Trends in incidence of head and neck cancers in India

Information relating to cancer incidence trends forms the scientific basis for the planning and organization of prevention, diagnosis and treatment of cancer in a community. An attempt was here made to study the trends in the age adjusted incidence rates for the sites of head and neck cancers in Mumbai, Bangalore, Chennai, Delhi, Bhopal, and Barshi registry's populations. For carrying out trend analysis the gum, the floor of mouth, the mucosa of cheek, the hard and soft palate and the uvula were grouped together and assigned as cancers of mouth. The trend analysis was carried out for all sites together, tongue, mouth, hypopharynx and larynx in males and all sites together and mouth in females. Sites such as lip, hypopharynx and nasopharynx were not considered. In males, for all sites together linear regression showed no increase or decrease in age adjusted rates overall for Bangalore and Delhi registries, a significant decrease for Mumbai and Delhi registries, but a rising trend for Chennai and Bhopal registries over a period of time. In females, for all sites together no change was observed in age adjusted incidence rates for Mumbai, Chennai, Bhopal, Bangalore and Barshi registries while a decreasing trend was noted for Delhi registries over a period of time. For the specific sites, variation among registries was also apparent. The results point to local differences in sub-site specific risk factors which might be elucidated by analytical epidemiological assessment.     

Trends in cancer incidence in female breast, cervix uteri, corpus uteri, and ovary in India.

Trends in breast, cervix uteri, corpus uteri and ovarian cancers in six population based cancer registries (Mumbai, Bangalore, Chennai, Delhi, Bhopal, and Barshi) were evaluated over a period of the last two decades. For studying trends we used a model that fits this data is the logarithm of Y=ABx which represents a Linear Regression model. This approach showed a decreasing trend for cancer of the cervix and increasing trends for cancers of breast, ovary and corpus uteri throughout the entire period of observation in most of the registries. The four cancers, breast, cervix, corpus uteri and ovary, constitute more than 50% of total cancers in women. As all these cancers are increasing, to understand their etiology in depth, analytic epidemiology studies should be planned in a near future on a priority basis.     

Epidemiology of breast cancer in Indian women

Breast cancer has ranked number one cancer among Indian females with age adjusted rate as high as 25.8 per 100,000 women and mortality 12.7 per 100,000 women. Data reports from various latest national cancer registries were compared for incidence, mortality rates. The age adjusted incidence rate of carcinoma of the breast was found as high as 41 per 100,000 women for Delhi, followed by Chennai (37.9), Bangalore (34.4) and Thiruvananthapuram District (33.7). A statistically significant increase in age adjusted rate over time (1982–2014) in all the PBCRs namely Bangalore (annual percentage change: 2.84%), Barshi (1.87%), Bhopal (2.00%), Chennai (2.44%), Delhi (1.44%) and Mumbai (1.42%) was observed. Mortality‐to‐incidence ratio was found to be as high as 66 in rural registries whereas as low as 8 in urban registries. Besides this young age has been found as a major risk factor for breast cancer in Indian women. Breast cancer projection for India during time periods 2020 suggests the number to go as high as 1797900. Better health awareness and availability of breast cancer screening programmes and treatment facilities would cause a favorable and positive clinical picture in the country.     

Trends in the prostate cancer incidence in India.

Trends in prostate cancer in five population-based cancer Registries (Mumbai, Chennai, Bangalore, Delhi & Bhopal) in India were studied over a period of two decades using a model that fitting the data as the logarithm of Y=ABx which represents a Linear Regression model. This approach showed increasing trends in the age adjusted incidence rates throughout the entire period of observation for most of the registries, especially in Chennai and Bhopal and to the least extent in Mumbai. Particularly in Asia we face a future major increase in the rates of prostate cancer. Collaborative action now is a high priority to allow the preparations necessary for effective control of prostate cancer.     

