Thursday, August 15, 2013

Kidney cancer linked to the herb "Aristolochia" aka birthwort

From Urology Times published online Aug 9, 2013:

Using genomic sequencing, researchers have confirmed a link between a plant compound contained in common herbal remedies and upper urinary tract cancer.

For their study, genomic sequencing experts at Johns Hopkins University, Baltimore partnered with pharmacologists at Stony Brook University, Stony Brook, NY to reveal a striking mutational signature of upper urinary tract cancers caused by aristolochic acid, a plant compound contained in herbal remedies used to treat a variety of ailments such as arthritis, gout, and inflammation.

Aristolochic acid is found in the plant family "Aristolochia," a vine known widely as birthwort, and while the FDA first warned of its cancer-causing potential in 2001, botanical products and herbal remedies containing it can still be purchased online. Moreover, the vine has been found to be an environmental carcinogen through the contamination of food supplies of farming villages in the Balkans, where Aristolochia grows wildly in the local wheat fields.

For years, scientists have known of some mutations in upper urinary tract cancer patients exposed to the plant toxin. But the genome-wide spectrum of mutations associated with aristolochic acid exposure remained largely unknown.

For the current study, which was published in Science Translational Medicine (2013; 5:197ra102), the authors used whole-exome sequencing on 19 Taiwanese upper urinary tract cancer patients exposed to aristolochic acid and seven patients with no suspected exposure to the toxin.

"Genome-wide sequencing has allowed us to tie aristolochic acid exposure directly to an individual getting cancer," said co-author Kenneth Kinzler, PhD, of the Johns Hopkins Kimmel Cancer Center. "The technology gives us the recognizable mutational signature to say with certainty that a specific toxin is responsible for causing a specific cancer. Our hope is that using the more targeted whole-exome-sequencing process will provide the necessary data to guide public health decisions related to cancer prevention."

Specifically, Dr. Kinzler and colleagues said they found an average of 753 mutations in each tumor from the toxin-exposed group compared with 91 in tumors from the non-exposed group. This level of mutation is more than that found in melanomas caused by ultraviolet radiation and lung cancer caused by smoking.

Members of the toxin-exposed group had a large number of a particular, rare type of mutational signature in the ATCG chemical code of their DNA. The predominant mutation type in the toxin-exposed tumors (72%) was an A substituted with a T. In one instance, the scientists used the mutational signature to uncover an artistolochic-related tumor in a patient who was unaware of prior exposure.

Saturday, February 2, 2013

Mesh and the FDA Regulatory Process


The FDA is perceived and promoted as the guardian of public safety, but many are critical of the FDA approval and regulatory process for being either slow or broken. Some groups see the FDA as being too slow to approve new drugs or treatments that can extend for save lives, while others see the FDA as being reckless and approving drugs and devices that then get recalled after complaints or complications become known.

 

When it comes to mesh used for vaginal prolapse and incontinence surgery, there is a lack of knowledge about the FDA and the approval process and the necessary requirements that must be met prior to FDA allowing a manufacturer's device to come to market. Currently there are approximately 100 mesh kits or devices approved/cleared by the FDA to be used in vaginal surgery. Here is a brief synopsis.

 

Stemming from the 1970’s the FDA passed regulations related to the classification and safety of surgical devices that we still use today with little updating. The FDA’s Center for Devices and Radiological Health (CDRH) is vested with the responsibility of ensuring the safety and effectiveness of ALL medical devices marketed in the US. The Food Drug and Cosmetic Act outlines devices to be classified into three categories based on the risk it poses to the human body:

 

Class I Device: Low risk device, where clinical data is not needed for approval, but general manufacturing controls are needed. An example of this is simple surgical instruments

 

Class II Device: Intermediate risk device. Surgical mesh falls into this category, and it requires “special controls” and labeling, but clinical trials are not absolutely required prior to marketing. A device can be approved if it is “substantially equivalent” to a prior device that is used for the same purpose. Vaginal mesh was deemed “substantially equivalent” to prior approved hernia mesh. This is known as the 510(k) Pre-Market Notification Process. It is used a s “piggyback process” to bring devices to market without strict human trials.

