WEBVTT 1 00:00:00.480 --> 00:00:02.640 Hi, all, and welcome to today's lecture 2 00:00:02.640 --> 00:00:05.591 on the epidemiology of ovarian cancer. 3 00:00:05.591 --> 00:00:06.660 (mouse clicks) 4 00:00:06.660 --> 00:00:08.640 So in this lecture, we have several goals. 5 00:00:08.640 --> 00:00:11.040 We'll begin by describing the global burden 6 00:00:11.040 --> 00:00:12.810 of ovarian cancer. 7 00:00:12.810 --> 00:00:15.600 We'll next identify high and low-risk populations, 8 00:00:15.600 --> 00:00:17.010 and then look at the detection 9 00:00:17.010 --> 00:00:19.830 and staging of ovarian cancer. 10 00:00:19.830 --> 00:00:23.460 Next we will review studies of risk factors, 11 00:00:23.460 --> 00:00:25.650 look at the genetics of ovarian cancer, 12 00:00:25.650 --> 00:00:28.590 and look at the use of oral contraceptives. 13 00:00:28.590 --> 00:00:30.180 Finally we'll conclude by looking 14 00:00:30.180 --> 00:00:32.283 at screening and monitoring issues. 15 00:00:33.750 --> 00:00:35.370 So to begin with, 16 00:00:35.370 --> 00:00:37.020 there are two key diseases 17 00:00:37.020 --> 00:00:39.990 of the ovarian tract that we'll look at. 18 00:00:39.990 --> 00:00:42.060 The first is ovarian cysts. 19 00:00:42.060 --> 00:00:43.770 So ovarian cysts are follicular 20 00:00:43.770 --> 00:00:47.310 and luteal cysts within the cortex of the ovary. 21 00:00:47.310 --> 00:00:49.773 They usually have a few symptoms. 22 00:00:51.780 --> 00:00:53.160 They lead to an accumulation 23 00:00:53.160 --> 00:00:58.160 of serous fluid and can be diagnosed with an ultrasound. 24 00:00:58.200 --> 00:01:01.920 The second, the Stein-Leventhal syndrome 25 00:01:01.920 --> 00:01:05.550 is identified by bilateral polycystic ovaries, 26 00:01:05.550 --> 00:01:09.420 so ovaries on both sides with more than one cyst. 27 00:01:09.420 --> 00:01:10.770 This has numerous symptoms, 28 00:01:10.770 --> 00:01:14.193 including bleeding, hypermenorrhea, and virilism. 29 00:01:18.120 --> 00:01:21.090 The diagnosis of this syndrome 30 00:01:21.090 --> 00:01:25.713 is by palpation, ultrasound, or by pathologic examination, 31 00:01:26.580 --> 00:01:29.013 and it's typically treated with surgery. 32 00:01:30.780 --> 00:01:32.070 So next we'll look 33 00:01:32.070 --> 00:01:35.580 at the incidence rates of ovarian cancer globally. 34 00:01:35.580 --> 00:01:37.710 In 2012, ovarian cancer accounted 35 00:01:37.710 --> 00:01:40.080 for about 4% of female cancers, 36 00:01:40.080 --> 00:01:42.810 and 80 to 90% of cases were diagnosed during 37 00:01:42.810 --> 00:01:44.760 or after menopause. 38 00:01:44.760 --> 00:01:46.170 The peak incidence occurs 39 00:01:46.170 --> 00:01:50.039 at 50 to 60 years when it's 60 per 100,000. 40 00:01:50.039 --> 00:01:53.580 And 25,580 new ovarian cancer cases 41 00:01:53.580 --> 00:01:55.563 are diagnosed in the US per year. 42 00:01:56.820 --> 00:01:58.380 In the US there's a little 43 00:01:58.380 --> 00:02:01.600 over 16,000 deaths from ovarian cancer per year 44 00:02:02.790 --> 00:02:04.953 when these data were published in 2012. 45 00:02:06.990 --> 00:02:10.560 So the global patterns of ovarian cancer incidence 46 00:02:10.560 --> 00:02:13.260 and mortality are similar to that of breast cancer 47 00:02:13.260 --> 00:02:15.300 and high incidence immortality rates are found 48 00:02:15.300 --> 00:02:18.480 among Caucasian women living in industrialized nations such 49 00:02:18.480 --> 00:02:21.360 as the US, Canada, Europe, Scandinavia, Australia, 50 00:02:21.360 --> 00:02:23.403 New Zealand, Japan, and Russia. 