Projection of cancer incidence in five cities and cancer mortality in India

Background: Cancer is second largest non-communicable disease and it has a sizable contribution in the total number of deaths. It is important for the public health professionals to understand the dynamics of cancer incidence for future strategies. Therefore, this paper is attempted with the objective of projecting number of cancer incidence for five cities namely, Bangalore, Chennai, Delhi, Bhopal and Mumbai and to estimate the cancer mortality rate for all India for the year 2008. Materials and Methods: The data were used from the Indian Council of Medical Research's publication of Population-Based Cancer Registry for the year 1999-2000. The population was calculated from the Census reports of 1991 and 2001. Causes-specific mortality report by the Central Bureau of Health Intelligence was used for estimating cancer mortality for all India. The age-specific rate method is utilized to project number of cancer incidence for the cities of Bangalore, Chennai, Delhi, Bhopal and Mumbai and to estimate cancer mortality in 2000 for all India. Results and Conclusion: About 26.6% increase is expected in the registered number of cancer cases in these five cities and 52.68% increase is projected for Delhi which would mean highest number of cases in Delhi among these five cities within a span of eight years. And in Mumbai it is expected to have a marginal decline in the number of cases for the year 2008 (around -3.25%). The age adjusted analysis indicates that Mumbai is experiencing the higher incidence rate among the five cities studied herein. It is estimated about 50% cancer mortality is reported from the age group 55 and above years.     

Projections of Number of Cancer Cases in India (2010-2020) by Cancer Groups

Introduction: Recently, NCRP (ICMR), Bangalore, has published a report on Time Trends in Cancer Incidence Rates. The report also provided projected numbers of cancer cases at the India country level for selected leadingsites. Objective: In the present paper, an attempt has been made to project cancer cases for India by sex, years and cancer groups. Sources of data: The incidence data generated by population-based cancer registries (PBCRs) at Bangalore, Barshi, Bhopal, Chennai, Delhi and Mumbai for the years 2001-2005 formed the sources of data. In addition, the latest incidence data of North Eastern Registries for the year 2005-06 were utilized. Methods: The crude incidence rate (CR) was considered suitable for assessing the future load of cancer cases in the country. The Linear Regression method (IARC 1991) was used to assess the time trend and the projection of rates for the periods 2010-2020. For whichever sites where trends were not found to be significant, their latest rates were taken into consideration and assumed to remain same for the period 2010-2020. Results: The total cancer cases are likely to go up from 979,786 cases in the year 2010 to 1,148,757 cases in the year 2020. The tobacco-related cancers for males are estimated to go up from 190,244 in the year 2010 to 225,241 in the year 2020. Similarly, the female cases will go up from 75,289 in year 2010 to 93,563 in the year 2020. For the year 2010, the number of cancer cases related to digestive system, for both males and females, are estimated to be 107,030 and 86,606 respectively. For, head and neck cancers, the estimates are 122,643 and 53,148 cases, respectively. and for the lymphoid and hematopoietic system (LHS), for the year 2010, are 62,648 for males and 41,591 for females. Gynecological-related cancers are estimated to go up from 153,850 in 2010 to 182,602 in 2020. Among males and females, cancer of breast alone is expected to cross the figure of 100,000 by the year 2020.     

Pattern of Reproductive Cancers in India

Background: Reproductive cancers are those that affect the human organs that are involved in producingoffspring. An attempt is made in the present communication to assess the magnitude and pattern of reproductivecancers, including their treatment modalities, in India. The cancer incidence data related to reproductive cancerscollected by five population-based urban registries, namely Bangalore, Bhopal, Chennai, Delhi and Mumbai, forthe years 2006-08 were utilized. The reproductive cancers among females constituted around 25% of the totaland around 9% among males. Among females, the three major contributors were cervix (55.5%), ovary (26.1%)and corpus uteri (12.4%). Similarly among males, the three major contributors were prostate (77.6%), penis(11.6%) and testis (10.5%). For females, the AAR of reproductive cancers varied between 30.5 in the registryof Mumbai to 37.3 in the registry of Delhi. In males, it ranged between 6.5 in the registry of Bhopal to 14.7 inthe registry of Delhi. For both males and females, the individual reproductive cancer sites showed increasingtrends with age. The leading treatment provided was: radio-therapy in combination with chemo-therapy forcancers of cervix (48.3%) and vagina (43.9%); surgery in combination with chemo-therapy (54.9%) for ovariancancer; and surgery in combination with radio-therapy for the cancers of the corpus uteri (39.8%). In males,the leading treatment provided was hormone-therapy for prostate cancer (39.6%), surgery for penile cancer(81.3%) and surgery in combination with chemo-therapy for cancer of the testis (57.6%)     