 

Class III Device: Complex/High risk. (3-5% of all products.) Requires stringent Pre-Market Approval, known as the 522 Process, requires strict manufacturing inspections, trials, post-Approval study of data, annual reporting to the FDA. An example of this is hemostatic agents (surgical foam that prevents bleeding).

 
The FDA is currently forcing manufacturers to conduct “522 studies” on their mesh products for vaginal surgery to evaluate prolapse surgery done with and without mesh. There are more than a hundred studies reporting outcomes of mesh, and except for a few, there are lacking large comparative trials which are now underway. For the standard mesh slings (TVT or TVT-O, and similar slings), the FDA is not requiring these studies as ample outcome and safety data exist. Depending on the outcome of the prolapse mesh studies, mesh may or may not be reclassified as a Class III. This does not mean that mesh is off the market or cannot be used in the meantime. Mesh complications can and should be reported to the FDA, but exact percentage of complications from mesh is difficult to know because mesh complications are underreported and the total number of mesh cases are not known.

Sunday, November 4, 2012

Vaginal Laxity (Looseness): What does the Woman's Doctor Think?


Stretching of the vagina and its opening (introitus) can occur from vaginal delivery or from pelvic organ prolapse (dropping of the bladder, uterus, rectum), however it may also be a natural process. It is thought that looseness or stretching may contribute to diminished sexual satisfaction from loss of sensation, and affect body image. It is not clear how many women may experience this condition, but 83% of urogynecologists from a recent survey described vaginal laxity as underreported by their patients. These physicians felt that laxity may be a bothersome condition to patients that may impact on “happiness and sexual function”. It is the most obvious physical change that physicians felt women experienced after childbirth.

Some studies conflict about where repair of pelvic organ prolapse improves sexual function. If prolapsing organs are uncomfortable or affect urination or bowel movements, these conditions will be repaired regardless if the woman is sexually active or not. Since prolapse also usually affects an older population of women who may already be less sexually active due to their own libido, health or their partner’s health, it is difficult to sometimes judge whether prolapse surgery improves sexual function. “Vaginoplasty” is the tightening surgery, often done for cosmetic reasons  or with the intention of improving sexual function, but studies measuring whether this actually improves sexual function are poorly designed so a true answer  is elusive.

Conversely, it is also known that with age, hysterectomy and reconstructive surgery for prolapse the length of the vagina shortens. Dyspareunia, or pain with sex, can occur from either being “too tight”, from having a narrow introitus, or from reduced vaginal length. Vaginal dilators can be used to stretch the introital opening after scarring/narrowing develops with age, radiation, and surgery.

So, does the woman’s doctor (urologist or urogynecologist) feel comfortable talking about sexual health to their patients? The vast majority of those surveyed (>90%) feel comfortable discussing sexual health, but often feel than time pressure in the office may limit the depth of the conversation. 83% felt that vaginal looseness was an underreported concern among patients, 57% believed that vaginal laxity directly affects the quality of life of relationship happiness, while only 31% felt that vaginal looseness was an issue driven by the male partners of patients. 4% responded that vaginal laxity was an industry invented condition. Some of the concerns cited about sexual impact were: less confidence, perceived inability to please partner, altered sensation and less satisfaction.

The prime location of looseness was cited as being the introitus, and the most frequently recommended treatments were Kegel muscle exercises and pelvic floor physical therapy, though physical therapy was noted to be more effective. Only 54% of doctors recommended surgery to correct looseness, yet it was felt to be a more effective therapy.

Overall, vaginal laxity is not well studied and may affect sexual quality of life. Yet, there is a keen interest in addressing it, but there is inconclusive evidence to date that any one therapy works well or is the best option. There is debate and scant data, and this means, more study is definitely needed.

Sunday, September 16, 2012

Obstructed Sling: Can’t Pee From Your Sling? How to Prevent it and What to Do If This is Your Problem.


Sling surgery may be the perfect combination of mixing the art and science of medicine. Urinary incontinence, for which sling surgery is indicated, is a well-known quality of life problem that millions of women in the US and worldwide experience. When stress urinary incontinence is bothersome enough and conservative measures have failed, a sling is indicated to correct it. There are many surgical procedures for stress incontinence, but the sling has become the standard of care, and the mesh sling has become the most performed and the standard of care in the US and worldwide as well.