51 00:02:25.080 --> 00:02:28.170 When we look at mortality of ovarian cancer, 52 00:02:28.170 --> 00:02:30.180 we see that trends, for the most part, 53 00:02:30.180 --> 00:02:32.673 follow those of incidence. 54 00:02:33.690 --> 00:02:36.210 In 2020, ovarian cancer had 55 00:02:36.210 --> 00:02:40.380 an age standardized global incidence of 6.6 per 100,000 56 00:02:40.380 --> 00:02:45.063 and an age standardized mortality of 4.2 per 100,000 women. 57 00:02:46.440 --> 00:02:47.770 Next when we look at 58 00:02:49.250 --> 00:02:50.940 the staging of ovarian cancer, 59 00:02:50.940 --> 00:02:52.890 we see that it typically develops silently 60 00:02:52.890 --> 00:02:54.180 over a period of many years 61 00:02:54.180 --> 00:02:57.240 without clinically detectable signs or symptoms. 62 00:02:57.240 --> 00:03:00.240 Unfortunately due to the silent spread, 63 00:03:00.240 --> 00:03:02.100 when cases are diagnosed, 64 00:03:02.100 --> 00:03:04.620 more than 70% of ovarian cancers have spread 65 00:03:04.620 --> 00:03:08.610 to lymph nodes, surrounding tissues, or beyond. 66 00:03:08.610 --> 00:03:09.540 As a consequence 67 00:03:09.540 --> 00:03:12.690 of the failure to detect ovarian cancer at an early stage, 68 00:03:12.690 --> 00:03:15.990 ovarian cancer generally has an extremely poor prognosis 69 00:03:15.990 --> 00:03:18.210 and worldwide, the five-year survival rate 70 00:03:18.210 --> 00:03:22.241 of ovarian cancer is only about 30%. 71 00:03:22.241 --> 00:03:24.120 (mouse clicks) 72 00:03:24.120 --> 00:03:26.220 Looking at the anatomy of the human ovary, 73 00:03:26.220 --> 00:03:27.300 we see that it is covered 74 00:03:27.300 --> 00:03:30.930 by surface epithelium and the inner core, or the cortex 75 00:03:30.930 --> 00:03:33.330 that consists of multiple cell types. 76 00:03:33.330 --> 00:03:35.130 There are follicles within the cortex 77 00:03:35.130 --> 00:03:37.200 that contain the oocytes or eggs, 78 00:03:37.200 --> 00:03:40.170 granulosa cells, and theca cells. 79 00:03:40.170 --> 00:03:42.570 Granulosa cells surround and nourish the oocytes 80 00:03:42.570 --> 00:03:45.930 in response to follicular-stimulating hormone or FSH, 81 00:03:45.930 --> 00:03:48.420 which is secreted by the pituitary gland. 82 00:03:48.420 --> 00:03:51.810 And theca cells respond to the luteinizing hormone or LH 83 00:03:51.810 --> 00:03:53.100 and synthesize androgens 84 00:03:53.100 --> 00:03:55.500 that are subsequently aromatized estrogens 85 00:03:55.500 --> 00:03:57.870 by the granulosa cells. 86 00:03:57.870 --> 00:04:00.570 Upon ovulation, the remnant of the follicle, 87 00:04:00.570 --> 00:04:01.830 or the corpus luteum, 88 00:04:01.830 --> 00:04:04.113 secretes progesterone as well as estrogen. 89 00:04:05.340 --> 00:04:07.590 So as I mentioned before, 90 00:04:07.590 --> 00:04:10.470 the pathogenesis of ovarian cancer. 91 00:04:10.470 --> 00:04:12.330 The ovarian cancer arises 92 00:04:12.330 --> 00:04:15.153 from epithelial cells at the surface of the ovary. 93 00:04:16.590 --> 00:04:18.090 The genesis of ovarian cancer 94 00:04:18.090 --> 00:04:20.250 is likely related to incessant ovulation 95 00:04:20.250 --> 00:04:21.420 and repetitive disruption 96 00:04:21.420 --> 00:04:25.050 in wound healing of the surface epithelium coincident 97 00:04:25.050 --> 00:04:28.950 with the menstrual cycle during the reproductive years. 