Disability Adjusted Life Years for Cancer Patients in India

The disability adjusted life year (DALY) has been employed to quantify the burden of diseases. This measureallows for combining in a single indicator “years of life lived with disabilities (YLD)” and “years of life lost frompremature death (YLL)”. The present communication attempts to estimate the burden of cancers in-terms ofYLL, YLD and DALY for “all sites” and leading sites of cancer in India for the years 2001, 2006, 2011 and 2016.The YLL, YLD and DALY were estimated by employing Global Burden of Disease (GBD) methodology usingthe DISMOD procedure. The published data on age, gender and site specific cancer incidence and mortality forthe years 2001-2003 relating to six population-based cancer registries viz. Bangalore, Barshi, Bhopal, Chennai,Delhi and Mumbai, expectation of life by gender for urban areas of the country for 1999-2003 and the projectedpopulation during years 2001, 2006, 2011 and 2016 were utilized for the computations. DALYs were found tobe lower for males (2,038,553, 2,313,843, 2,656,693 and 3,021,708 for 2001, 2006, 2011 and 2016 respectively)as compared to females (2,560,423, 2,961,218, 3,403,176 and 3,882,649). Amongst males, highest DALYs werecontributed by cancer of the lung and esophagus while in females they were for cancers of breast and cervix uteri.It is estimated that total DALYs due to cancer in India combined for both genders would increase from 4,598,976in 2001 to 6,904,358 by 2016. Premature mortality is a major contributor to disease burden. According to thepresent estimates, the YLL component of DALY is about 70.0%. The above described computations reveal anurgent need for initiating primary and secondary prevention measures for control of cancers.     

Trends in the brain cancer incidence in India

Trends in cancers of the central nervous system in both sexes in five Indian population based cancer registries (Mumbai, Chennai, Bangalore, Delhi and Bhopal) were evaluated over a period of the last two decades. For this purpose we applied a model that fits the data to a Linear Regression model. This approach revealed an increasing trend in cancers of nervous system in both sexes throughout the entire period of observation in almost all registries. As CNS cancers are increasing, analytic epidemiological studies should be planned in a near future on a priority basis to understand the etiology of these cancers in depth.     

Descriptive Epidemiology of Female Breast Cancer in Delhi,India

Background: Breast cancer is the most frequently diagnosed cancer in females worldwide. The Population Based Cancer Registry data of Delhi were here used to describe the epidemiology and trends in breast cancer incidence in Delhi. Methods: Crude rate, age-standardized incidence rates (ASR) and age-specific incidence rates were calculated using the data collected by Delhi PBCR for the year 2012. The time trend of breast cancer incidence was evaluated by joinpoint regression using the PBCR data from 1988-2012. Results: A total of 19,746 cancer cases were registered in 2012, 10,148 in males and 9,598 in females. Breast cancer was the leading site of cancer in females accounting for 2,744 (28.6%) of cases with a median age of 50 years. The crude and age standardized incidence rates for breast cancer were 34.8 and 41.0 per 100,000 females, respectively. Age specific incidence rates increased with age and attained a peak in the 70-74 years age group..A statistically significant increase in ASR with an annual percentage change (APC) of 1.44% was observed. Conclusions: The breast, which was the second most common cancer site in Delhi in 1988, has now surpassed cancer of cervix to become the leading site over the years. A similar trend has also been noted for other metropolitan cities viz. Bangalore, Bhopal and Chennai. Though the ASRs in these are comparable, they are still low compared to Western countries. Changing life styles in metropolitan cities like delayed marriage, late age at first child birth, lower parity and higher socio-economic status, may be some of the probable primary cause for higher incidences of breast cancer in urban as opposed to rural areas.     

An Alternative Approach to Study the Changes in the Cancer Pattern of Men in India (1988-2005)

