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Drs. Neil B. Rosenshein, Hyung S. Ryu and Dwight D. Im were all presenters at the recent Women's Health: Back to Basics conference held recently in downtown Baltimore.

"Woman's Health: Back To Basics — A Mini-Medical School Course," Led By Mercy's Dr. Neil B. Rosenshein, Reaches Several Hundred Physicians And Medical Professionals Throughout Maryland

Women’s Health : Back to Basics, A Mini-Medical School Course, was held Sat., Oct. 24th, 7 a.m. to 4:30 p.m. at the Baltimore Marriott Waterfront Hotel. Neil B. Rosenshein, M.D., FACOG, was course director for the conference. Dr. Rosenshein is medical director of The Weinberg Center for Women’s Health & Medicine at Mercy and for The Gynecologic Oncology Collaborative. Media please note: A copy of each physician’s slide presentation is available; if of interest, contact Dan Collins, Mercy Media Relations, dcollins@mdmercy.com or 410-332-9714.

Hyung S. Ryu, M.D., The Gynecologic Oncology Center, Mercy Medical Center

Robotics in Gynecology

There’s been a significant rise in laparoscopic surgery programs at hospitals in the past 10 years. There are 35 major programs across the country and only aware of two that don’t practice robotic surgery.

Robots are becoming a lot more common for treating such gynecologic conditions as fibroids, pelvic masses, abnormal bleeding, endometriosis, pelvic floor disorders, pre-cancerous lesions and cancer.

Surgical options include radical hysterectomy, hysterectomy with pelvic and para-aortic lymph node removal and radiation/chemotherapy for advanced stage cancers

Hysterectomy facts: Hysterectomy is the most common female surgery apart from c-section or tubal ligation, with 650,000 procedures performed annually; advances in minimally invasive surgery (MIS) for hysterectomy—vaginal hysterectomy isn’t always possible; more surgeons are now performing MIS for hysterectomy.

Surgical Options: Vaginal Surgery

Pros: Minimally invasive, less pain than abdominal hysterectomy, shorter length of stay inhospital.

Cons: Difficult to perform, reduced visualization, not indicated for many patients, i.e. some patients with cancer, multiple fibroids, nulliparious, adhesions like endometriosis and prior pelvic surgery.

Minimally Invasive Surgery (MIS)

Reduced blood loss, fewer complications, shorter length of stay, faster recovery and less scarring

Laparoscopic Surgery

MIS, ability to operate through small keyhole incisions through which camera/instruments may be inserted, better visualization than open surgery

Drawbacks of conventional laparoscopy

• Surgeon operates from a 2D image
• Working with straight, rigid instruments resulting in a limited range of motion
• Instrument tips controlled at a distance and in counterintuitive fashion
• Reduced dexterity, precision and control
• Unsteady camera controlled by assistant
• Dependent on assistant for surgical support through accessory port
• Greater surgeon fatigue
• Makes complex operations more difficult.

“I know surgeons who have had rotator cuff injury from doing this, two to three hours at a time and you’re doing multiple procedures in day, that’s a lot of pressure on your shoulder,” Dr. Ryu said.

How do we overcome these drawbacks?

Achieve better visualization, instrument control and ergonomics with improved dexterity and “that’s the daVinci. You have a surgeon immersed in the 3-D image of the surgical field. The surgeon directs precise movements of the instrument using console controls. Conventional laparoscopic instruments simply open and close. The da Vinci opens, closes, rotates and operates more like your wrist, it pronates and suppinates. These ‘Endowrist’ instrument tips move like a human wrist and you can fit them through dime-sized incisions,” Dr. Ryu said.

FDA clearance—for general laparoscopic surgery in 2000, radical prostatectomy in 2001, coronary revascularization, 2004, urologic surgery 2005 and gynecologic laparoscopic surgery in 2005.

The da Vinci surgery is appropriate for a broader range of gynecologic conditions and patient situations versus conventional laparoscopy

Indication--uterine fibroids, endometriosis perfect application, vaginal or uterine prolapse, obese patients, those with endometrial cancer, cervical cancer, etc.

Why robotics? Overcomes the limitations of conventional laparoscopy, no 2-dimensional “straight sticks,” no counter intuitive hand movement, unsteady image, significant learning curve; may allow more complex cases to be performed minimally invasively.

Goals of da Vinci hysterectomy: enables more precise, meticulous dissection around the ureters and bladder, increases the ability to visualize, treat endometriosis, patients with pelvic prior surgery, c-sections, can suture more easily and quickly.

Shorter hospital stay, less blood less, less infection, complications, pain faster recovery better outcomes.

Data present by Dr. Roseanne Kho of the Mayo Clinic, review of 91 dVH (da Vinci hysterectomy) patients, dVH performed safely with acceptable operative times in 122 minutes, short docking time, less blood less, short hospital stay mean of 1.3 days

Da vinci enables endoscopic approach for sacral colpopexy, have much faster and easier suturing.

Goals of da Vinci gynecologic cancer surgery: enables a minimally invasive surgery approach, conventional laparoscopic surgery is difficult to learn and perform, not widely adopted or generalized among GYN-oncologists for early sttge GYN surgery. Can do more advanced operations with minimally invasive approach with da Vinci.

Data presened by Dr. John Boggess at SGO (Society of Gynecologic Oncologists) 2007, found that da Vinci surpasses laparoscopy for surgical and patient outcomes for treatment of endometrial cancer, shorter operative time, superior lymph node yield, OR times drop significantly with robotic proficiency, little over two hours vs 4 hours before.

More lymph nodes than with open cases, as proficiency increases, robotic procedure become faster than open surgery, 206 vs. 248 traditional open surgery

Superior access precision and control; reproducible for cervical and endometrial cancer; superior outcomes to open and laparoscopy, simplification of techniques, restores open surgical technique to mis, teachable to fellows and residents, will make MIS more generalizable. “It has made me a better surgeon,” Dr. Ryu said.

Potential patient benefits:

DR. KATHY J. HELZLSOUER, M.D., MHS, Director, Prevention and Research Center, Mercy Medical Center

BASIC GENETICS: Genes and genetic testing

DNA, the molecule of life, composed of trillions of cells, each cell, 46 human chromosomes, 2 meters of DNA, 3 billion DNA subunits, approximately 30,000 genes code for proteins that perform most life functions.