98 00:04:28.950 --> 00:04:31.200 Incessant ovulation could sustain exposure 99 00:04:31.200 --> 00:04:32.400 of the ovarian epithelium 100 00:04:32.400 --> 00:04:35.520 to hormones like estrogen, progesterone, 101 00:04:35.520 --> 00:04:38.430 and growth factors secreted by the ovarian cortex 102 00:04:38.430 --> 00:04:41.370 as well as increasing the inflammatory microenvironment 103 00:04:41.370 --> 00:04:43.830 of cytokines and prostaglandins leading 104 00:04:43.830 --> 00:04:46.920 to cell damage and oxidative stress. 105 00:04:46.920 --> 00:04:48.960 In support of the incessant ovulation model, 106 00:04:48.960 --> 00:04:50.880 several epidemiological studies have determined 107 00:04:50.880 --> 00:04:53.460 that the number of successive ovulatory cycles 108 00:04:53.460 --> 00:04:54.960 uninterrupted by pregnancy, 109 00:04:54.960 --> 00:04:57.150 lactation, and/or contraception, 110 00:04:57.150 --> 00:04:59.613 increases the risk of ovarian cancer. 111 00:05:02.383 --> 00:05:04.890 (mouse clicks) 112 00:05:04.890 --> 00:05:07.890 This diagram depicts the relationship 113 00:05:07.890 --> 00:05:09.750 between the hypothalamus, 114 00:05:09.750 --> 00:05:13.320 the pituitary gland, and the ovaries in relation 115 00:05:13.320 --> 00:05:16.677 to the roles of follicle-stimulating hormone 116 00:05:16.677 --> 00:05:19.650 and luteinizing hormone on the ovary, 117 00:05:19.650 --> 00:05:21.780 and the production of estrogens and progesterone 118 00:05:21.780 --> 00:05:24.300 by the ovary. 119 00:05:24.300 --> 00:05:28.170 Perimenopausal events, including diminished ovarian hormones 120 00:05:28.170 --> 00:05:31.680 and excess pituitary gonadotropins, 121 00:05:31.680 --> 00:05:33.390 are temporarily related to the onset 122 00:05:33.390 --> 00:05:36.750 of ovarian cancer in the postmenopausal years. 123 00:05:36.750 --> 00:05:38.760 So when these events occur, 124 00:05:38.760 --> 00:05:40.180 women are more likely to 125 00:05:42.360 --> 00:05:46.203 develop ovarian cancer after menopause. 126 00:05:47.910 --> 00:05:51.330 There's several key risk factors for ovarian cancer. 127 00:05:51.330 --> 00:05:54.030 These include early menarche, late first pregnancy, 128 00:05:54.030 --> 00:05:57.930 late menopause, infertility, obesity and hypertension. 129 00:05:57.930 --> 00:06:01.110 A familial history of breast or ovarian cancer, 130 00:06:01.110 --> 00:06:05.820 as well as presence of the BRCA1 and BRCA2 mutations. 131 00:06:05.820 --> 00:06:09.360 Talc exposure, lactose or galactose intolerance, 132 00:06:09.360 --> 00:06:13.170 and hypergonadotropic, hypogonadism. 133 00:06:14.340 --> 00:06:17.986 This final risk factor, 134 00:06:17.986 --> 00:06:20.133 hypergonadotropic, hypogonadism, 135 00:06:21.000 --> 00:06:24.840 is known also as ovarian dysgenesis. 136 00:06:24.840 --> 00:06:28.140 So there's two key syndromes that are related to this. 137 00:06:28.140 --> 00:06:29.640 The first Klinefelter syndrome, 138 00:06:29.640 --> 00:06:32.580 which we covered in the breast cancer lecture, 139 00:06:32.580 --> 00:06:37.323 are when a male has two X chromosomes and one Y chromosome. 140 00:06:38.280 --> 00:06:40.170 And also Turner syndrome, 141 00:06:40.170 --> 00:06:41.400 which is when an individual only 142 00:06:41.400 --> 00:06:46.023 has one X chromosome and no second X or Y chromosome. 143 00:06:51.270 --> 00:06:53.640 A breast, or a strong family history 144 00:06:53.640 --> 00:06:55.890 of breast or ovarian cancer increases the risk 145 00:06:55.890 --> 00:06:58.830 of ovarian cancer by three to five-fold 146 00:06:58.830 --> 00:07:00.420 and a genetic predisposition 147 00:07:00.420 --> 00:07:02.700 is identifiable for approximately 5 to 10% 148 00:07:02.700 --> 00:07:05.073 of women diagnosed with ovarian cancer. 