Background: Changes in cancer pattern are often studied with regard to rank of leading sites, variation inage adjusted rates of sites over the time or with the help of time trends. However, these methods do not quantifythe changes in relation to overall changes that occurred in the total cancer cases over the period of time. Analternative approach is therefore necessary, particularly to identify emerging new cancers. Methods: The cancerincidence data of various sites for men, over the periods 1988-90 and 2003-05 in India, for five urban registriesnamely Bangalore, Bhopal, Chennai, Delhi and Mumbai, functioning under the network of National CancerRegistry Programme (ICMR), formed the sources of data for the present analysis. Changes in incidence cases byvarious cancer sites for men are assessed by calculating the differences in incidence cases over the two period oftime. Based on the contribution of each site to total change, the ten most leading sites are identified separately foreach registry. The relative changes in the sites with time are taken to identify the most emerging new cancer casesover the period of time. Results: The pooled cancer cases for men among five urban registries increased from30042 cases in 1988-90 to 46946 cases in 2003-05 registering an increase of about 55.8%. The lowest percentageof increase is observed in the registry of Mumbai (25.6%) and the maximum in Bhopal (96.4%). Based on thepooled figures of five urban registries, the lung cancer contributed the maximum % change (9.7%), followedby cancer of prostate (9.2%), mouth (7.5%), tongue (5.9%) and NHL (5.9%). Based on the pooled figures andthe relative changes, the emerging new cancers are prostate (140%), liver (112%) and mouth (95%). The %change by sites and the emerging new cancers varied between the registries.     

An Alternative Approach to Study the Changes in the Cancer Pattern of Women in India (1988-2005)

Background: The changes in the cancer pattern are often studied with the help of changes in the rank ofleading sites, changes in the Age Adjusted Rates of the sites over the time or with the help of time trends. However,these methods do not quantify the changes in relation to overall changes that occurred in the total cancer casesover the period of time. An alternative approach was therefore used to assess the changes in cancer pattern inrelation to overall changes in time and also an attempt was made to identify the most emerging new cancers inIndia. Methods: The cancer incidence data of various sites for women, over the periods 1988-90 and 2003-05 inIndia, for five urban registries namely Bangalore, Bhopal, Chennai, Delhi and Mumbai, functioning under thenetwork of National Cancer Registry Programme (ICMR), formed the sources of data for the present analysis.The changes in incidence cases by various cancer sites for women were assessed by calculating the differences inincidence cases over the two period of time. Based on the contribution of each site to total change, the ten mostleading sites were identified separately for each registry. The relative changes in the sites with time were takento identify the most emerging new cancer cases over the period of time. Results: The pooled cancer cases forwomen among five urban registries increased from 29447 cases in 1988-90 to 48472 cases in 2003-05 registeringan increased of about 63.3%. The lowest percentage of increase was observed in the registry of Chennai (41.5%)and the maximum in Bhopal (102.0%). Based on the pooled figures, the breast cancer contributed to the maximum% change (38%), followed by ovarian (8.0%), gallbladder (5.1%), corpus uteri (4.9%) and cervix uteri (4.1%).Based on the pooled data and relative changes, the emerging new cancers were corpus uteri (187%), gallbladder(162.1%) and lung cancer (136.1%). The % change by sites and the emerging new cancers varied between theregistries.     

Trends in cancer incidence in esophagus, stomach, colon, rectum and liver in males in India.

Time trends in cancers of the esophagus, stomach, colon, rectum and liver cancers among the male population in five Indian urban population based cancer registries (Mumbai, Bangalore, Chennai, Delhi, and Bhopal) were examined over the period of the last two decades. The model applied fits data to the logarithm of Y=ABx. This Linear Regression method showed decreasing trends in age-adjusted incidence rates for cancers of the stomach and esophagus, especially in Bjopal, and increasing trends for colon and rectum and liver, throughout the entire period of observation in most of the registries. The five cancers together constitute more than 80% of the total gastro intestinal cancers and are serious diseases in both sexes. To understand the etiology of these cancers in depth, analytic epidemiological studies should be planned in the near future on a priority basis.     

A Model Approach to Calculate Cancer Prevalence From 5 Year Survival Data for Selected Cancer Sites in India

