2 and c-Myc had no independent prognostic value over T category (P < 0.001), mitotic index (P = 0.008) and combined nuclear grade (P = 0.056).

Adenocarcinoma↗
PubMed1995

The value of history-taking, physical examination, and computer assistance in the diagnosis of acute appendicitis in patients more than 50 years old.

BACKGROUND: The accuracy of the clinical diagnosis of acute appendicitis in patients more than 50 years old was studied in connection with the Research Committee of the World Organization of Gastroenterology (OMGE) survey of acute abdominal pain. Criteria for inclusion and the diagnostic criteria in this prospective study were those set out by the OMGE Research Committee. METHODS: The clinical findings in each patient were recorded in detail, using a predefined structured data collection sheet, and the collected data were compared with the final diagnosis of the patients. Twenty-three preoperative clinical history variables, 14 clinical signs, and 3 tests were evaluated in a single variable and multivariate analysis. RESULTS: In multivariate logistic regression analysis the most significant predictors of acute appendicitis in patients more than 50 years old were tenderness (relative risk (RR) = 39.4), rigidity (RR = 18.8), and pain at diagnosis (RR = 11.0). The sensitivity of the preoperative clinical decision is detecting acute appendicitis in the aged was 0.87, with a specificity of 0.92, an efficiency of 0.91 and a usefulness index (UI) of 0.69. The computer-aided diagnostic score (DS) reached a sensitivity of 0.92 in detecting acute appendicitis, with a specificity of 0.90 and an efficiency of 0.90. When the patients with a DS value between -0.47 and 0.07 were considered nondefined (n = 43, follow-up required before the decision to operate), the efficiency of the computer-aided diagnosis in detecting acute appendicitis in the aged improved to 0.97. In patients more than 50 years old whose body temperature was available (n = 374), tenderness, rigidity, location of pain at diagnosis, and body temperature predicted significantly acute appendicitis. At a cut-off level of -1.49 the diagnostic score reached a sensitivity of 0.94 in detecting acute appendicitis, with a specificity of 0.91, an efficiency of 0.92 and a UI of 0.80. When the patients with a DS value between -1.49 and 0.46 were considered nondefined (n = 43, follow-up required before the decision to operate), the sensitivity of the computer-aided diagnosis in detecting acute appendicitis in the aged was 0.92, with a specificity of 0.99 and an efficiency of 0.98, and the UI improved to 0.84. CONCLUSION: Acute abdominal pain at the right lower quadrant, with tenderness, rigidity, and increased body temperature (> or = 37.1 degrees C), is indicative of acute appendicitis in patients more than 50 years old. The diagnostic scoring system did perform well, increasing the sensitivity, specificity, efficiency, and usefulness index of the diagnosis of acute appendicitis in the aged.

Acute Disease↗
PubMed1995

Biochemical parameters as prognostic factors in prostatic adenocarcinoma.

The serum levels of creatinine (CR), alkaline phosphatase (ALP), acid phosphatase (ACP) and tartrate inhibitable acid phosphatase (TIAP) were related to Gleason score, TM-category, disease progression and survival in 325 prostatic adenocarcinoma patients followed up for over 12 years. Elevated serum levels of CR, ALP, ACP and TIAP were related to invasive and metastatic disease as well as with a high Gleason score. Elevated serum levels of CR, ALP, ACP and TIAP, all significantly predicted prognosis in a univariate analysis. In the M0 tumours, ACP and TIAP and TIAP had prognostic value, as they did in the T1-2M0 tumours respectively. Cox's multivariate analysis showed that serum creatinine level at diagnosis had independent prognostic value additional to the TM-classification, Gleason score and patient age. In the M0 tumours, ALP had independent prognostic significance additional to the T-category, Gleason score and patient age. In the T1-2M0 tumours, TIAP had independent prognostic value supplementary to the Gleason score, T-category and patient age, whereas in the T1M0 tumours, the gleason score was an independent prognostic parameter. The results indicate that these simple laboratory tests give important prognostic information in prostatic adenocarcinoma.

Acid Phosphatase↗
PubMed1994

Expression of proliferating cell nuclear antigen (PC10), p53 protein and c-erbB-2 in renal adenocarcinoma.