DNA is a double polymer, linked by hydrogen bonds. Focus on double stranded helix.

What does DNA look like? A-T, G-C, patterns of three make up codes for making proteins. One of the four bases in DNA that make up the letters ATGC, adenine is the "A". The others are “G” for guanine, “C” for cytosine, and “T” for thymine. Adenine always pairs with thymine. Cytosine always pairs with guanine. These letters are used as shorthand for the sequences of fragments of DNA e.g. CCAAGTAC. These sequences are the code for genetic information.

DNA functions as the memory of the cell and make proteins that makes our bodies work. Carries genetic material in the cell, replication, codes for making proteins, protein synthesis, mutation a problem in the translation, doesn’t translate at all, missing a protein or not so much

Gregor Mendel, 1822-1884, Augustine monk who cross bred pea plants with different characteristics, led to laws regarding heredity.

Mendel’s laws Principle of segregation—two members of gene pair segregate from each other in the form of gametes, each gene has two copies or “alleles,” “one from mom and one from dad,” principle of independent assortment, genes for different traits assort independently of one another in gamete production.

Dominant, only one allele of a gene necessary to express the trait; recessive, both alleles of a gene must be identical to express the trait; heterozygous = alleles of a particular gene are non-identical; homozygous = alleles of a particular gene are identical

The Punnett Square, applying Mendelian concepts

Dark hair dominant over light, curly dominant over straight, ability to curl one’s tongue over not, blue eyes are recessive to not being blue, widow peak dominant, bent finger, straight finger recessive.

Mutations, changes in DNA that affect genetic information.

Gene mutations—point mutations, changes in one or few nucleotides, substitution, insertion, deletion

Substitution: The fat cat ate the rat, vs. the fat hat ate the rat

Insertion: The fat cat ate the rat vs. the fat cat XLW ate the rat

Deletion: The fat cat ate the rat vs. the fat ate the rat

Frameshift mutations — shifts the reading frame of the genetic message so that the protein may not be able to perform its function: so by example,

Insertion: the fat cat ate the rat vs. the fat hca tat eth era t

Deletion: the fat cat ate the rat vs. tef atc ata tet ger at …can’t read the protein

Chromosome mutations, changes in number and structure of entire chromosome, again deletion, duplication, inversion, translocation.

BRCA1 BRCA1 tests, are looking for the types of mutations noted above.

Significance of mutations: Most are neutral, effecting eye color, birth marks; some are harmful, sickle cell anemia, Down syndrome; some are beneficial, sickle cell anemia resistant to malaria, immunity to HIV.

Polymorphism—gene change present in at least 1 percent of population; is it color or colour? Understand same thing, works fine. Does it change meaning/function? If risk is associated, small risk; environment important, does it matter if you’re exposed to certain things in environment.

What causes mutations? Two ways in which dn can be mutated; mutations can be inherited, parent to child or mutations acquired, enviornmantl damage, mistakes when dna is copied.

Molecular genetic testing: medical care

Diagnostic testing in symptomatic persons: predictive testing in asymptomatic persons when treatment is available; pharmacogenetics, dosing of medications such as Coumadin and tamoxifen.

Medical care: establish a diagnosis, e.g Huntington’s disease, HD gene testing is the only way to make the diagnosis with certainty and confirm diagnosis.

Medical Care: for the at-risk asymptomatic person, there is predictive testing, identify family members who have the disease causing mutation before symptoms appear so they can be monitored for early signs of disseae and be treated promptly.

Penetrance—proportion of individuals with amuation causing a particular disorder who exhibit clinical symptosm of that disorder; BRCA1/2 mutations have incomplete penetrance…complete is where all individuals who have issue have symptoms.

Information Sources:

www.genetests.org (University of Washington at Seattle, funded by NIH)

www.genome.gov/27527599 (Genetics and Genomics for Health Professionals, NIH)

http://www.genome.gov/27527639 (quick links for patient care, NIH)

Use it in assessing cancer risk, family history, maternal and paternal history and environmental exposures, e.g. radiation exposure.

***TAKING A FAMILY HISTORY: obtain at least a three generation pedigree, ask about all individuals in the family and record the following: age at cancer diagnosis, age at and cause of death, distinguish primary from metastatic sites, precursor lesions, bilateral multiple cancers, pertinent prophylactic surgeries, associated congenital abnormalities, and record ethnicity and race***

And updating, taking family history once is not enough, may be changes, colon cancer age 50 and sister has it at a very young age, so need to stay on top of this.

When to suspect hereditary cancer syndrome: cancer in two or more close relatives on same side of family, early sage of diagnosis, multiple primary tumors in the same individual, bilateral or multiple rare cancers constellation tumors consistent with cancer syndrome, breast and ovarian, evidence of autosomal dominant transition, multiple affected generations, etc.

Genetic testing: search for specific mutation in known disease associated gene, e.g cancer susceptibility testing, incomplete but mutation have high penetrance, e.g BRCA1/2.

Whole genome scanning, testing of specific SNPS across the genome.

www.23andme.com/howitworks “Get the latest on your DNA with $399” get a kit, dna from saliva, send back to them, get a report, advertised as the “most comprehensive at home DNA testing”

“This is a big concern, as there is only one company licensed to test BRCA1 and BRCA2 testing that is clearly associated with breast and ovarian syndrome and they don’t test for that.” So someone with a strong family history and see if they carry the gene and it won’t test for that.

Another, deCODE your Health, www.decodeme.com, “discover your genetic risk for 45 diseases and traits ranging from heart attack and diabetes to alcohol flush reaction and male pattern baldness”

Another, www.navigenics.com, try to sell you vitamins as well, $999.

Future will be patients will be coming, I had this test, what’s this mean, what do I do…?

Role of inheritance for cancer susceptibility that about 10 percent of all types of cancer are due to an inherited susceptibility, highly penetrant rare genetic mutations not tested with whole genome scnas; many chronic diseases, including cancer, have complex inheritance, with multiple genes with low penetrance involved; gene environment interaction—genetic alterations in DNA repair pathways and sun exposure. Environment can be “inherited.” Patterns that are cultural patterns that translate down the family, how they ate growing up, sun exposure, you can pass along by family traditions, etc.