Balancing dryness after a sling with the ability to void urine is of paramount importance. One would not want to reasonably trade being constantly wet with being dry but unable to pee. Therefore a work up before sling surgery is necessary. Urodynamics should always be performed to determine what the preoperative bladder function is in order to properly determine whether and which type of sling should be performed. The two archetype slings are the retropubic “TVT”, and the transobturator “TVTO”, but there are many iterations of these original types that are equally successful. The minislings, such as the Miniarc as one example, are not well studies and fall under the recent 522 FDA requirement for further studies.

Sling obstruction essentially means, that even if placed correctly, the female patient cannot void. This does not mean 1 or two days, or even 7 days, but obstruction is considered if the patient still needs a catheter for at least 28 days. The rate of retention can be as high as 10% with this definition. What’s important to determine is when the inability to void began after surgery. It can present with obvious symptoms: straining, weak stream, sense of incomplete emptying, bladder cramps/spasms, urinary frequency, burning with urination and UTIs. Obstruction can even occur after many years and symptoms and a work up are needed to properly determine this.

Urodynamics are needed to access a variety of things in terms of bladder and urethral function. Of paramount importance is how strong (or weak) is the bladder contraction. Even if placed well, if the bladder contraction is weak, then the patient may not void well and the sling will act to obstruct the flow. A normal bladder contraction is required to overcome the normal resistance of the urethra and all the more so if a sling is present.   Women who void by Valsalva (or straining), and do no not necessarily relax to void, are at risk for retention after a sling as well. The sling will simply do what it is designed to do- block urine from coming out when a woman strains, whether it is during aerobics or straining to void.

Retropubic slings, whether mesh or autologous tissue, tend to hug the urethra more snugly and have a tendency to lead to retention and obstructive symptoms. This generally does not occur with transobsturator sling, as this type of sling is configured more splayed out. Both types have equal efficacy in curing stress incontinence. Retropubic slings may be favored if incontinence is more severe, or if a prior sling failed, yet, an important judgment call is deciding between being 95% dry with a transobturator sling even if the incontinence is severe, versus begin “105%” dry with a retropubic sling, which may make the patient dry but is now causing obstruction. “Dry” does not always mean “perfect”.  If may be better to leak rarely with a sling, than have constant trouble with emptying.

A weaker flow rate on Urodynamics, higher residual bladder urine before surgery, or older patients (>75 yrs), many also be at risk for post sling obstruction.  Alternatively, if a sling erodes into the urethra or extrudes into the vagina, sling obstruction symptoms will likely occur. In addition, if a bladder prolapse is not identified or fixed at the time of sling surgery, or if one develops later, the sling will effectively kink off the urethra at the point where the bladder drops. It will be difficult to empty the bladder in these cases as well. If the sling is not positioned well, either too close to the urethral opening or too far back off the urethra or if it migrates after placement, the sling can obstruct as well. These constitute the discoverable pre- and intra-operative factors that are the science of sling surgery.

Physician factor is equally important. There is really no standardized way of preventing obstruction. Each physician performs tensioning as he/she sees fit based on the sling type, body habitus, degree of incontinence and urodynamic factors. Retropubic tissue slings are most difficult to “eyeball”, and can obstruct right away or tighten and obstruct over time. This type of arbitrary tensioning of slings underscores the physician’s experience in performing slings. The more a physician has done, and the more slings the physician may also have re-done, whether his own or from another physician, the better the physician is at setting sling tension. That is the art of sling surgery without a doubt. As the old saying goes “caveat emptor”, let the buyer beware. Seek out a physician that is experienced in incontinence diagnosis and treatment.

A thorough pelvic exam, cystoscopy and urodynamics after the sling are required to evaluate and determine the correct treatment plan. Sometimes biofeedback or pelvic floor retraining may be all that is required if no obstruction is suspected or diagnosed. Sling transection, removal, or incision and release of the urethra is often needed if obstruction is diagnosed, and often will remedy the problem. However, this must be balanced with the risk of recurrence incontinence. Some patients may opt to self-catheterize versus risking being wet again after sling release. If diagnosed early enough, the sling maynot need to be removed, but rather can be loosened.

Tuesday, August 14, 2012

Urinary Tract Complications/Injury after Laparoscopic Hysterectomy


Gynecologic surgery is performed for many reasons, such as cervical, uterine or ovarian cancer, abnormal or severe menstrual bleeding, ovarian cysts, pelvic pain, large fibroids and endometriosis. Urological or urinary tract injury can be a serious complication of these surgeries and can lead to significant morbidity, loss of work time and permanent injury or need for corrective surgery. Laparoscopic surgery is a great advance and is used in gynecology as well as other specialties and affords great benefit to the patient such as: less post-operative pain, quicker recovery, shorter hospital stay, better cosmetic results, and quicker return to work. However it can be technically challenging, and may not be appropriate for all gynecological surgery. Such complications can even occur in the most experienced hands. The key to treatment is early appreciation, identification, and correction of injuries to minimize long term problems.

What are some of the most common complications that can occur?

The most common organ to be injured is the bladder. It is a floppy, hollow organ that lies on top of the vagina and must be separated from it during hysterectomy. The bladder can be inadvertently entered leading to a “hole” that requires closure. This injury is often recognized right away and can be easily closed in most cases, but it does require a bladder catheter to drain the bladder and allowing healing for at least a week.

The ureters are delicate thin tubes carrying urine from the kidneys to the bladder. Unfortunately, often these can be missed, misidentified and injured inadvertently during hysterectomy or ovary removal. They run beneath important arteries to the uterus. They can be cut, incorporated in sutures, or injured by heat/cautery. Often ureter injury in not appreciated right away and most commonly presents as pain, or obstructed kidney function, fever, flank pain or a combination of these several days after surgery. If the injury is recognized at the time of gynecological surgery the ureter can be repaired, but if the injury is noted later then the ureter or kidney on the affected side will require drainage with a tube or stent to allow for surgical inflammation to resolve over time and then delay repair the ureter till a later time.

Sometimes, and more rarely, if the bladder or ureter are injured by heat or incorporated into suturing of the vagina during surgery, a fistula can develop a week or so after surgery. The abnormal fistulous connection between the bladder/ureter and vagina will present sometimes with pain, blood in the urine and fever, but will most often present with fluid leaking from the vagina; this fluid being urine. A thorough exam of the vagina, bladder exam with x-ray and scope, and ureters with x-ray as well, all must be undertaken to determine where and how many injury points exist. Repair of the damaged ureter or bladder is then undertaken.

It is prudent and important for the female patient to ask her gynecologist prior to surgery which surgical approach is better or safer- this will depend on the problem at hand, how experienced the doctor is and what type of patient characteristics may predispose to injury.

An open incision for surgery may take longer to heal but if large fibroids are present or severe endometriosis exists, it may be safer. If the cervix is cancerous but not bulky, a laparoscopic surgery may do just fine. Laparoscopic surgery requires a special skill set and is itself a minor risk for urological injury. Large patient body size/high BMI, prior C-section, multiple fibroids, pelvic adhesions and severe endometriosis are considered risks during laparoscopic surgery. That is not to say that these injuries cannot occur if the surgery is done “open”, as they certainly can and unfortunately do occur from time to time.

The best defense is a good offense. Select the appropriate surgeon, review the best method of surgery based on the disease and patient limitations. And, don’t be afraid to ask how many cases a surgeon has done.

Saturday, July 14, 2012

After Your Sling, Check Your Bladder Function Prior to Leaving the Hospital. Avoid a Late Night ER Visit.

I have noticed a number of comments on the blog related to women who have had sling surgery and then leave the hospital afterwards without having voided yet, only to end up in the emergency room later that night unable to urinate, requiring then a catheter to be placed.