Expressions of proliferating cell nuclear antigen (PC10), p53 protein (CMI) and c-erbB-2 (NCL-1) were immunohistochemically analysed in 123 renal adenocarcinomas with known follow-up data. c-erbB-2 protein was weakly and focally expressed in 10% of the tumours, and the expression was not related to clinical or histological variables or survival. p53 protein was expressed in 33% of the tumours. Expression of p53 protein was independent of stage, grade and prognosis, while expressions of c-erbB-2 and p53 were weakly interrelated. Proliferating cell nuclear antigen was expressed in all tumours, and the fraction of PC10-positive nuclei was significantly related to grade, stage and prognosis. Multivariate analysis of clinical, histological and immunohistochemical prognostic factors indicated that the extent of the tumour, its histological differentiation and proliferation rate of the cancer cells are the most important prognostic factors. Recurrence-free survival was related to the fraction of PC10-positive nuclei, histological differentiation, sex and expression of p53 protein. Over-expression of p53 protein was related to a long recurrence-free survival. Our results show that PC10 immunolabelling can be used to determine the prognostic category in renal adenocarcinoma, whereas the expressions of p53 protein or c-erbB-2 are only weak prognostic indicators.

Adenocarcinoma↗
PubMed1994

Expression of E-cadherin (E-CD) as related to other prognostic factors and survival in breast cancer.

A series of 208 breast cancer biopsies were analysed immunohistochemically for expression of E-cadherin (E-CD). Altogether, 72 per cent of the tumours showed E-CD positivity in over 50 per cent of cells, the staining being heterogeneous in nearly all tumours. In only 16 per cent of ductal carcinomas was positive staining seen in less than 1 per cent of cells. Expression of E-CD was not related to tumour diameter, nodal status, metastasis at diagnosis, histological grade, DNA ploidy, S-phase fraction, nuclear area, mitotic frequency, or PR content. There was a significant relationship between expression of E-CD, histological type (P = 0.01), the proportion of intraductal growth (P = 0.008), the density of tumour-infiltrating lymphocytes (P = 0.0007), ER content (P = 0.012), and morphometric nuclear factors (P < 0.02). Expression of E-CD showed a weak association with a high survival probability (P = 0.02), while the relation to recurrence-free survival was not significant (P = 0.1). In axillary lymph node-negative tumours, E-CD expression was not related significantly to survival (P = 0.11) or to recurrence-free survival (P = 0.06). In multivariate analysis, E-CD expression had no independent prognostic value, while the axillary lymph node status, tumour diameter, patient age, and mitotic frequency were independent prognostic factors. The results indicate that E-CD expression is related to several histological features in breast cancer, but has no independent prognostic value over standard prognostic factors.

Adult↗
PubMed1994

Tumour vascularity and basement membrane structure in breast cancer as related to tumour histology and prognosis.

A series of 202 breast cancer biopsy specimens were analysed immunohistochemically for collagen IV to demonstrate basement membrane (BM) structures and blood vessels within tumour tissue. Integrity of the BM was graded into four categories and the number of vascular channels per square millimetre of tumour tissue were counted. Defective BM structures were significantly related to high grade, lack of tubule formation, invasive disease, high S-phase fraction and variability in nuclear size and shape. High vascular channel density was related to poor tumour differentiation and a high proliferation rate of cancer cells as well as to the absence of tubule formation, inconspicuous intraductal growth and low progesterone receptor content. High vascular density and defective BM structures were signs of poor prognosis and short recurrence-free survival in the entire cohort and also in local tumours. In multivariate analysis, the vascular density had independent prognostic value, as did the diameter, axillary lymph node status and mitotic rate. The counting of vascular channels within the tumour provides additional prognostic information in breast cancer, in contrast to analysis of the BM integrity which shows hardly any prognostic information additional to that provided by the special histological features, e.g. tubule formation and intraductal growth pattern.

Adult↗
PubMed1994

Acute appendicitis in patients over the age of 65 years; comparison of clinical and computer based decision making.