PHYSIOLOGY OF PAIN AND ITS MANAGEMENT

David Maine, M.D., Mercy Medical Center, Center for Interventional Pain Medicine at Mercy

Easing your patient’s pain, an overview of pain mechanism and treatment options

Outline: Epidemiology, definitions, signaling pain, abnormal/normal; opioids and opiates, metabolism, etc.

“Pain is a growing field, gets a tremendous amount of lay media attention,” in the last two years, have seen front cover stories in publications like Newsweek, NY Times Magazine, TIME, “can physicians be sued in a criminal vs. civil court for not adequately treating a patient’s pain? FDA panel recently released recommendation regarding new labels for over the counter analgesics, take some of the most common off the market like Vicadin and Oxycodone, Percocet, principle players in pain management.

California case primary care physician and an oncologist who were sued for providing inadequate pain treatment for a patient going into hospice, case settled for $11 million. If you don’t treat, you could have some problems, it’s a delicate line for sure.

How big’s the problem? About ¼ patients primary care patients report pain; about ¼ of nursing home residents experience pain daily, 83 million adults in U.S., a third of chronic pain patients report receive little or no relief form past treatments, about 30 percent believe there is no solution. 4.5 million patients die in pain each year.

Economically huge problem, employee absences, lost $50 million in lost productivity, estimated annual cost in the U.S., $110 billion. In adequate pain control will lengthen the average patient’s hospital stay by 1.2 days which comes to $8,434 per patient.

Decade of Pain Control and Research Begins January 1, 2001, Clinton signed bill into law, second medically declared decade.

Defining pain: an unpleasant unsensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Patient has pain, you have to figure out what type and treatment options

Acute process or chronic pain, a disease? In a hospital setting, see patients with preexisting pain conditions, but someone has surgery, has acute pain, different, different ways to treat

Acute pain, degree of pain corresponds to tissue damage, good treatment outcomes

Chronic pain—According to the International Association for the Study of Pain (IASP), chronic pain is defined as pain out of proportion to clinical signs, serves no beneficial purpose, has high degree of psycho-social co-morbidities, and poor treatment outcomes.

Nociceptive pain: results from mechanical, thermal or chemical excitation of nociceptors (a sensory receptor that reacts to potentially damaging stimuli by sending nerve signals to the spinal cord and brain); distributed iin skin, bone; neuropathic pain has poor treatment outcomes (may be opioid resistant or require higher doses) opioid are last drug for this kind of pain, doesn’t work well; responsive to adjunct therapies such membrane stabilizers and TCAs

1664, Rene DesCartes called pain “fast moving particles of fire, the disturbance passes along the nerve filament until reaches the brain.”—wasn’t far off re; how pain works

How does pain work, the peripheral and central pathways for pain…Transduction, transmission to spinal cord, modulation, up spinal tract to pain perceived, elasticity in spinal and cordical level. Need to break up this cycle repeatedly so that brain begins to perceive things differently. Takes time.

Pain mechanisms, modulation in the spinal dorsal horn.

Gate Control Theory: Melzack and Wall (1965), neural gate in spinal cord, opens, sometimes closes, if it stays open, “things get out of control” and impacts how pain is perceived.

Central sensitization—repetitive firing in spinal dorsal horn, neighboring neurons are gathered into this firing, creating a sensitized state, so dermatomal expanse of pain is much much wider, “burning along incision, and if don’t treat it, becomes wider”

OPIOIDS/OPIATES--Classification

Narcotic: drug that can cause dependence, obsolete medical term, still used legally.

Opiate: drugs derived from opium or are relatives of morphine

Opioids: semi synthetics may not possess morphine like qualities

Opioid receptors: highly specific high affinity binding sites

Classifications of Opium derivatives: morphine, codeine, heroin, hydromorphine, hydrocodone, oxycodone

Synthetic opiods: Demerol, Dolophine, Darvon, Levo-Dromoran

Opiod antagonists: drugs that bind to opiod receptors and may antagnozie or partially stimulate like Talwin, Buprenex, Stadol, Nubain

Pure antagonists, like Narcan (naloxene), ReVia (naltrexone), Revex (nalmefine), Methylnatrene

METABOLISM—clinical applications

Codeine is a prodrug, morphine is active; 10 percent of caucasions have a polymorphism that prevents codeine to morphine conversion; 30% EThiiopians and 1-% hispancies that increases codeine to morphine conversion

May have renal failure with this class of drug, so need to keep in mind if dealing with patients with renal issues.

Meperidine (Demerol)—can see tremors, muscle twitching, convulsions. Not generally good to use beyond 24 hours as does build up.

www.hopweb.org site analgesic calculator to help with pain medication conversion.

ADVANCED INTERVENTIONAL TECHNIQUES

Spinal Cord Stimulation: neurostimulators delivers low volatage electrical stimulation to the spoinal cord or targeted peripheral nerve…technology similar to pacemakers

Intrathecal catheters—used with cancer patients, for a year, less than 6 months, unwise.

What about the future? Oxycodone time release REMOXY, high viscosity, liquid formation in hard gelatin capsule, safer for patient, maintains time release mechanism under attempts to chew or extract drug in high proof alcohol or water. Expect to resubmit in 2010 for FDA approval.

POSIDUR, TRANSDUR (Sufen), ELADUR—Transdur, last 8-12 hours, used in operative setting, “big impact on surgeons”

RELISTOR, FDA approved in 4/08, indicated for opiod induce constipation I palliative care patients

GLUTAMATE ANTAGONIST “also in the pipeline”

CYTOKINE INHIBITORS

ION CHANNEL BLOCKERS

DR. PANAYOTIS “PETER” LEDAKIS, M.D., Medical Oncology and Hematology, Mercy Medical Center

Clinical aspects in clotting disorders (with focus on thrombosis in Gynecology)

Principle of Hemostasis

Circulatory hemostasis (the formation of a solid clot from fluid blood while maintaining blood flow through a damaged vessel, resulting in repair, involving four components that contribute to this healing are the blood vessels themselves, platelets, the coagulation system and the fibrinolytic system) is achieved by hemorrhage (bleeding) and thrombosis (clotting).

Process of arresting bleeding which includes four components: vascular system, platelets, coagulation factors, control of fibrinolysis. Less important factors include complement, kinins, and serine protease inhibitors.