149 00:07:06.630 --> 00:07:10.020 The two key heritable genetic mutations play a role 150 00:07:10.020 --> 00:07:12.420 in predisposing individuals to familial breast 151 00:07:12.420 --> 00:07:16.410 and ovarian cancer, and those are BRCA1 and BRCA2. 152 00:07:16.410 --> 00:07:18.810 BRCA1 was discovered in 1990 153 00:07:18.810 --> 00:07:22.350 and it occurs on the long arm of chromosome 17 154 00:07:22.350 --> 00:07:25.800 and BRCA2 was identified in 1994 155 00:07:25.800 --> 00:07:28.500 on the long arm of chromosome 13. 156 00:07:28.500 --> 00:07:30.180 A mutation in either gene 157 00:07:30.180 --> 00:07:32.190 predisposes heterozygous female carriers 158 00:07:32.190 --> 00:07:34.173 to breast cancer and ovarian cancer. 159 00:07:35.010 --> 00:07:37.860 The lifetime risk of breast cancer in women who carry one 160 00:07:37.860 --> 00:07:41.670 of these mutations is approximately 85% 161 00:07:41.670 --> 00:07:45.070 where the lifetime ovarian cancer risk for women with 162 00:07:46.679 --> 00:07:49.830 a BRCA1 mutation is 54% compared 163 00:07:49.830 --> 00:07:52.623 to 24% with a BRCA2 mutation. 164 00:07:53.730 --> 00:07:56.700 These two genes are tumor suppressor genes 165 00:07:56.700 --> 00:07:58.110 that upon transcription, 166 00:07:58.110 --> 00:07:59.460 form proteins that are essential 167 00:07:59.460 --> 00:08:02.070 for the repair of double-stranded DNA breaks. 168 00:08:02.070 --> 00:08:06.090 So it makes sense then that when these two genes are mutated 169 00:08:06.090 --> 00:08:09.810 and they're not being transcribed correctly, 170 00:08:09.810 --> 00:08:12.030 that these double-stranded DNA breaks 171 00:08:12.030 --> 00:08:14.610 are not being repaired as often 172 00:08:14.610 --> 00:08:18.573 or as well as they would without the mutation. 173 00:08:20.640 --> 00:08:23.520 Another key genetic condition that predisposes 174 00:08:23.520 --> 00:08:25.290 to ovarian cancer is hereditary 175 00:08:25.290 --> 00:08:27.900 nonpolyposis colorectal cancer, 176 00:08:27.900 --> 00:08:30.540 or also known as Lynch syndrome. 177 00:08:30.540 --> 00:08:31.800 This is caused by mutations 178 00:08:31.800 --> 00:08:35.550 of mismatch repair genes like MSH2 and MLH1 179 00:08:35.550 --> 00:08:38.580 that normally repair DNA during cell division. 180 00:08:38.580 --> 00:08:41.820 So we see with both BRCA1, BRCA2, 181 00:08:41.820 --> 00:08:43.710 and these other genes, 182 00:08:43.710 --> 00:08:45.690 is that mutations in genes that are responsible 183 00:08:45.690 --> 00:08:46.860 for repairing cells 184 00:08:46.860 --> 00:08:50.070 and playing a role in cell division are oftentimes related 185 00:08:50.070 --> 00:08:52.503 to increased risk of cancer. 186 00:08:55.500 --> 00:08:57.000 Here in this figure, 187 00:08:57.000 --> 00:08:58.180 we see that 188 00:08:59.700 --> 00:09:01.830 when a mother is affected with one 189 00:09:01.830 --> 00:09:06.000 of these genes or mutations like BRCA1 or BRCA2, 190 00:09:06.000 --> 00:09:08.730 the sons have a 50% chance of becoming a gene carrier 191 00:09:08.730 --> 00:09:10.470 and the daughters have a 50% chance 192 00:09:10.470 --> 00:09:13.713 of inheriting the syndrome and becoming a gene carrier. 193 00:09:15.540 --> 00:09:18.360 Other key risk factors of ovarian cancer are the use 194 00:09:18.360 --> 00:09:21.030 of fertility drugs, perinatal talcum powder, 195 00:09:21.030 --> 00:09:23.700 dietary lactose, a high BMI, 196 00:09:23.700 --> 00:09:25.683 and estrogen replacement therapy. 