This is one of my pet peeves in regards to sling surgery, or any pelvic surgery. General anesthesia, spinal anesthesia, or any urological, gynecological, or pelvic surgery can and should be expected to have an effect on the bladder and one's ability to void after surgery. Though a minor surgery, sling surgery requires dissection around the urethra, and it may be difficult for some women to void afterwards. This should be expected and is not abnormal. The bladder is quite sensitive to surgery/anethesia and will recover function quite easily afterwards, but there are times when it simply is "on the fritz" and will not work. This takes forethought, time and patience to see through.

Though sling surgery is championed by many to be quick and easy, "routine", "minimally invasive", the perception that nothing can go wrong, is, wrong.

I routinely send the patient from the operating room to recovery with a catheter and guaze packing in the vagina. After the effect of anesthesia wears off about an hour or so later, I will have my recovery room nurses remove both, and then give the patient time to try to void over the next hour or so. Waking up with a catheter will give the sensation of needing to void, but it is better, in my opinion, than waking up with a full bladder and then unable to void. I have my patients void after surgery prior to leaving the hospital and will check their "residual urine" with a bladder scanner to be sure there is little leftover. This lets me know that the bladder is functional and an ER visit will be unlikely later that night.

If bladder function is known to be not so good going into surgery, I do not expect the bladder to function promptly right away, and I will therefore send the patients home with a catheter for a day or so. This may sound uncomforable, but the catheter is better than having the pain or bloat of a bladder that won't empty. Having it in overnight will also help sleep since it eliminates the need to wake up for the bathroom.

When the bladder cannot empty after surgery and goes into retention, it stretches, and this transient stretch injury needs to recover prior to normal voiding. Simply removing the catheter one day later after a retention episode is not enough time. Leaving the catheter in the bladder for 3-7 days ensures good bladder recovery and minimizes the need for further repeat catheterization. If the catheter is removed too soon after it has been stretched, the bladder will simply not work well, and patients will experience pain and small volume voids with urge and spasms. Repeated catheterizations increase infection risk.

If you are considering sling surgery or other urologic/gynecologic surgery, simply ask your urologist/gynecologist to do a bladder scan on you in recovery prior to leaving. An ounce of prevention...

Monday, June 4, 2012

Ever have a Foley (Bladder) catheter and develop an infection? You are not alone.


A urinary bladder catheter, more commonly called a Foley catheter after its inventor, is frequently necessary and required when undergoing bladder or other urology procedures, or when after surgery the bladder is not expected to function right way. Often patients go home with the Foley to a leg bag and it can be managed easily, though it can be annoying. Often when debilitation occurs such as after stroke or long term immobility, the Foley is left in the bladder long term, months or even years and needs to be changed at least monthly to avoid bladder infections.

Despite good hygiene and Foley changes, bladder infections can still occur. However more often than infection, bacteria can colonize the catheter and urine, but remain asymptomatic and not lead to overt infection. These are not infections per se.

Foley catheters should be inspected on a periodic basis, can be taken into the shower and cleaned with soap (not with alcohol), and the urethra and skin around the urethra must be cared for as it can develop irritation and discharge.  The catheter can stir up blood in the urine which is expected but is usually minor and resolves with water consumption. Individuals who take blood thinners (aspirin, Plavix, warfarin, pradaxa) are going to be at higher risk of bleeding in the urine with a chronic catheter in the bladder, which leads to irritation (which resolves after it is removed).

Foley trauma is equally an issue. The catheter drains and is usually connected to a legbag or long bedside bag. If the catheter pulls inadvertently, or gets tugged on, it will be painful, may stop draining or stir up blood and then stop draining as well. This is especially an issue in those requiring catheters for longer periods of time. When the catheter is left in too long the tip can become encrusted with stone deposit making it difficult to remove or traumatic upon removal. Sometimes if the urethra is narrow or the anatomy is difficult the Foley may not pass in easily and trauma can occur to the urethra which then will lead to bleeding, infection or both. These types of problems require overseeing by urologists, yet unfortunately, if issues occur over the weekend this leads to emergency room visits.

Taking antibiotics for infections is often required, and sometimes the catheter leads to infections itself, but constant or repeated antibiotic usage when catheters are present will lead to bacterial resistance to antibiotics. Antibiotics are like torpedoes, they need to be aimed precisely and used only when absolutely necessarily. Overuse can also lead to diarrhea, yeast infection, and other side effects.