The role of clinical and computer based decision in the diagnosis of acute appendicitis in the elderly was studied in connection with the Research Committee of the World Organization of Gastroenterology (OMGE) survey of acute abdominal pain. A total of 220 patients over the age of 65 years presenting with acute abdominal pain were included in the study at the Central Hospital of Savonlinna and at the University Hospital of Tampere. Twenty-two preoperative clinical history variables, 14 clinical signs and three tests were evaluated in a single variable and multivariate analysis to find the best combination of predictors of acute appendicitis in the aged. In order to sum up the contributions of independent diagnostic factors, a diagnostic score (DS) was built: DS = 2.81 x (rectal digital tenderness; 1 = yes, 0 = no) + 2.54 x (rigidity; 1 = yes, 0 = no) + 2.06 x (renal tenderness; 1 = no, 0 = yes) + 2.33 x (bowel sounds; 1 = normal, 2 = absent/abnormal) - 8.13. The sensitivity of preoperative clinical decision in detecting acute appendicitis in the aged was 0.79 with a specificity of 0.92, an efficiency of 0.90 and usefulness index (UI) of 0.56. At a cut-off level of -2.78 the DS reached a sensitivity of 0.84 in detecting acute appendicitis with a specificity of 0.87, an efficiency of 0.87 and UI of 0.68. When the patients with a DS value between -2.78 and -0.45 were considered as non-defined (n = 28, follow-up required before the decision to operate), the sensitivity of the computer-aided diagnosis in detecting acute appendicitis in the elderly was 0.77 with a specificity of 0.97, an efficiency of 0.96 and UI of 0.57. In the elderly patients where a leucocyte count was available (n = 157), location of pain, rectal digital tenderness and leucocyte count predicted significantly acute appendicitis. At a cut-off level of -2.62 the DS reached a sensitivity of 0.81 in detecting acute appendicitis with a specificity of 0.92, an efficiency of 0.91 and UI of 0.59. When the patients with a DS value between -2.62 and 0.06 were considered as nondefined (n = 12, follow-up required before the decision to operate), the sensitivity of the computer-aided diagnosis (leucocyte count available) in detecting acute appendicitis in the elderly improved to 0.86 with a specificity of 0.94, an efficiency of 0.93 and UI of 0.69. In our study the diagnostic scoring system for the elderly performed well considering the simple nature of its structure.(ABSTRACT TRUNCATED AT 400 WORDS)

Abdominal Pain↗
PubMed1994

Apoptosis in breast cancer as related to histopathological characteristics and prognosis.

Apoptotic cells were quantitated by light microscopy in a series of 288 breast carcinomas, and their number (cells/mm2 of neoplastic epithelium, i.e., the apoptotic index, AI) was related to various histopathological features and disease outcome. High AI was associated with tumour necrosis (P = 0.003), lack of tubule formation (P = 0.03), dense stromal lymphocyte infiltration (P = 0.0009), high grade of the tumour (P < 0.0001), DNA aneuploidy (P = 0.049), high S-phase fraction (P = 0.010), high mitotic rate (P < 0.0001), lack of sex steroid receptors (P = 0.004), expression of p53 tumour suppressor gene (P = 0.004), and high values of morphometrically measured nuclear factors (P < 0.05). In survival analysis, an AI greater than 3/mm2 was related to short recurrence-free survival in the entire cohort (P = 0.0079) as well as in the axillary lymph node-negative tumours (P = 0.0253). Survival of the patients with node-negative tumours (P = 0.0356), node-positive tumours (P = 0.0085) and in the entire cohort (P = 0.004) was related to AI. Recurrence-free survival was related to the mitotic index (P = 0.0012), ductal type (P = 0.011), S.D. of the nuclear area (P = 0.075), and axillary lymph node status (P = 0.096). Cox's analysis showed that only the tumour diameter (P < 0.001), axillary lymph node status (P = 0.001), progesterone receptor content (P = 0.004) and ductal type (P = 0.041) had independent prognostic value, whereas AI did not.

Adult↗
PubMed1994

Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma.

A series of 325 prostatic adenocarcinomas with a long-term clinical follow-up were subjected to light microscopic analysis of histological prognostic factors, including three grading systems (Gleason score, WHO grade, nuclear grade), perineural infiltration of the tumour (PNI), tumour infiltrating lymphocytes (TIL) and the presence of apoptotic cells (APO). All three histological classifications correlated significantly with the prognosis, but in multivariate analysis, the Gleason score was superior to the WHO grading or nuclear grading in predicting patient survival. PNI was significantly related to poor differentiation of the tumour, its progression and ominous disease outcome, particularly in T1-2MO tumours. The density of TIL was independent of the tumour differentiation, and absent or weak TIL were signs of a high risk of tumour progression and of a fatal disease. Apoptotic cells were commonly detected in poorly differentiated tumours and apoptosis was related to disease progression and low survival probability. The results suggest that the Gleason score, PNI and the density of TIL should be included in routine pathology reports, to be used by clinicians while making therapeutic decisions in prostatic cancer.

Adenocarcinoma↗
PubMed1994

Transitional cell carcinoma of the bladder: failure to demonstrate human papillomavirus deoxyribonucleic acid by in situ hybridization and polymerase chain reaction.