General Features

Vascular damage occurs and blood flow slows down, causing viscosity and accumulation of cells to increase “and you have a clot.”

Coagulation Pathway—begins with intrinsic or extrinsic pathway.

Factors: Vitamin K dependent factors

Thrombophilia (means a person has an increased tendency to form internal blood clots due to a genetic or immune system abnormality) usually refers to potentiality for great blood loss

True incidence of VTE (process by which blood clots occur and travel through the veins is known as venous thromboembolism or VTE), in pregnancy is unknown, believed to be one in 1,000 deliveries. Antepartum DVT (deep vein thrombosis) at least as common as postpartum DVT. 35% VTE diagnosed after leaving hospital.

VTE (DVT and PE, pulmonary embolism) in pregnancy—PE is the leading cause of maternal mortality; risk factors, age over 35, previous VTE, related to pregnancy or estrogen, recurrent, transient, distal, prolonged immobilization (four days) multiple pregnancy, preeclampsia, obesity, c-section, hereditary thrombophilia.

DVT increases in incidence by trimester.

DVT survivors, early quality of life, DVT patients severe leg pain and swelling, blood clot blocks vein; improves gradually over weeks to months, in a third of patients, don’t recover “and can become a major problem.”

DVT survivors, post thrombotic syndrome or PTS causes chronic leg pain, fatigue, swelling skin changes nad ulcers; PTS is common lifelong, has no consistently effective treatments, venous ulcers often recur and are difficult and expensive to treat. PTS, acute DVT is a chronic disease.

Thromboprophylaxis in pregnancy…insufficient data for clear recommendation in prior DVT with transient risk factor and in women with thrombophilia without established DVT.

Diagnosis of VTE in pregnancy: compression ultrasound has limitations due to venous dilatation and higher frequency of iliofemoral DVT; duplex scanning, color Doppler; MRI for pelvic and iliofemoral thrombosis, and V/Q scan and spiral CT for PE.

How to treat VTE during pregnancy? Adjusted dose of Heparin; anticoagulants should be continued for at least six weeks postpartum; discontinue drug at least 24 hour prior to elective induction of labor.

Women with recurrent early pregnancy loss or unexplained late pregnancy loss, screen for APLAs.

Thrombosis in Gynecologic Oncology: 1.5% incidence post breast cancer surgery increases to 5% with chemotherapy.

Incidence up to 20-25% post Wertheim procedure and while on adjuvant chemo; risk higher with age greater than 60; risk higher with bed rest prior to surgery; high BMI increases risk; extent of pelvic lymphadenectomy, more lymph node removal increases risk.

Malignancy a “big one” re: risk for VTE. Major risk factor is MALIGNANCY.

All patients should receive low dose Heparin unless high risk of bleeding or active bleeding; start 1-2 hours pre-op or 12-16 hours post-op. It should be given 7-10 days at least and prolonged for four weeks in high risk patients.

Thrombosis prophylaxis in gynecologic oncology surgery: Patients with known VTE: if surgery cannot be delayed for four weeks, patients should receive full preoperative anticoagulation. Anticoagulation with Heparin to be stopped at least 12 hours pre-op. May add graduated compression stockings or intermittent pneumatic compression devices.

MARC C. HOCHBERG, M.D., MPH, Professor of Medicine, University of Maryland School of Medicine, Baltimore, MD

Osteoporosis: Introduction to Bone Biology

Why would gynecologists be interested in bone biology? You take care of women with postmenopausal osteoporosis.

Wasn’t a big issue until 20th century as most women didn’t live past menopause, i.e. postmenopausal osteoporosis didn’t have a chance to develop.

Define: skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue with consequent increase in bone fragility and susceptibility to fractures (according to NIH National Institutes of Health Consensus Conference, 1991)

Bone mineral density that is 2.5 standard deviations or more below the mean of young persons aged 20-29 years (definition of osteoporosis, WHO 2004).

NIH Consensus Conference, a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture; bone strength reflects both bone mass and bone quality, bone mass estimated by bone mineral density.

Bone: Functions

Support and movement of the body; protection of vital organs and soft tissue;p maitnenacne of mineral homeostasis,--calcium, acid-based

Types of bone: cortical (located at diaphysis—shaft—of long bones and surface of flat bones) and cancellous (trabecular, located at epiphysis and metaphysic of long bones and within cortical shell of flat bones nad short bones); bone surfaces (periosteum, the outer fibrous sheath; endosteum, in direct contact with bone marrow)

Interested in endosteum, in direct continuity with bone marrow, cells for bone remodeling come from the bone marrow.

Cortical bone fulfils primarily mechanical and protective function; 80-90% calcified; turnover occurs from the endosteal surface.

Trabecular bone provides mechanical but also metabolic function; 3-Dimensioanl lattice composed of plates and columns, 20-30% calcified, turnover occurs at all surfaces.

Bone constituents. Bone is a protein derived matrix, primarily Type I collagen, about 90% of the protein.

BONE REMODELING

Purpose of bone turnover, process by which we repair damaged bone, under hormonal control, not only in periphery but recent studies in past decade have demonstrated there is neural hormonal control which is involved in energy metabolism. In growth and development we remodel bones to heal bone from microfractures. Osteoporosis in adulthood is considered a disorder where the individual during growth and development didn’t make enough bone, didn’t reach bone mineral density max, some environmental factors but genetic/heredity, and turnover in later years due to hormonal deficiencies and due to disease states and medications.

Process of bone remodeling involves efforts of cells referred to as the bone remodeling unit or BMU.

There are four steps in bone remodeling process—activation, resorption, reversal, formation.

Mechanical stimulation of the bone as bone is a dynamic tissue. Osteocyte is becoming of greater importance and interest in the last decade. Activation leads to bone resorption mediated by osteoclasts, osteoclast is finished, reversal, removed, resorption with preosteoblasts which matures into osteoclasts, lays in mineral, calcified, reforms the bone and that formation.

Lining cells, osteoclast precursors to bone surface, osteoclasts in cavity, osteoblasts than signaled, fills cavity and forms new bone and may become lining cell. Formation takes 3-4 months.

Bone remodeling upclose

Cells for resorption are called osteoclasts and are derived from hematopoetic stem cells.