197 00:09:27.150 --> 00:09:28.500 While some studies suggests 198 00:09:28.500 --> 00:09:30.120 that fertility drugs increase the risk 199 00:09:30.120 --> 00:09:32.700 of developing ovarian cancer, 200 00:09:32.700 --> 00:09:33.930 due to their increase 201 00:09:33.930 --> 00:09:36.990 in the secretion of follicle-stimulating hormone or FSH, 202 00:09:36.990 --> 00:09:40.413 and luteinizing hormone or LH to help stimulate ovulation, 203 00:09:41.280 --> 00:09:43.650 other studies found no increases in risk 204 00:09:43.650 --> 00:09:46.450 among women who use fertility drugs and become pregnant. 205 00:09:49.860 --> 00:09:52.080 Some studies have also found that the use 206 00:09:52.080 --> 00:09:54.600 of talcum powder has increased the risk 207 00:09:54.600 --> 00:09:57.000 of developing ovarian cancer. 208 00:09:57.000 --> 00:09:59.070 Though a meta-analyses 209 00:09:59.070 --> 00:10:01.500 of 16 case-control studies determined 210 00:10:01.500 --> 00:10:03.540 a modest increase in the risk, 211 00:10:03.540 --> 00:10:05.040 but also revealed 212 00:10:05.040 --> 00:10:07.680 that there were differences between studies. 213 00:10:07.680 --> 00:10:11.130 The biological basis of the carcinogenicity 214 00:10:11.130 --> 00:10:13.740 of talc remains controversial since inhaled talc 215 00:10:13.740 --> 00:10:15.990 in mining and milling operations has not been found 216 00:10:15.990 --> 00:10:19.623 to be associated with the development of cancers. 217 00:10:21.720 --> 00:10:23.820 Next, a recent study found that the use 218 00:10:23.820 --> 00:10:26.850 of the synthetic male hormone danazol increased the risk 219 00:10:26.850 --> 00:10:29.370 of developing ovarian cancer. 220 00:10:29.370 --> 00:10:31.650 This hormone is sometimes prescribed to women who suffer 221 00:10:31.650 --> 00:10:34.200 from endometriosis, a condition associated 222 00:10:34.200 --> 00:10:37.290 with dysplasia and bleeding of the endometrium. 223 00:10:37.290 --> 00:10:39.720 A pooled analysis of eight case-control studies found 224 00:10:39.720 --> 00:10:42.783 that endometriosis increased the risk of ovarian cancer. 225 00:10:46.320 --> 00:10:49.420 Also when we look at polycystic ovaries syndrome 226 00:10:50.340 --> 00:10:52.620 this is a relatively common female endocrine disorder 227 00:10:52.620 --> 00:10:55.500 that affects five to 10% of women of reproductive age. 228 00:10:55.500 --> 00:10:57.840 This syndrome is a leading cause of female infertility 229 00:10:57.840 --> 00:10:59.430 and develops when the ovaries are stimulated 230 00:10:59.430 --> 00:11:01.950 to produce excessive amounts of male hormones, 231 00:11:01.950 --> 00:11:04.440 particularly testosterone either through the release 232 00:11:04.440 --> 00:11:06.450 of excess luteinizing hormone 233 00:11:06.450 --> 00:11:08.100 by the interior pituitary gland 234 00:11:08.100 --> 00:11:10.450 or through high levels of insulin in the blood. 235 00:11:11.670 --> 00:11:14.490 One small study found that there was a slight increase 236 00:11:14.490 --> 00:11:17.760 in the risk of ovarian cancer with this syndrome, 237 00:11:17.760 --> 00:11:21.063 but this study has not been confirmed with other studies. 238 00:11:23.010 --> 00:11:26.130 We also see that as mentioned before, 239 00:11:26.130 --> 00:11:28.050 interruption of the menstrual cycle 240 00:11:28.050 --> 00:11:29.280 by a first pregnancy early 241 00:11:29.280 --> 00:11:32.340 in the reproductive years may serve 242 00:11:32.340 --> 00:11:34.800 as a protective factor due 243 00:11:34.800 --> 00:11:37.890 to an interruption in the 244 00:11:37.890 --> 00:11:39.933 presence of certain hormones. 