Background: Prevalence is a statistic of primary interest in public health. In the absence of good followupfacilities, it is difficult to assess the complete prevalence of cancer for a given registry area. Objective: Anattempt was here made to arrive at complete prevalence including limited duration prevalence with respect toselected sites of cancer for India by fitting appropriate models to 1, 3 and 5 years cancer survival data availablefor selected population-based registries. Materials and Methods: Survival data, available for the registries ofBhopal, Chennai, Karunagappally, and Mumbai was pooled to generate survival for breast, cervix, ovary, lung,stomach and mouth cancers. With the available data on survival for 1, 3 and 5 years, a model was fitted andthe survival curve was extended beyond 5 years (up to 35 years) for each of the selected sites. This helped ingeneration of survival proportions by single year and thereby survival of cancer cases. With the help of survivalproportions available year-wise and the incidence, prevalence figures were arrived for selected cancer sites andfor selected periods. Results: The prevalence to incidence ratio (PI ratio) stabilized after a certain duration for allthe cancer sites showing that from the knowledge of incidence, the prevalence can be calculated. The stabilizedP/I ratios for the cancer sites of breast, cervix, ovary, stomach, lung, mouth and for life time was observed tobe 4.90, 5.33, 2.75, 1.40, 1.37, 4.04 and 3.42 respectively. Conclusions: The validity of the model approach tocalculate prevalence could be demonstrated with the help of survival data of Barshi registry for cervix cancer,available for the period 1988-2006.     

Incidence, mortality and survival in cancer of the cervix in Bangalore, India.

Cancer of the cervix is the most common cancer among women in India, constituting between one-sixth to one-half of all female cancers with an age-adjusted incidence rate ranging from 19.4 to 43.5 per 100,000 in the registries under the National Cancer Registry Programme (NCRP) (Annual Reports, NCRP, ICMR). It has been estimated that 100,000 new cases of cancer of the cervix occur in India every year, and 70% or more of these are Stage III or higher at diagnosis. However, the incidence of cancer of the cervix as suggested in this report appears to be on the decline in Bangalore. Besides incidence and clinical stage at presentation knowledge of survival is essential to complete the picture of establishing baseline indicators to monitor and evaluate cancer control programmes. Survival analysis was carried out in 2121 patients diagnosed during 1982-89 in the population of Bangalore, India. The observed 5 year survival was 34.4% and the relative survival 38.3%. Clinical stage at presentation was the single most important variable in predicting survival. The 5 year observed survival for stage I disease was 63.3%, for stage II 44.0%, for stage III 30.3% and for stage IV 5.7%.     

Changing Trends in Incidence of Ovarian Cancer - the Indian Scenario

Ovarian cancer has emerged as one of the most common malignancies affecting women in India. The presentcommunication reports the trends in the incidence rate of ovarian cancer for Indian women. The data publishedin Cancer Incidence in Five Continents for various Indian registries for different periods and / or publication bythe individual registries served as the source material. Mean annual percentage change (MAPC) in rates wascomputed using relative differences between two time periods. During the period 2001-06, the age-standardizedincidence rates (ASR) for ovarian cancer varied from 0.9 to 8.4 per 100,000 person years amongst variousregistries. The highest incidence was noted in Pune &Delhi registries. The Age Specific Incidence Rate (ASIR)for ovarian cancer revealed that the disease increases from 35 years of age and reaches a peak between the ages55-64. The trend analysis by period showed an increasing trend in the incidence rate of ovarian cancer in mostof the registries, with a mean annual percentage increase in ASR ranged from 0.7% to 2.4 %. Analysis of databy ASIR revealed that the mean annual percentage increase was higher for women in the middle and older agegroups in most of the registries. Estimation of annual percent change (EAPC) in ovarian cancer by Poissonregression model through Maximum Likelihood Estimation (MLE) for the data of 3 population-based cancerregistries vs. Mumbai, Chennai and Bangalore for the period 1983-2002 revealed that linear regression wasfound to be satisfactory fit between period and incidence rate. Statistically significant increase in EAPC wasnoted with the crude rate (CR,) ASR, and ASIR for several age-groups. Efforts should be made to detect ovariancancer at an early stage by educating population about the risk factors. Most of the ovarian cancers areenvironmental in origin and consequently, at least in principle avoidable.     

Prevalence of Tobacco Use and Tobacco-dependent Cancers in Males in the Rural Cancer Registry Population at Barshi,India

Background: In the Rural Cancer Registry at Barshi (western Maharashtra, India), it has been found thatthe incidence of cancer is relatively low. Aim: To explain the low incidence of tobacco related cancers in maleson the basis of prevalence of their tobacco habits. Setting and Design: Simple random sample of villages fromBarshi Rural Cancer Registry. Material and Methods: A tobacco survey was carried out in 5,319 adult males.Site specific incidence data for Barshi and Mumbai Cancer Registries were available from published reports inthe National Cancer Registry Programme. Published report of prevalence of tobacco habits in Mumbai maleswas available. Results: The tobacco survey showed that the prevalence of smoking compared to Mumbai waslow (9.9% vs 23.6%) and the incidence of smoking dependent cancers viz., cancers of oropharynx, larynx andlung were significantly low (P<0.05). However, although the proportion of tobacco chewers is higher in Barshicompared to Mumbai, the incidence rates for cancer of hypopharynx and oral cancer which are predominantlychewing dependent did not show higher rate than in Mumbai. Conclusions: The low incidence of smokingdependent cancers in males can be explained by the low prevalence of smoking habit but further studies areneeded to explain the observed incidence of predominantly chewing dependent cancers.     