OSTEOCYTES—derived from osteoblasts; embedded within the bone in small lacunae, fluid filled. Numerous long processes that are in contact with processes from other osteocytes or bone lining cells; respond to mechanical loading signals; mechanical strains may regulate local bone turnover, produce sclerostin, a protein that regulates osteoblast differentiation and function.

OSTEOBLASTS==bone lining cells responsible for production of matrix constituents; derived from bone marrow stromal stem cells; surface receptors for estrogene and PTH; become flat lining cells, osteocytes or undergo apoptosis.

Regarding regulators of bone formation: hormones like parathyroid hormone (PTH) you have state of increased bone turnover which favors bone resorption; also calcitonin, insulin, growth hormone. Local factors include growth factors synthesized by bone cells; prostaglandins and cytokines synthesized by T-cells and MOs.

Bone has unique structure and function; three types of bone cells; bone remodeling is meditated by the couple of bone resorption by osteoclasts and formation of osteoblasts.

J. LAWRENCE FITZPATRICK, M.D., FACS, Chief of Surgery, Mercy Medical Center

Wound Healing: A New Look at an Old Subject

Certain number of things that keep coming up—molecular biology…see this again. Can’t do a lot to accelerate wound healing…

“We cause damage every day, our operative interventions, our biopsy, how does the body repair itself? Lot of new research…”

Wound Healing: 1990s was an era of intense investigation, millions spent on basic science of wound healing, seeing many applications coming up over and over again. Now what do we do with new information?

Primary healing—most common. Take a wound, make incision, sew or staple it shut, skin level and below. Secondary healing—with infected wound and left open or contaminated and laid open; delayed primary healing, take dirty wound, cleanup, dressing, then suture.

Phases of wound healing: three basic phases

Hemostasis and inflammation (Days 1-3)

Proliferation (Days 4-14) when healing actually occurs

Maturation and remodeling (10+ how does body add or subtract to get a final result?)

Inflammation brings in white cells to remove foreign bodies, takes to next phase, proliferation and remodeling.

Hemostasis and Inflammation: Attraction of platelets, plugging “in holes”, multiple factors that transforming growth factor beta, prostaglandin, fibronectin, etc. Also vasoconstriction to minimize blood loss.

As clot forms, earliest phase of wound healing. It provides preliminary scaffolding and ingrowth of PMN, macrophages, devour bacteria, release enzymes, VEGF (vascular endothelial growth factor) and intracellular adhesion molecules (ICAM)—very essential in tumor biology, body can use in healthy way for wound healing, but in a sinister way, tumor cells, involved in this same process.

White cells—lymphocytes

Then comes PROLIFERATION, where tissue continuity is reestablished. We think about a defect in a wound, it goes away, and that occurs in proliferative phase. First phase of proliferative phase is ANGIOGENESIS, promotes in-growth of new blood vessels which actually bridges the defect and provides framework for delivery of other cells, collagen and fibroblasts. With deposit of collagen, eventual crossbridging from both sides of wound so wound itself is bridged, when that happens contraction and structural healing.

MATURATION AND REMODELING is the final step, why might it fall apart? The function and quality of collagen being laid down, is it crosslinking. Begins 8-10 days, continues 6-12 months. Collagenase, collagenolysis promotes breakdown and remodeling of collagen (scar), balance of deposition degradation leads to eventual healing. Wait 6-12 months before decide to do something about scar as healing still taking place.

Also healing on the epithelial surface. Basal cells migrate in one day, epithelial cells then migrate. Bridging of epithelial cells recognizes coverage of wound. Negative feedback turns off future epithelial migration and growth.

Mechanical strength of wound never achieves that of non-injured tissue. Given that, when do we consider a wound healed? We say that in six weeks for normal healing we have achieved 90% of the tensile strength that that wound is going to achieve. That’s why no heavy lifting, pull-ups, etc., give six weeks to heal.

On a clinical basis, in terms of skin healing, take s7-10 days to heal, and six weeks for muscle and fascia.

Sutures and staples need to stay in 7-10 days and absorbable sutures need to retain tensile strength for 7-10 days.

Factors which delay/impair wound healing: poor nutrition, infection, technical issues, diabetes, steroids, ischemia, age, tension, anemia, HIV radiation, chemotherapy, metabolic disorders, etc.

CONTROVERSIES/ISSUES

Surgical dressings—what kind do you need? Well closed wounds are impervious to bacteria in 24-48 hours, prior to that, need sterile dressing.

Sutures, staples, dermabond, steri strips? Depends on size of wound, wound healing, tension.

How to treat open wounds?

If contaminated, go wet to dry dressings (Debride);

Alginates—keeps wounds moist, avoids disruptive healing

wet-to-dry dressings

VAC (vacuum assisted wound closure)

negative pressure, reduces exudates, hastens wound healing with more rapid closure because its applying a gentle negative pressure, slowly pulling wound together

Regarding Laparocopic port sites: port sites that are greater than 10 mm should be closed whether by suture or other devices. Question of new “spreading” versus cutting ports. Last few years spreading vs. cutting tips on our ports. Some tips are conical will spread tissue rather than cut through it and destroy it. By using the conical ports, spreading, tissue collapses around it after you remove it.

What about keloids and hypertrophic scars? The latter cannot extend beyond boundary of original wound but keloids do. Both due to over abundance of collagen. For some reason, no message that wound is healed. Little to offer once established except excision.

So recognize risks; Mediterranean, Africans, dark skinned, more at higher risk. Ask if they had prior surgery, do they have sutures, things that predispose them. Many women have keloids where they have earrings means they may be predisoposed. Use subcuticular sutures, minimize tension, may inject the wound with steroids, may even consider tangential radiation. Also pressure garments, physical pressure, may help break up the formation of collagen.

PAUL J. THULUVATH, MD, FRCP

Medical Director of Michelle L. Posner Institute for Digestive Health & Liver Disease

Hepatology for Clinicians

Liver diseases burden in general population and in women

Liver disease in pregnancy

Look at a case…33 year old female with abnormal liver enzymes…no risk factors for viral hepatitis, no alcohol, no family history of liver disease, no non-prescribed drugs, past history of endometriosis.

Her weight was normal, radiology showed a normal liver ultrasound. Platelets normal. Question we would ask, should we do anything further or “it’s just normal for her”? Now redefining what’s normal.

Difference in Diagnosis of Abnormal Liver Enzymes, like Hepatitis C/B…didn’t have this, wasn’t obese, but Crohn’s Disease.

Liver Disease in Women: Acute liver disease, Hepatitis E; chronic autoimmune hepatitis, primary bilary cirrhosis, pregnancy related liver disease, neoplasms?

“I wasn’t convinced she had Crohn’s Disease.” Thought she should confirm.

Hepatitis C—4 million in USA, 200 million in the world.

Hepatitis B-1.3 million in USA, 400 million in the world. One out of 10 Asian patients have Hepatitis B.

Non-alcoholic fatty liver disease—60 million in USA

Liver cancer—greater than 10,000 deaths in USA and 1 million in the world.

Did upper endoscopy on this patient. Found she had Celiac Disease.

How often do we see abnormal liver enzymes in celiac disease? Almost half. Prevalence ranges 39-60%.

Common Misunderstandings—many people think mild elevations in liver enzymes isn’t important. There is an excellent correlation between the degree of liver enzyme elevation and severity of liver disease.

Kayser-Fleischer rings, brownish or gray green in the eyes—19 year old with jaundice…so diagnosis?

Wilson’s Disease—prevalence is 1 in 30,000 births; autosomal recessive disorder. Impairment of the biliary copper excretion leading to accumulation in liver, brain, cornea and kidney. It’s rare to present before age six but almost always before age 30. But liver cancer is extremely rare. Diagnosis—24 hour urine copper is elevated, best test.

Treatment is lifelong, two phases: removal (chelators) and prevention of reaccumulation (low doses of chelators or zinc, 50mg).

Acute Liver failure — Common causes:

• Acetaminophen
• Hepatisis A
• Hepatitis B-D
• Other medications

Less common causes: Autoimmune hepatitis; Wilson’s Disease

Prognosis: very poor without transplant. Survival with liver transplant, 60-70%.

Nonalcoholic Fatty Liver Disease (NAFLD)

In general population: 20%

Obese adults: 57-74%

Obese children: 22-52%

Leads to cirrhosis which is a precursor to liver cancer.

Management: liver biopsy is helpful for prognosis. Statins are very safe.

“We have made major improvements in treatment in Hepatitis B in past few years, now highly effective with few side effects.”

Treatment options—drugs

We hardly ever transplant anyone with Hepatitis B, even with liver failure, can treat effectively.

What about Hepatitis C? Treatment is changing, we can cure about 50%. New drugs being approved by FDA, looking at 65%. In next five years will be able to cure over 75% of all Hepatitis C.

How do we assess severity of liver disease.

Liver enzymes have no prognostic significance. 10 percent of cirrhotics have normal liver tests.

Biochemical tests to predict prognosis.

Child-Turcotte-Pugh Score (CTP), based on three lab values and two physical findings. Help to measure “how bad liver disease is.”

Liver Disease in Pregnancy: Viral hepatitis is the most common cause in the world, so check with Hepatitis B and C if have test showing abnormal liver enzymes.

CONCLUSIONS: Prevalence of liver disease and cancer is increasing. There is a poor correlation between the degree of liver enzyme elevation and severity of liver disease; patients with cirrhosis and portal hypertension have a very high morbidity and mortality after abdominal surgery.

Olga Ioffe, M.D. Associate Professor of Pathology, Greenebaum Cancer Center, University of Maryland Medical Center

Gynecologic Pathology Update

Endometrial intraepithelial neoplasia (EIN)—a precursor to endometroid endometrial adenocarcinoma, has 45 fold elevated cancer risk.

Types of Endometrial Carcinoma

Type A and B

Type A, Younger; Type B, Older

Uterine Serous Carcinoma: 5-10 percent of all endometrial carcinomas; High stage at presentation/upstaged at surgery

Minimal Uterine Serous Carcinoma—not precursor but early form of cancer, 45% will have spread outside the uterus.

Prognosis in minimal serous carcinoma—careful staging is important; if there is no extra-uterine spread, prognosis is excellent.

Carcinosacroma (malignant mixed mesodermal or Mullerian tumor)

• most common malignant uterine tumor after carcinoma
• 2-3% of all uterine malignancies
• incidence in African American women is twice as high as in white women
• malignant epithelial and glandular components are intimately admixed
• only one component may be present in bx or hysterectomy
• postmenopausal women media age of 65
• postmenopausal bleeding
• polypoid mass filling uterine cavity
• necrosis

Peritoneal Implants—Not really implants, more surface ovarian involvement, may involve peritoneum with no tumors in ovaries.

Heredity of FT (Fallopian Tube) Cancer

1% of all GYN malignancies

Associated with BRCA1 and BRCA2 malignancies. 17% of Ashkenazi women with FT cancer have BRCA mutations

Of 180 women with familial breast-ovarian cancer syndrome, 11 had occult carcinoma, most in FT.

17% of BRCA1 mutation carriers had FT cancer.

Edward Sausville, M.D., Ph.D., FACP

Associated Director for Clinical Research, Greenebaum Cancer Center, University of Maryland Medical center

Biology of Cancer

Oncogene: gene that can cause or influence course of a tumor

Viruses can cause tumors. Or virus inserts itself next to a gene in the animal /human genome causing tumor phenotype

Cytogenetics—activated or expressed oncogenes

Names derive from the virus with which they were originally associated or the diseases from which they were derived or the mutated version revealing a phenotype in a model system such as flies, worms, etc.

Nuclear Oncogenes and Cytoplasmic Oncogenes

Signatures of Oncogene participation in cancer—overexpression in lung, stomach, etc.; over expression may result from gene amplification

What can an activated oncogene do? Can serve as growth factors, growth factor receptors, intermediates in growth factor signaling, nuclear transcription factors downstream of growth factor activation; also serve as “Monster” molecules produced by translocation conferring new functions

Tumor Suppressor Gene—calm things down, to say “don’t grow” If you fuse a cancer cell with a normal cell, it won’t grow. How do you detect TSG? Familial cancer syndromes.

Importance of BRCA in Ovarian Carcinogenesis— -10% of 25,000 new ovarian cancers per year have familial connection.

Apoptosis is a morphologically and biochemically distinct form of cell death.

Cell cycle control. Cancer is a self-signaling disease. Genes that drive tumors, alterned normal signal of molecules. Misinterpretation of or ignore environmental clues. Clues for therapy discovery and development.

Evidence Based Medicine Practice

Ira R. Horowitz, M.D., SM, FACOG, FACS,
Associate Director, The Emory Clinic
Chief Medical Officer, Emory University Hospital

Evidence based medicine = The integration of best research evidence with clinical expertise and patient values.

Now, we have evidence based PRACTICE. It is the conscientious use of current best evidence in making decisions about patient care. EVP is not cookie cutter or cookbook approach to developing or managing clinical practice. It requires a degree of flexibility and fluidity based on a firm scientific and clinical evidence validating appropriate and sustainable clinical practice.

Components of EBP—evidences for research and evidence based theories, opinion leaders, expert panels, clinical experience, patient preferences, etc.

Quality of Evidence: At least one randomized controlled trial; controlled trials without randomization; cohort or case control studies; multiple time series or dramatic results; agreement among respected authorities.

Effective use of data: seek usefulness, not perfection; use a balanced set of measures; plot data over time; do not wait for the IS department; use qualitative as well as quantative data, choose summary statistics with caution.

Google scholar, Emedicine—resources for data/information

Is study, info, is it useful to my patients? If no, why? Seek usefulness, not perfection…use a balanced set of measures…plot data over time…use both qualitative and quantitative data…choose summary statistics with caution.

Frequently there is an inverse relationship between dogma and the strength of the evidence.

Hyung S. Ryu, M.D.

The Gynecologic Oncology Center, Mercy Medical Center

Innovations in Cervical Cancer Prevention

11,000 cervical cancer cases in the U.S. (2007)

Deaths in 2007, 3,700

Number of cervical cancer deaths in the US have decreased by 75% since the advent of Papanicolau screen (Pap smear)

Risk factors: persistent high risk HPV infection, little or no history of pap screening, history of cervical dysplasia, smoking, early age of sexual debut, immunosuppression, other sexually transmitted infections.

HPVs are a diverse family, high risk are types 16, 18 (which make up 70% of all cervical cancers).

HPV in US, 22 million currently infected, 6-7 million infected annually, sexually active are 80% likely to pick up some form of HPV

What happens after an HPV infection? Usually nothing. Immune system will usually eliminate HPV infection; HPV becomes undetectable within 2 years of 90% immunocompetent women. As you get older, chances of getting HPV infection decreases.

Risk factors—frequency of condom use, number of sexual partners, number of previous partners of sex partners.

HPV infection, 90% time clear it; if you have persistent infection may develop CIN1, and will also clear; if you have a high risk HPV infection, CIN2/3 and in 20 year time frame, develop into cancer.

Cervical cancer mortality rates, 1946-1984, has dropped off

Cervical cancer by state, more south you go, higher cancer rate, due to larger African-American population, lack of screening.

Factors contributing to cervical cancer diagnosis-- 50-60% rarely or never screened.

How to screen for cervical cancer? Costs $3.5 billion a year to manage in terms of screenings, false positive paps, invasive cancers, warts, CIN 1, 2,3.

How good is HPV testing? Sensitivity is amazing but specificity is horrendous.

Let’s limit unnecessary pap smears, HPV testing and Low Risk Women:

Women 30 and over, both cytology and HPV testing are both negative and rescreen in 3 years. Risk of CIN3 is .24% at 45 months.

No changes in interim, CIN2 is less than 10 percent, triage with HPV testing to prove infection, if negative, repeat in 12 months, if positive, colposcopy.

Adolescents, ages 20 or younger—74% of new infections are in this age group, prevalence up 54% , 92. Million women currently infected but cervical cancer occurs only in 1-3 million female adolescents

Let’s limit unnecessary paps for teens—when to start screening?

90% infections clear within 2 years. Avoid unnecessary harm through aggressive screening and treatment . Begin three years after coitarche(sexual debut) or age 21.

HPV testing in adolescents—HPV testing is NOT helpful.

Pregnancy and HPV—cancer rate is 5 in 100,000, you observe don’t’ treat; pregnancy doesn’t accelerate HPV.

Can defer colposcopy until postpartum for ASCUS or LSLIL.

NO ROLE for HPV DNA testing:

Screening in women under 20

Diagnosis of genital warts

Testing in males

Triage of aSCH LSIL or higher grade lesions

Evaluation of sexually active female prior to vaccination

Expected benefits of vaccine—reduce number of abnormal paps, reduce incidence of genital warts and cost of treatment, reduce vulvar and vaginal lesions, reduce cervical cancer deaths, cost effective for preteen girls.

Current recommendations? Routine vaccination of females ages 11-12 and as young as nine with catch up vaccinations for females ages 13-26. Can be given despite history of abnormal pap, HPV, warts, not recommended in pregnancy, no change in cervical cancer screening recommendations and contraindications being allergy to yeast or other vaccine component, severe illness

Vaccine Safety? There are NO PROVEN ASSOCIATION of death from Gardasil, 21 deaths occurred after Gardasil vaccine; 12 investigated and found to be unrelated; five no patient identification in the report thus unable to be investigated; four in foreign countries, unable to be investigated.

Since 2005, the CDC notes that racial disparities in childhood vaccines are closing.

Dwight Im, M.D., FACOG, Director, The Gyneoclogic Oncology Center at Mercy

Biology of Endometrial Cancer

Epidemiology, Risk factors, clinical features, diagnosis, screening, molecular histopathology

Endometrium, 42,160 cases, 7,780 deaths

Ovary, 21,550 cases, 14, 600 deaths

Cervix, 11,270 cases, 4070 deaths

Endometrial cancer, rates higher in Caucasians; mortality 2X higher in African Americans, 7.1 vs. 3.9 per 100,000, AA population a higher incidence type II, more aggressive endometrial cancer

Life time risk is 1 in 40. Two types, type I and II.

Type I makes up 80 percent of new cases; chronic exposure to unopposed estrogen; risk factors include obesity, nulliparity, diabetes, hypertension; low-grade tumors with favorable prognosis

Type II are nonentrometriod, 20% of new cases, hormonal risk factors not identified, typically older than women with type I, can find a premalignant phase, propensity for early spread and poor prognosis, usually present in stages three and four.

Risk factors for type I—long term estrogen exposure, tamoxifen use, obesity, diabetes, hypertension, age, diet, alcohol intake, coffee, early menarche/late menopause, physical activity, etc.

Other risk factors include…

Tamoxifen use, inhibitor of estrogen but partial agonist activity. Makes endometrial lining thicker.

Country getting more obese; body mass index (less than 25 is normal) overweight is 30, over 35, class 2-3 obesity; 40% of all patients with endometrial cancer are considered obese with BMI greater than 30.

Diabetes & hypertension—related to being obese, but also shown independent risk factors, seems higher with Type II diabetes vs. Type I, diet high in carbohydrates, higher levels of insulin.

Age—late 50s, early 60s, 25% are diagnosed in premenopausal women, and 5-10% under age 40.

Beginning to see more cases of endometrial cancer in young women.

Genetics? Lynch syndrome, autosomal dominant

Lynch Syndrome: Gynecologic cancer precedes colon cancer by an average of 11 years—test for Lynch Syndrome

Nulliparity, high frequency of anovulatory cycles in infertile women; diet (soy may increase incidence of endometrial hyperplasia), alcohol, coffee (does seem to decrease risk of endometrial cancer, antioxidants?)

Drinking coffee appears to decrease risk…Drink 7 cups daily, reduce Endometrial Cancer risk by 40%...but probably not good to drink that much coffee.

Oral contraceptives—reduced risk by 50-80%

Postmenopausal hormone therapy—most studies show lower rate of endometrial cancer, continuous daily use of progestin

Smoking—risk reduced only in postmenopausal women but don’t want to encourage smoking to have women not get endometrial cancer!

Clinical Presentation: 5-20% of PMB (premenstrual bleeding), sign of endometrial cancer

RE: Diagnosis of Endometrial Cancer: Endometrial sampling: office endometrial biopsy, hysteroscopy with D&C, tumor seen on hysteroscopy or biopsy specimen are undergraded with sampling (up to 30% of cases). Transvaginal ultrasonography—if six mm or greater, need to do more testing.

Screening? Women in general population, on tamoxifen, obese women, etc.

Be aware of difference between Type I and Type II patients; know the risk factors for each; traditional Rx based on histopathology and Rx based on molecular biology, targeted therapy.

Neil B. Rosenshein, M.D., FACOG

Medical Director, The Weinberg Center for Women’s Health & Medicine at Mercy and of The Gynecologic Oncology Collaborative

The Biology of Gynecologic Cancer as it Relates to Ovarian Cancer

Biology may require us to rethink how we approach epithelial ovarian cancer.

“It is the most lethal of all gynecologic cancer. 21,000 cases, 14,000 deaths.”

Why is that? One, no early target symptoms? Certain symptoms? No prospective randomized clinical trial showing decreased mortality with screening. We don’t know an identifiable precursor lesion and diagnosed at an advanced stage.

Need to change our thinking…where does ovarian cancer start? We say ovarian cancer, but in future is that the right terminology to use? Is the origin for what we are calling ovarian cancer if it is sporadic vs. hereditary event? Do those with mutations start at the same place as those with sporadic cancer?

Hypotheses for increased risk?

• Incessant ovulation
• Gonadotropin stimulation
• Hormonal stimulation
• Inflammation

Incessant ovulation—repetitive stimulations, process of repair, susceptible to mutations. Pregnancy, lactation and oral contraceptives decreases chance of ovarian cancer. But those who aren’t, like nuns, have high incidence of ovarian cancer.

The progesterone only contraceptive is equally effective in reducing ovarian cancer but it does not stop ovulation. And those with polycystic ovarian syndrome don’t ovulate yet they get ovarian cancer.

Gonadotropin stimulation. Fertility drugs show increase risk but only in one study, not repeated.

Hormonal stimulation—high concentrations of testosterone promote cancer. Increased testosterone and estrogen levels like PCOS (polycystic ovarian syndrome), acne, Hirsutism, have increased risk.

Inflammation—damage to the ovarian surface with ovulation causes inflammation found reduced risk of ovarian cancer taking nonsteroidal NSAIDs

Still don’t have precise mechanism for process of why ovarian cancer takes place.

Now we see two types of Ovarian Cancer: Type I, slow developing, low grade, endometrioid, mucinous; versus Type II, precursor lesion not identified and rapid progression of disease.

Type I are less responsive to chemotherapy, diagnosed at a younger age, have longer survival and 60% of these tumors contain low malignant potential tumors.

Type II rapidly growing, are chemo sensitive, have high degree of p53 mutations which is rare in Type I.

Type II but it starts on the FT, the “Tubal Model.”

Type II prevention…do you only have to do a fimbriectomy or salpingectomy (maintain ovaries)?

Detection: Type I, less than 25% incidence, remains confined to ovary for a long time.

Type II-- Detection of Minimal Ovarian Cancer—try to pick up advanced ovarian cancer as early as we can.

Lots of interesting information but going back what is the impact on our current management and to me we have learned much and progressed but I don’t think it changes our standards of care and how we manage ovarian cancer.

Epithelial ovarian cancer

Can you diagnose ovarian cancer by symptoms?

Not early. We don’t have target symptoms. Issue for us is timing of appearance, i.e. when symptoms do arise, cancer is advanced and symptoms aren’t gynecologic.

PREVENTION

Primary—removal of the organ at risk

Either chemo prevention, we should be risk reducing salpingo-oopherectomy.

Surgical indication is only risk reduction for ovarian cancer—only reduces risk and should only be with patients who are high risk.

Recommendations? BRCA1 age 35, should have RRSO. “Earlier you do it, the greater benefit in risk reduction.”

Tell patients that it isn’t 100% protective. 60-95% protective. Why? You can find microscopic disease. Always that risk.

RRSO: serial sectioning, entire fallopian tube ovary

SECONDARY PREVENTION DETECTION

Want to identify problem in the pre-malignant stage and eradicate it. No evidence that tests for CA-125 and ultrasonography for the purpose of screening asymptomatic women is effective.

CONCLUSIONS: Oral contraceptives and RRSO for primary prevention; secondary ineffective for early detective, tests lack specificity.

Ovarian Cancer Surgery Conclusions: Accurate staging, aggressive primary cytoreduction, appropriate secondary cytoreduction.