245 00:11:42.000 --> 00:11:44.340 Countries with widespread oral contraceptive use 246 00:11:44.340 --> 00:11:47.160 also have declining ovarian cancer rates. 247 00:11:47.160 --> 00:11:48.540 Oral contraceptives interfere 248 00:11:48.540 --> 00:11:52.710 with pituitary hormones FSH and LH, 249 00:11:52.710 --> 00:11:54.480 while multiple epidemiological studies 250 00:11:54.480 --> 00:11:55.800 have found significant reductions 251 00:11:55.800 --> 00:11:57.570 in the risk of ovarian cancer 252 00:11:57.570 --> 00:12:00.063 in women who use oral contraceptives. 253 00:12:00.990 --> 00:12:01.823 And in fact, 254 00:12:01.823 --> 00:12:04.920 a comprehensive meta-analysis of 45 studies looking 255 00:12:04.920 --> 00:12:08.220 at over 100,000 individuals 256 00:12:08.220 --> 00:12:11.070 found that the use of oral contraceptives reduced the risk 257 00:12:11.070 --> 00:12:12.790 of developing ovarian cancer 258 00:12:13.710 --> 00:12:17.673 by as much as 29% per five years of use, finally, 259 00:12:21.510 --> 00:12:22.920 we'll conclude by looking 260 00:12:22.920 --> 00:12:27.090 at the incidence of ovarian cancer in Caucasian women 261 00:12:27.090 --> 00:12:28.860 and ovarian cancer by age. 262 00:12:28.860 --> 00:12:32.010 So approximately 75% of breast cancers are diagnosed 263 00:12:32.010 --> 00:12:34.200 in women after they undergo menopause. 264 00:12:34.200 --> 00:12:35.550 There's a general consensus 265 00:12:35.550 --> 00:12:37.020 that estrogen replacement therapy, 266 00:12:37.020 --> 00:12:38.190 with or without progesterone, 267 00:12:38.190 --> 00:12:41.730 elevates the risk of postmenopausal breast cancer 268 00:12:41.730 --> 00:12:43.350 by two to threefold 269 00:12:43.350 --> 00:12:46.920 and may play a role in the development 270 00:12:46.920 --> 00:12:49.590 of ovarian cancer as well. 271 00:12:49.590 --> 00:12:52.470 However, these study results 272 00:12:52.470 --> 00:12:54.210 are not as cut and dry 273 00:12:54.210 --> 00:12:56.190 as have previously been reported, 274 00:12:56.190 --> 00:12:59.520 and it's important to check out the podcast 275 00:12:59.520 --> 00:13:01.320 and New York Times Magazine article linked 276 00:13:01.320 --> 00:13:04.593 in this module to learn more about these conclusions. 277 00:13:06.199 --> 00:13:08.280 (mouse clicks) 278 00:13:08.280 --> 00:13:11.880 As mentioned at the beginning of this presentation, 279 00:13:11.880 --> 00:13:13.890 we note that there's no early stage detection 280 00:13:13.890 --> 00:13:17.520 of ovarian cancer as it's oftentimes asymptomatic. 281 00:13:17.520 --> 00:13:20.250 Because of that, more than 70% of ovarian tumors 282 00:13:20.250 --> 00:13:22.170 are diagnosed after they've metastasized 283 00:13:22.170 --> 00:13:25.623 to contiguous tissues or/and nearby lymph nodes. 284 00:13:26.850 --> 00:13:28.500 While several studies have looked 285 00:13:28.500 --> 00:13:33.130 at the CA-125 biomarker as that 286 00:13:35.591 --> 00:13:37.800 has shown to be 287 00:13:37.800 --> 00:13:40.710 present and measurable and being secreted 288 00:13:40.710 --> 00:13:44.220 by ovarian cancer cells at the time of one's diagnosis, 289 00:13:44.220 --> 00:13:47.640 attempts that have been made to use this biomarker 290 00:13:47.640 --> 00:13:49.380 as a screening tool or 291 00:13:49.380 --> 00:13:52.743 as a tool of early detection have not been successful.