Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

Background Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival. Objective and design  This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. Results 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer. Conclusion  Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and path_MMR variant. We have updated our open-access website www.lscarisk. org to facilitate this

Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database

Objective Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers? Design Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants. Results 1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%). Conclusions Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94-1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer

Studies on Intraspecific Biodiversity of Horticultural Traits and in vitro Shoot Morphogenetic Response in Walnut (Juglans regia L.) Germplasm

The present investigation entitled “Studies on intraspecific biodiversity of horticultural traits and in vitro shoot morphogenetic response in walnut (Juglans regia L.) germplasm” was carried out in order to document the available genetic variability in walnut germplasm and to select elite walnut genotypes possessing superior attributes and quality traits. During the survey, data was recorded on one hundred fifty two (152) walnut trees growing in different areas of Kashmir valley. The study also involved establishment of response of elite walnut selections to different plant growth regulators in shoot morphogenesis. Remarkable variability was observed in seedling walnut trees for different morphological, nut and kernel characters. Tree canopy/spread varied between (1.20-12.50 m), stem diameter (0.3-3.6 m), leaf length (5.25-24.50 cm), leaf width (2.55-13.50 cm), nut weight (8.5-35.0 g), nut diameter (24.5-50.5 mm), nut length (30.0-60.0 mm), kernel weight (3.50-15.0 g), kernel percentage (31.03-70.0), protein content (14.15-24.25 %) and oil content (50.22-70.0 %). Similarly, variations were also reported for other characters viz., tree vigour, growth habit, branching habit, leaflet shape, shoot colour, nut shape, shell texture, shell colour, shell seal, shell strength, shell integrity, kernel shrivel and kernel colour. Woody species have been found to be far more difficult to clone in vitro than herbaceous plants. Poor response of the explants from mature woody species to in vitro manipulation is usually associated with the problem of browning and explant necrosis. The present studies were conducted on forced explants from three walnut selections (SKUAST 002, SKUAST 008, SKUAST 010). Murashiage and Skoog’s basal medium supplemented with 0.3 mg/l-1 Benzylamino purine and 0.1 mg/l-1 indole-3-butyric acid gave best response in the establishment of initiating cultures, minimum media browning (80.44 %), minimum explant browning (78.22 %) and minimum mean browning score per explant (9.17 %). The survival (23.45%) and growth of the cultures (21.77%) was also found to be maximum in MS medium supplemented with BAP 0.3 mg l-1 and IBA 0.1 mg l-1

Returning of cyclicity in infertile Corriedale sheep with natural progesterone and GnRH based strategies

Objective: To evaluate the return of ovarian cyclicity with four hormone based protocols during non-breeding season in infertile Corriedale sheep. Methods: The return to ovarian cyclicity was considered in terms of percent estrus response rate (ERR). The time of exhibition of estrus after either sponge removal or last PGF2α injection, was considered as time to onset of estrus. Infertile Corriedale ewes were randomly selected and distributed into four groups corresponding to four hormonal protocols such as PsE (intravaginal progesterone sponges for 12 days and eCG (equine chorionic gonadotropin) at 24 h before sponge removal; n = 6), GP (GnRH on day 0 and PGF2α on day 5; n = 7), GPG (GnRH on day 0, PGF2α on day 5 and second injection of GnRH on day 7; n = 7) and PsPG (Intravaginal progesterone sponges for 12 days, PGF2α and gonadotropin-releasing hormone (GnRH) respectively, at 24 h before and after sponge removal; n = 8). Results: PsPG protocol produced significantly (P  0.05) higher than GP (85.71%) and PsE (66%). Estrus was compact and more synchronized in PsPG group because 75% of ewes exhibited estrus during the first 48 h. The collective incidence of estrus (78.94%) was also maximum during the first 48 h. Conclusion: PsPG estrus induction strategy has a potential to replace eCG based protocols for returning of ovarian cyclicity in infertile Corriedale sheep

Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a prospective lynch syndrome database

Background: we have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. Methods: the cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Results: cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). Conclusions: the hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval