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Autosomal recessively inherited non-polyposis colorectal cancer: genotype and phenotype


Gut 2010;59:A111-A112; doi:10.1136/gut.2009.208983k

Neoplasia and cancer pathogenesis posters
PWE-067 Recessively inherited non-polyposis colorectal cancer: genotype and phenotype

K J Monahan1,2, K Pack2, C Cummings1, H J W Thomas1, I P M Tomlinson2

1 Family Cancer Clinic, Imperial College and St Mark’s Hospital, London, UK
2 Department of Molecular and Population Genetics, Cancer Research UK, London, UK

Introduction: Patients diagnosed before 50 years of age have a likely strong genetic or environmental aetiological factor. There is good evidence from population studies1 that recessive inheritance is common in young colorectal cancer patients.

Methods: A cohort of 133 colorectal cancer patients were diagnosed under the age of 50 years who did not have multiple polyps or a family history suggestive of dominant inheritance. They were identified and recruited from the Bobby Moore Database in the Family Cancer Clinic, St Mark’s Hospital, Harrow. MUTYH was screened for germline mutations. As these patients fulfilled Bethesda criteria they were tested for hereditary non-polyposis colorectal cancer (HNPCC) by microsatellite instability analysis and immunohistochemistry of mismatch repair proteins. Immunohistochemistry was also performed on β-catenin and P53. Loss of heterozygosity of the APC locus at 5q21–22 was tested using a set of microsatellite markers. Sequencing was used to identify somatic mutations in KRAS and BRAF.

Results: Forty-four patients (33%) had cancers proximal to the splenic flexure, 79 (59%) distal and had 11 (8%) synchronous colorectal cancers. Thirty-seven patients (28%) had an affected sibling and 33 (25%) patients had a second-degree relative with cancer at any site. The median age of diagnosis of colorectal cancer was 39 years (range 14–49 years of age). Twenty-six patients (20%) were found to harbour sequence variation in the MUTYH gene but none of these variants were likely to be pathogenic, and there was no difference in the frequency of these compared to a control group of 50 patients. Eighty percent of tumours were found to be microsatellite stable. 20/30 cancers had nuclear localisation of β-catenin and 21/30 had nuclear localisation of P53 antibodies on immunohistochemistry. Loss of heterozygosity of the APC locus at 5q21–22 was present in 14/30 cases. Thus Wnt pathway activation is likely by over half of this group of cancers. Four cancers had BRAF V600E mutations and five had KRAS codon 12 or 13 mutations.

Conclusion: In a cohort of 133 young colorectal cancer patients without multiple polyps, most tumours demonstrated Wnt pathway activation and other somatic changes consistent with the classical adenoma-to-carcinoma sequence. Germline mutations in the colorectal neoplasia predisposition gene MUTYH appear to be rare events in such patients. The majority of recessive inheritance in young patients is probably caused by mutations in unknown predisposition genes.

Talking Turkey About Lynch Syndrome – Webinar 11/14/2012


 

– Were you diagnosed with colon or rectal cancer before the age of 50?
– Was anyone in your family diagnosed with colon cancer before the age of 50?
– Was anyone in your family diagnosed with uterine (endometrial) cancer before the age of 50?
– Are there cancers across several generations on one side of your family?

If you answered YES to just one of these questions, it’s time to talk turkey about Lynch syndrome.

Lynch syndrome is an inherited genetic mutation, and having it increases your chance of getting colorectal cancer to 80%. Unfortunately, nearly every person living with Lynch syndrome is completely unaware of it.

Lynch syndrome also puts you at higher risk for brain, breast, kidney, melanoma, ovarian, pancreas, small bowel, stomach, or uterine/endometrial cancers. Knowledge is power and will help your medical team act more aggressively with their screening measures.

Brian Mansfield, a music critic for USA Today, didn’t know he had Lynch syndrome until he was diagnosed with colorectal cancer earlier this year at the age of 48. After his diagnosis, he began talking with his family about their health history, “then the family tree lit up like a Christmas tree.” Brian is chronicling his journey through a weekly USA Today online column, “My Semicolon Life.”

Join national patient advocacy group Fight Colorectal Cancer as we host Brian and his doctor, Dr. Bill Harb, a colorectal surgeon at Cumberland Surgical Associates, along with Associate Director of Human Genetics at Ohio State University Heather Hampel as they tell you more about Lynch syndrome and how to dig into the medical mystery that may be lurking within your family tree. With the holidays coming up, never has there been a more appropriate time to talk turkey…and Lynch syndrome.

**Fight Colorectal Cancer thanks Can’t Stomach Cancer, the Colon Club, Kidney Cancer Association, Myriad Genetics, and Ovarian Cancer National Alliance for their assistance with this webinar.**

FightColorectalCancer.org

The Aetiology of Hyperplastic Polyposis Syndrome


THE AETIOLOGY OF HYPERPLASTIC POLYPOSIS SYNDROME IN A LARGE FAMILY FROM THE WEST OF IRELAND

K. J. Monahan1, L. Carvajal-Carmona2, T. Guenther3, T. O’Gorman4, J. Cazier2, I. P. Tomlinson2, H. J. W. Thomas1. 1Family Cancer Clinic, St Mark’s Hospital, 2Molecular and Population Genetics Lab, Cancer Research UK, 3Academic Department of Pathology, St Mark’s Hospital, London, UK, 4Department of Medicine, University College Hospital, Galway, Ireland. Gut 2008;57:A1-A172. BSG 2008.

Introduction: We have identified a family with a dominantly inherited predisposition to mixed histology multiple polyps and colorectal cancer. The family meet WHO criteria for hyperplastic polyposis syndrome. We have attempted to elucidate the gene which predisposes to this condition.

Aims & Methods: Mutations in APC, MYH, SMAD4 and genes which cause HNPCC were excluded by direct sequencing and other methods. Somatic mutations were screened in genes often mutated in colorectal cancers. Genome wide genotypes were obtained for over 10000 SNPs using Affymetrix 10k plus 2 arrays and linkage analysis was performed. Genome wide copy number variation analysis was also performed using the Goldengate SNP platform. Whole genome expression analysis profiles were obtained on cell line RNA using the Affymetrix U133 Plus 2.0 GeneChip oligonucleotide arrays.

Results: The polyps appear to follow a hyperplastic/serrated polyp to mixed serrated/adenomatous (see fig) to adenocarcinoma sequence. Linkage analysis shows a maximum parametric LOD score of 2.71 at 8p22–21.3. Genome wide copy number and loss of heterozygosity (LOH) studies reveal LOH at 8p and 17p in the cancers. A number of genes at that locus including BMP1 and MTUS1 have been screened, the latter gene having more than a fivefold up-regulation in expression.

Conclusion: We have identified a locus on chromosome 8p which predisposes to hyperplastic polyps and colorectal cancer in a large family from the West of Ireland. This is the first time such an association has been identified and may be useful in screening families at risk of colorectal neoplasia.

Related Article: Hyperplastic Polyposis SyndromeTHE AETIOLOGY OF HYPERPLASTIC POLYPOSIS SYNDROME IN A LARGE FAMILY FROM THE WEST OF IRELAND

A dedicated service for the Management of Hereditary Colorectal Cancer Improves Adherence with Molecular Testing for Lynch Syndrome


A DEDICATED SERVICE FOR THE MANAGEMENT OF HEREDITARY COLORECTAL CANCER IMPROVES ADHERENCE WITH MOLECULAR TESTING FOR LYNCH SYNDROME

UEGW Amsterdam 2012

Leon Sergot, Sophie Stevens Poster, Fiona Turkes, Jason Smith, Kevin J. Monahan

The Family History of Bowel Cancer Clinic, West Middlesex University Hospital, London, United Kingdom

INTRODUCTION/OBJECTIVES:

Lynch Syndrome (LS) is responsible for 2-3% of colorectal cancer (CRC) which equates to ~1000 cases of CRC in the United Kingdom annually. Previous studies have demonstrated that in current practise less than 10% of these cases are identified as LS due to lack of appropriate testing. The international Bethesda guidelines were devised in 2002 to help identify such cases for tumour testing for the molecular features of LS, such as immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 expression, or DNA microsatellite instability analysis (MSI). These criteria include all individuals diagnosed

AIMS & METHODS:

We identified all new cases of CRC over 1 year before and after the establishment of a dedicated ‘Family History of Bowel Cancer Service’ in our hospital in March 2011. Adherence to the Bethesda guidelines was determined by examination of medical records and UK National Bowel Cancer Audit Programme (NBOCAP) data. Pathology reports were studied in patients aged 50-59 years at diagnosis for features consistent with MSI-type histology.

RESULTS:

In total, 198 cases of CRC were discussed at the CRC multidisciplinary meeting over a 2 year period. 12 individuals were diagnosed under the age of 50 years (~6%) consistent with Office of National Statistics (ONS) data. 31 patients were diagnosed between 50-59 years, of which 4 patients had MSI-type histology. A further 25 patients had a significant family history of CRC or a LS-related cancer diagnosed under 50 years. Therefore in total 41 patients fulfilled Bethesda criteria (20.7%). Between March 2010-March 2011 there were 18 such cases with only 1 patient’s tumour tested for the molecular features of LS (5.6%) compared to 19/23 cases tested in the subsequent year (82.6%), p value = 9.7e-7 (Chi=23.9956).  Six out of 20 (30%) cases tested demonstrated these molecular features with MSI and abnormal IHC, and are undergoing germline genetic testing.

CONCLUSION:

The establishment of a dedicated family history of bowel cancer service resulted in a significant improvement in testing individuals diagnosed with CRC with a possible diagnosis of LS. We recommend that this service be applied to identify such families throughout the United Kingdom to improve clinical pathways for these patients.

via Abstract View.

Family Health History | Genetic Alliance


Family Health History

A peek into the past can reveal a lot about your future.

Family health history is the story of diseases that run in your family. It is one part of the entire history of your family. Along with culture, values, environment, and behaviors, family health history influences the way you live your life. Learning about your family health history can help you make healthy choices: it is a cheap, easy way to improve your own health and the health of your family. Share the information you gather with your healthcare provider to further reduce your risk of disease and create a partnership around your health.

Check out the Does It Run In the Family? toolkit in English and Spanish! “A Guide to Family Health History” explains the importance of family health history, how to collect it, and how to organize it. “A Guide to Genetics and Health” explains genetics 101 and gives information on conditions that can run in the family, such as heart disease, diabetes, and cancer.

Customize these booklets for your family, organization, or community.

A Guide to Family Health History, English version, cover A Guide to Family Health History English

A Guide for Understanding Genetics and Health, English version, cover A Guide for Understanding Genetics and Health English

A Guide to Family Health History, Spanish version, cover A Guide to Family Health History Spanish

A Guide for Understanding Genetics and Health, Spanish version, cover A Guide for Understanding Genetics and Health Spanish

“A Guide to Family Health History” is also available in Chinese.

View several different versions on the Genetic Alliance YouTube Channel.

Tips For Collecting Your Family Health History

Learn all you can about your family’s health!

How do I collect family health history?

Talk to your family!

Holidays and other family events (birthdays, weddings, religious gatherings) provide a great opportunity to ask family members about their lives.

Plan individual conversations to get more information.

Use what you have—existing charts or trees, photo albums, baby books, birthday date books, etc.

Send a survey. This can be part of a holiday newsletter or school project.

What information should I collect?

Collect this information for you, your parents, siblings, and children, and then move on to the extended family:

  • name and relationship to you (myself, parent, child, etc.)
  • ethnicity, race, and/or origins of family
  • place and date of birth (or your best guess—for example, “1940s”)
  • if deceased, age and cause of death
  • health history—include conditions such as heart disease, diabetes, and cancer—and when the disease started
  • lifestyle (occupation, exercise, diet, habits such as smoking and regular doctor check-ups)

Collect stories about your heritage and culture. This is an excellent opportunity to preserve your family’s memories.

“Conversations about family health history should be ongoing, not a one-time topic to be discussed and forgotten. What you learn can shape your future and even save your life.”

Sharon Terry, President & CEO, Genetic Alliance

What should I do with the information I collect?

Bring it to your healthcare provider. S/he might refer you to a genetics specialist or recommend early screening.

Use it to make healthy lifestyle choices. You can change your diet and exercise habits to reduce your risk for many conditions.

Share it with your family. Shared knowledge can lead to support.

Keep adding to your family health history. It is a lifelong process!

For more family health history resources, click here.

via Family Health History | Genetic Alliance.

 

My Semicolon Life: Just like that, I’ve got cancer by Brian Mansfield


My Semicolon Life: Just like that, I’ve got cancer

Brian Mansfield, Special for USA TODAY

USA TODAY’s Nashville music critic on fighting colon cancer and learning he has a genetic disorder called Lynch syndrome.

5:25PM EST November 4. 2012 – When USA TODAY’s Nashville music critic Brian Mansfield was diagnosed with colon cancer at age 48, he figured that a lifetime of Southern-fried foods, extra-large sodas and stress eating on deadline had brought it on. Turned out he had a genetic syndrome that gave him an 80% chance of developing colon cancer. He chronicles his life with the disease — and with only a small part of his colon.

Luckily, the sedation hadn’t quite worn off when the gastroenterologist told my wife that the colonoscopy had revealed a 5-centimeter tumor eating into my colon wall. I absorbed the blow, internalizing it without fully reacting to it.

Before I had completely gathered my senses, I already had started taking the next necessary steps: getting a CT scan to see if the cancer had spread, meeting with a surgeon, calling family and friends, including a colleague who’d had a persistent cough at the same time I had the digestive problems that finally sent me to a doctor. We had joked that she probably had lung cancer and I had stomach cancer. Off by a couple organs.

“Did you have cancer?” I asked. ” ‘Cause I do!” She didn’t think that was nearly as funny as I did.

Who should we contact?

Nancy and I drew up a list of people to call before taking the news to Facebook and Twitter. Eventually, I cut it off at People Who’ll Get Really Ticked If They Hear From Somebody Else. Breaking the news to our four kids wasn’t as easy.

The oldest, Nick, 20, was away for the weekend; we waited until he got back to tell him. Zach, our 18-year-old, had just taken anatomy and knew the questions to ask. Yes, there’d been polyps. Yes, there’d been something else, too.

“Is it bone cancer?” asked 8-year-old Annalise. Don’t know where that came from, but no. “Oh, thank goodness.”

The 10-year-old, Gracelyn, had a more practical line of questioning. “Will it affect my trip to New York?” And that’s when the tears came.

That vacation, the one she’d been planning since she was 4, got to me. I could get my head around surgery and treatment: I get cut, I get chemo, my hair falls out, I get better. Doesn’t sound like much fun, but it’s a plan.

I could handle having cancer. But I couldn’t handle breaking a 6-year-old promise to a 10-year-old girl.

Another diagnosis

This probably sounds horrific, but the reporter in me got a little excited about the cancer. It was the best story I’d get to tell all year. I had six weeks until surgery, so I cleaned up my diet and started walking. A month later, I had dropped 10 pounds and was in better shape than I had been in years. I was in the honeymoon phase.

But cancer is sneaky and lies in wait for you.

My surgeon wanted to test me for a genetic disorder called Lynch syndrome, which increases the likelihood of developing cancer before age 50 more than a hundredfold. My family didn’t meet the diagnostic criteria — which include having successive generations and a first-degree relative with a Lynch-associated cancer like colon, stomach, uterine or ovarian — so my doctor wasn’t seriously expecting a positive result.

But that’s what I got.

The honeymoon ended quickly. That good story I’d been looking forward to telling suddenly became a multi-generational epic. The hysterectomy my grandmother got in her 50s and never talked about looked like a pre-emptive strike. My 74-year-old father, who’d never had a colonoscopy, quickly scheduled one, as did my younger sister.

And my kids? Each of them has a 50/50 chance of inheriting my mutation, a defect in the genes that correct errors in DNA replication. It’s like having a broken copier that nobody’s watching, endlessly churning out flawed copies. Stack those copies high enough, they turn into a tumor.

I had never heard of Lynch, even though it’s nearly as common as hereditary breast and ovarian cancer syndrome. According to the Centers for Disease Control and Prevention, 800,000 people in the USA may have one of the mutations, with as many as 98% of them undiagnosed.

Good news

The Sunday before my surgery, I gave my preacher a USB drive filled with songs I wanted played at my funeral. Just in case. “I’ll need this back the next time you see me,” I told him. “One way or the other.”

Coming out of sedation, I dreamed I was curled up in the far corner of a dark room, grimacing and clenching every muscle as tightly as possible, trying unsuccessfully to force the pain from my body.

My surgeon felt confident he’d gotten all the cancer by laparoscopically removing four feet of colon. The post-surgery pathology report read like the next best thing to happily ever after. The tumor didn’t get into any of the 36 lymph nodes removed and tested. It didn’t get into the blood vessels. It was just a big ol’ tumor that hadn’t gone anywhere. No wonder my friends told me the surgeon came into the waiting room practically skipping.

‘What can I bring?’

What’s the very best thing you can say to someone with cancer?

I’m coming over. What can I bring?

One friend called every week and asked that. If he thought I hadn’t asked for enough, he came up with his own ideas, from homemade spaghetti sauce to Bruce Springsteen bootlegs.

A fellow journalist asked my favorite question upon hearing about my diagnosis: When does the hard part come for you?

It pushed my story ahead, bypassing small talk to giving me the opportunity to express what concerned me most about my illness. It’s the question I’ll remember to ask others.

Another pal was one of the first people to visit me in the hospital and to bring food to my family when I got home. When I got it into my head that I would run a 5K benefiting the Colon Cancer Alliance, she agreed to pace me.

I used to think I had a hard time making friends. Now I realize I just had a hard time recognizing them.

It’s up to you, New York

Gracelyn got her trip to New York during fall break, after I found out I wouldn’t need chemotherapy.

PHOTOS: A trip to New York, a promise fulfilled

We promptly set off for Coney Island, where Gracelyn wanted to eat a Nathan’s hot dog. She waded in the chilly October surf and screamed her way through the drops and the curves of The Cyclone.

In our five days there, Gracelyn marveled at the dinosaurs at the American Museum of Natural History and picked out skyscrapers from the observation decks of the Empire State Building. She listened to the wait staff sing at Ellen’s Stardust Diner and ordered lamb and noodle soup at Chinatown’s Xi’an Famous Foods. She shopped at Macy’s, posed for photos between the lions at the public library and hailed a cab near Herald Square.

Our tween caromed between childhood glee and almost-teenage cool, never more so than the day she lunched at the American Girl doll store, then went to a tattoo studio in Chelsea to get her ears pierced.

I don’t know that the trip felt sweeter for coming after this round of cancer, but it did feel like the last piece of unfinished business.

A new notion of ‘fair’

A college job at McDonald’s taught me an important lesson about fairness. Two guys came in, each wanting large fries. I filled the first box perfectly but accidentally overstuffed the second. Not wanting them to see me dump fries back into the bin, I decided to give the second guy more than he’d actually ordered.

The first guy was furious, believing I’d shortchanged him. Even though I hadn’t, I wound up giving him more fries, too, just to keep the peace.

That’s when I learned: It’s not that we want life to be fair, we just don’t want to have less than the next guy.

I prefer a baseline approach to fairness: Fair is dead. That’s the one thing we all wind up with. Anything that keeps me on this side of the dirt, I count that in the plus column.

I’m not going to beat cancer. We’re not in a competition. I understand why people feel they must take a war-like approach to the disease. But I don’t think of my long-term relationship with cancer as a battle. It’s more a workaround situation. Cancer will do what it’s going to do; I’ll do what I’m going to do.

For the moment, I don’t even have cancer. I have Lynch syndrome. Cancer is just a complication.

Granted, there’s that spot on my lung that’s going to need another look next month. My doctors and I will always need to keep vigilant watch to catch problems early. But even if I never receive another troubling test result, in my mind cancer will never be farther away than just around the corner. There’s always a better-than-average chance that it’ll be what eventually takes me out.

Cancer has given me unexpected gifts, too, and I hope I’m accepting them graciously. I’m leaner and healthier than I’ve been in years. I’ve learned how to appreciate a good day and not require anything more from it. The knowledge I’ve acquired about my inherited condition will equip my children to prevent cancer in their own lives. I might have even saved a life or two: My father had a large polyp removed during his colonoscopy that could have turned cancerous. I figure I bought him a few years.

When people ask how I’m doing now, I often reply, “Embarrassingly well.” I’ve enjoyed the attention, but the time has come to focus on the friends I’ve made who got their diagnoses around the same time I did and are now in chemotherapy, on those around me who have had much more trouble during these last four months — or who are about to.

As much as I love to tell my story, the real story isn’t about me. I’m happy just to have a part in it. Cancer or no, I’ve gotten far more than I deserve.

Aspirin cuts cancer risk in people with an inherited susceptibility


Aspirin cuts cancer risk in people with an inherited susceptibility

A trial suggests that people with a family history of cancer may benefit from taking daily aspirin

aspirin

Patients with an inherited condition called Lynch syndrome dramatically reduced their risk of cancer by taking aspirin. Photograph: Martin Godwin

Some people with a family history of cancer could halve their risk of developing the disease by taking daily doses of aspirin, according to the results of a 10-year trial of the treatment.

The study shows that regularly taking the medicine cuts the risk of bowel cancer by more than 60% in those with a particular genetic predisposition to get the disease – as well as reducing the risk of other hereditary cancers.

Scientists who led the study said people with several family members with cancers other than breast, blood and prostate might be advised to start taking aspirin daily from the age of 45.

They said those without a family history of the disease might also consider doing so, but that they should make a personal assessment of the risks and benefits and get medical advice. Anyone thinking of taking the drug regularly should consult their doctor first.

Doctors already prescribe low, daily doses of aspirin to people at increased risk of heart attacks and strokes, and evidence has been growing of anti-cancer properties for 20 years. However, this is the first long-term, randomised controlled trial to show such an effect.

The trial involved people with Lynch syndrome, a genetic abnormality that predisposes carriers to develop bowel cancer and other solid organ cancers including endometrial, ovarian, stomach, kidney, oesophageal, brain and skin tumours.

The condition affects at least one in 1,000 people. Carriers are around 10 times as likely to develop cancer and often do so at a young age.

Professor John Burn of Newcastle University, who led the study, estimated that if all 30,000 or so people with Lynch syndrome in the UK were to start taking two aspirin tablets a day then some 10,000 cancers would be prevented over the next 30 years, saving about a thousand lives. The downside of the treatment is that around an extra thousand people would develop stomach ulcers as a side-effect.

“People with a genetic susceptibility are a model system,” said Burn, whose work is published online in the Lancet on Friday. “They are more sensitive to the environmental triggers to cancer.

“If we can do something to change cancer progression in people at high genetic risk, then that’s telling us what we might all benefit. But we are not making a recommendation for the general population. Everyone can take this evidence and make their own choice.

“In between you have the people who have a family history [of cancer]. Those individuals may well decide to put themselves on aspirin and that would be a reasonable conclusion from the data currently available.”

Between 1999 and 2005, about half of a group of 861 Lynch syndrome carriers were given two aspirins (600mg) a day, while the rest took placebos.

By 2010 those who had taken aspirin for at least two years were 63% less likely to have developed bowel cancer.

Looking at all forms of the disease, almost 30% of those in the placebo group developed a Lynch syndrome-related cancer, compared with 15% for those given aspirin.

The most common side effects associated with taking aspirin are gastrointestinal ulcers and stomach bleeding. There is also an very small increased risk of haemorrhagic stroke, in which a blood vessel in the brain bursts.

There was no difference in the proportions of the study groups suffering such side-effects.

Burn added that he takes low-dose aspirin tablets as a preventative measure. “That was a balanced judgment based on weighing risks and benefits. I know I might get an ulcer or a cerebral bleed but I’d rather not have a heart attack, stroke or cancer. That’s my choice.”

Aspirin is a synthetic version of the active component of willow bark, salicylic acid, which has been used as a medicine for its anti-inflammatory properties for hundreds of years. Salicylates also trigger programmed cell death to help diseased plants contain the spread of infection.

“It’s not a huge stretch to think that if salicylate induces programmed cell death in plants to kill infected cells, maybe it’s doing similar things in the animal kingdom to enhance the death of aberrant cells causing cancer,” said Prof Burn.

“This adds to the growing body of evidence showing the importance of aspirin, and aspirin-like drugs, in the fight against cancer and emphasises how critical it is to carry out long-term international research,” said Prof Chris Paraskeva, a bowel cancer expert at the University of Bristol.

On Friday the researchers will launch a website to recruit 3,000 people with Lynch syndrome worldwide to take part in a five-year trial to determine the best dose of aspirin to take.

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