Human papillomaviruses have been implicated in the pathogenesis of a variety of malignancies, particularly those of the anogenital tract. Some recent reports on the presence of human papillomavirus in bladder cancer have raised the possibility that it might be involved in the development of this malignancy as well. To study this concept, a series of 108 transitional cell carcinomas of the bladder were screened for the presence of human papillomavirus deoxyribonucleic acid (DNA) by in situ hybridization with biotin-labeled human papillomavirus cocktail probe and polymerase chain reaction with human papillomavirus L1 consensus primers. Although the positive controls showed strong hybridization signals, no evidence for human papillomavirus DNA was found in any of the bladder carcinomas by in situ hybridization. Similarly, despite the amplification of a 450 bp product in cervical human papillomavirus lesions (used as positive controls), no signals were obtained in any of the bladder tumors studied. beta-globin gene sequences (110 bp), serving as internal controls, were consistently amplified from all tumor samples, suggesting that cellular DNAs from the carcinoma specimens were sufficient for the amplification reaction. These data indicate that human papillomavirus infection is rare in transitional cell carcinoma of the bladder. The significance of these findings is discussed in relation to previous reports on human papillomavirus involvement in bladder carcinomas.

Adult↗
PubMed1994

Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-term prognosis.

The expression of epidermal growth factor receptor (EGFR) was studied immunohistochemically in 234 cases of transitional cell bladder cancer. EGFR was overexpressed in 35% of cases and distinct nuclear localisation of EGFR positivity was found in 31% of the tumours. Overexpression was related to invasive growth, grade 2-3 histology, non-papillary type, DNA aneuploidy and high proliferation rate of cancer cells. The expressions of p53 and EGFR were interrelated, while expression of c-erbB-2 was independent of EGFR expression. Progression of superficial tumours, recurrence-free survival and survival were independently related to overexpression of EGFR in multivariate analysis. T category, S-phase fraction and non-papillary type included all the available prognostic information when the entire cohort was analysed by multivariate methods. The results show that overexpression of EGFR is related to several malignant features and prognosis in superficial bladder cancer. Moreover, the results suggest that overexpression of EGFR is usually a late event in bladder cancer development related to genetic instability rather than an early event in malignant transformation. Further studies are still needed to establish whether the direct measurement of cell proliferation or analysis of growth factor receptors and other oncoproteins gives more accurate prognostic information in bladder cancer.

Adolescent↗
PubMed1994

Progression and survival in prostatic adenocarcinoma: a comparison of clinical stage, Gleason grade, S-phase fraction and DNA ploidy.

Clinical data were reviewed in 325 patients with prostatic adenocarcinoma followed up for a mean of 13 years. Paraffin-embedded tumour biopsy specimens from the primary tumours were available for flow cytometry (FCM) in 273 cases. Intra-tumour heterogeneity in DNA index (DI) was found in 4% of the tumours (54 cases were analysed). S-phase fraction (SPF) and DNA ploidy were significantly interrelated. Aneuploidy and high SPF were significantly related to both a high T category and high Gleason score. The progression in T1-2M0 tumours was related to Gleason score (P = 0.009), DNA ploidy (P = 0.006) and SPF (P = 0.007), while the Gleason score (P = 0.0013), DNA ploidy (P = 0.002) and SPF (P < 0.001) had prognostic value in univariate survival analysis. In the entire cohort, the T category (P < 0.001), M category (P < 0.001), Gleason score (P < 0.001), DNA ploidy (P < 0.001) and SPF (P < 0.001) were significant prognostic factors. In Cox's analysis, the M category (P < 0.001), Gleason score (P < 0.001), T category (P = 0.003), age (P = 0.001) and SPF (P = 0.087) were independently related to prognosis. In the T1-2M0 tumours, Gleason score (P < 0.001), T category (P = 0.022) and SPF (P = 0.058) were independent predictors. A novel classification system in which the DNA ploidy or SPF and the Gleason score were combined was found to be of significant prognostic value in all M0 tumours (P < 0.001). The results suggest that FCM can be used as an adjunct to conventional histological assessments for determination of the correct prognostic category in prostatic adenocarcinoma.

Adenocarcinoma↗
PubMed1994

Sex-specific diagnostic scores for acute appendicitis.