Estimation of Time Trends of Incidence of Prostate Cancer – an Indian Scenario

Background: With increase in life expectancy, adoption of newer lifestyles and screening using prostatespecific antigen (PSA), the incidence of prostate cancer is on rise. Globally prostate cancer is the second mostfrequently diagnosed cancer and sixth leading cause of cancer death in men. The present communication makesan attempt to analyze the time trends in incidence for different age groups of the Indian population reportedin different Indian registries using relative difference and regression approaches. Materials and Methods: Thedata published in Cancer Incidence in Five Continents for various Indian registries for different periods and/orpublications by the individual registries served as the source materials. Trends were estimated by computing themean annual percentage change (MAPC) in the incidence rates using the relative difference between two timeperiods (latest and oldest) and also by estimation of annual percentage change (EAPC) by the Poisson regressionmodel. Results: Age adjusted incidence rates (AAR) of prostate cancer for the period 2005-2008 ranged from 0.8(Manipur state excluding Imphal west) to 10.9 (Delhi) per 105 person-years. Age specific incidence rates (ASIR)increased in all PBCRs especially after 55 years showing a peak incidence at +65 years clearly indicating thatprostate cancer is a cancer of the elderly. MAPC in crude incidence rate(CR) ranged from 0.14 (Ahmedabad)to 8.6 (Chennai) . Chennai also recorded the highest MAPC of 5.66 in ASIR in the age group of 65+. Estimatedannual percentage change (EAPC) in the AAR ranged from 0.8 to 5.8 among the three registries. Increase intrend was seen in the 5-64 year age group cohort in many registries and in the 35-44 age group in Metropolitancities such as Delhi and Mumbai. Conclusions: Several Indian registries have revealed an increasing trend inthe incidence of prostate cancer and the mean annual percentage change has ranged from 0.14-8.6.     

A Model Approach to Calculate Cancer Prevalence from 5 Years Survival Data for Selected Cancer Sites in India – Part II

Objective: Prevalence is a statistic of primary interest in public health. In the absence of good follow-upfacilities, it is often difficult to assess the complete prevalence of cancer for a given registry area. An attemptis made to arrive at the complete prevalence including limited duration prevalence with respect of selectedsites of cancer for India by fitting appropriate models to 1, 3 and 5 year cancer survival data available forselected registries of India. Methodology: Cancer survival data, available for the registries of Bhopal, Chennai,Karunagappally, and Mumbai was pooled to generate survival for the selected cancer sites. With the availabledata on survival for 1, 3 and 5 years, a model was fitted and the survival curve was extended beyond 5 years (upto 30 years) for each of the selected sites. This helped in generation of survival proportions by single year andthereby survival of cancer cases. With the help of estimated survived cases available year wise and the incidence,the prevalence figures were arrived for selected cancer sites and for selected periods. In our previous paper, wehave dealt with the cancer sites of breast, cervix, ovary, lung, stomach and mouth (Takiar and Jayant, 2013).Results: The prevalence to incidence ratio (PI ratio) was calculated for 30 years duration for all the selectedcancer sites using the model approach showing that from the knowledge of incidence and P/I ratio, the prevalencecan be calculated. The validity of the approach was shown in our previous paper (Takiar and Jayant, 2013). TheP/I ratios for the cancer sites of lip, tongue, oral cavity, hypopharynx, oesophagus, larynx, nhl, colon, prostate,lymphoid leukemia, myeloid leukemia were observed to be 10.26, 4.15, 5.89, 2.81, 1.87, 5.43, 5.48, 5.24, 4.61,3.42 and 2.65, respectively. Conclusion: Cancer prevalence can be readily estimated with use of survival andincidence data.