The role of clinical and computer-based decisions in the diagnosis of acute appendicitis was studied in connection with the survey of acute abdominal pain by the Research Committee of the World Organization of Gastroenterology (OMGE). One thousand three hundred and thirty-three patients presenting with acute abdominal pain were included in the study. Twenty-two preoperative clinical history variables, 14 clinical signs, and 3 tests were evaluated in a multivariate analysis to find the best combination of independent predictors of acute appendicitis for males and females. Independent predictors of acute appendicitis in males were tenderness, previous abdominal surgery, rebound, rigidity, location of pain at diagnosis, guarding, and body temperature. To sum up the contributions of the most significant diagnostic factors, a diagnostic score (DS) was built. When the male patients with a DS value between -2.00 and -0.48 were considered nondefined (n = 75, follow-up required before deciding to operate), the sensitivity of the computer-aided diagnosis in detecting acute appendicitis in males was 0.95, with a specificity of 0.89 and an efficiency of 0.91. In males whose leucocyte count was available (n = 476), previous abdominal surgery, leucocytosis, location of pain at diagnosis, tenderness, rigidity, rebound, guarding, rectal digital tenderness, and body temperature predicted significantly acute appendicitis. The DS reached a sensitivity of 0.94 (the cut-off level was -1.74), with a specificity of 0.80 and an efficiency of 0.84. (ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Contributions of history-taking, physical examination, and computer assistance to diagnosis of acute small-bowel obstruction. A prospective study of 1333 patients with acute abdominal pain.

BACKGROUND: The accuracy of clinical diagnosis of acute small-bowel studied in connection with the survey of acute abdominal pain by the Research Committee of the World Organization of Gastroenterology (OMGE). Criteria for inclusion and the diagnostic criteria of this prospective study were those set out by the OMGE Research Committee. METHODS: The clinical findings in each patient were recorded in detail on a pre-defined structured data collection sheet, and the collected data were compared with the final diagnosis of patients. RESULTS: The most efficient symptoms in the diagnosis of acute small-bowel obstruction were previous abdominal surgery (relative risk (RR) = 12.1) and type of pain (colic/intermittent versus steady) (RR = 2.4). The most efficient clinical tests were abdominal distension (yes versus no) (RR = 13.1) and bowel sounds (abnormal versus normal) (RR = 9.0). The sensitivity of the clinical decision was 0.75, with a specificity of 0.99 and an efficiency of 0.98. The computer-based diagnostic score reached a sensitivity of 0.87 with a specificity of 0.95 and an efficiency of 0.95. CONCLUSIONS: Acute abdominal pain with distension, abnormal bowel sounds, and previous abdominal surgery are indicative of a small-bowel obstruction. A computer-based diagnostic score increases the sensitivity and usefulness index of the diagnosis of acute small-bowel obstruction in comparison with clinical decision alone.

Abdomen, Acute↗
PubMed1994

Argyrophilic nucleolar organizer regions may help the differential diagnostic distinction between chronic pancreatitis and pancreatic ductal adenocarcinoma.

BACKGROUND: The aim of this study was to determine whether the number of argyrophilic nucleolar organizer regions (AgNORs) could be of diagnostic significance in differentiating between chronic pancreatitis and pancreatic ductal adenocarcinoma. METHODS: The number of AgNORs was enumerated in biopsy specimens of normal pancreas, chronic pancreatitis, and pancreatic ductal adenocarcinoma. RESULTS: The number of AgNORs was lower in patients with normal pancreas than in patients with chronic pancreatitis or pancreatic adenocarcinoma. In addition, the number of AgNORs was significantly lower in chronic pancreatitis than in pancreatic ductal adenocarcinoma (p < 0.001). CONCLUSIONS: The diagnosis of pancreatic adenocarcinoma is usually clear. Difficulties can be encountered, however, in cases of chronic pancreatitis, specially when biopsy material is small. Our results suggest that the number of AgNORs may help in distinguishing between chronic pancreatitis and pancreatic ductal adenocarcinoma, especially in diagnostically difficult specimens.

Adenocarcinoma↗
PubMed1994

Prognostic studies in breast cancer. Multivariate combination of nodal status, proliferation index, tumor size, and DNA ploidy.

We studied histological samples and clinical data from 111 breast carcinoma patients originally treated in 1975-1977 who did not have distant metastases at the time of diagnosis. A multivariate survival analysis using the Cox model selected the studied variables in the following order according to their prognostic association (breast cancer deaths, or deaths from any cause): axillary lymph node status, tumor size, mitotic index, and DNA ploidy status. The association of the different variables to the prognosis in respect to breast cancer deaths was evaluated 1-10 years after treatment by stepwise logistic regression. Lymph node status, tumor size, mitotic index, and DNA ploidy all showed significant relation to the prognosis but this association varied considerably with time of observation.

Adult↗