“Various trials have been held over the course of a few years that have significant promise in ivermectin inhibiting the growth of cancer. The good news mainly has been the broad-spectrum working of Ivermectin. It has proven to be fairly effective against a large variety of cancers. The types of cancers it worked against included ovarian cancer, breast cancer, Oesophageal Squamous Cell Carcinoma, and many others.” [Source]
“ivermectin might be a new potential anticancer drug therapy for human colorectal cancer and other cancers. studies have shown that ivermectin has an inhibitory effect on various tumor cells and may be a potential broad-spectrum antitumor drug” [Source]
BUT “ivermectin is the most nonsensitive to the prostate cancer cell line DU145” [Source]
Ivermectin is just one of many drugs that have surfaced in recent years that show promise against malignant tumors. There is a high possibility that ivermectin will be used in chemotherapy commonly in the near future, however, we must understand that tumor cells can easily develop drug resistance and render the effects of many drugs useless. Even so, the use of ivermectin with other drugs in conjunction with therapy can be highly effective for a vast number of malignant tumors. [Source]
ivermectin, at doses of 3–5 mg/kg, was able to suppress the growth of human melanoma and a number of other cancer xenografts in mice without adverse effects [Source]
FOR PROSTATE CANCER
sOURCE: Ivermectin inhibits AR pathway in prostate cancer models. Resistance to AR pathway inhibitors in prostate cancer is associated with AR amplification, mutations, and expression of truncated AR variants, the latter characterized by loss of AR’s ligand-binding domain and constitutively active transcription (24). HSP27 has an established role in AR trafficking and stability, and its inhibition by either apatorsen or si-HSP27 reduces AR protein levels and activity, thereby delaying progression of castration-resistant prostate cancer (CRPC) (7, 8, 25). Similarly to apatorsen (7), IVM significantly reduced AR and prostate-specific antigen (PSA) protein expression in castration-sensitive LNCaP cells and ARF876L protein expression in enzalutamide-resistant M49F cells, an effect that was enhanced in combination with androgen deprivation therapy (in LNCaP cells) or enzalutamide (in M49F cells) (Figure 4A). IVM increased sensitivity of LNCaP cells to androgen deprivation therapy and of enzalutamide-resistant ARF876L M49F cells to enzalutamide (Figure 4B). Interestingly, IVM also decreased AR variant 7 (AR-V7) protein levels in 22RV1 cells, similarly to either si-HSP27 or apatorsen (Figure 4C). The reduction of AR or AR-V7 protein expression was not related to modulation of mRNA levels (Supplemental Figure 4A). The functional effect of IVM on AR-V7 transcriptional activity was also assessed using a PC3V7_3TKNLuc system that incorporates a doxycycline-inducible AR-V7 and probasin-based ARR3tk-Nanoluciferase reporter construct. As shown in Figure 4D, IVM significantly inhibited AR-V7 transcriptional activity compared with PC3_3TKNLuc control. AR-V7 nuclear translocation in 22RV1 cells was also inhibited by IVM, decreasing nuclear AR-V7 levels, with a corresponding increase in the cytoplasmic fraction (Figure 4E).
This is the first step. “The normal urinary flow rate in young and middle aged men is generally greater than 15?ml/second and the flow pattern a bell shaped curve. ” “In those who have a urethral stricture the peak flow rate is typically low but the flow pattern is characteristically flat” [Source]
“With a flow rate of less than 5?ml/second, abnormalities such as those listed above are much more likely and the patient is potentially at risk of acute retention, although this is a lot less common than one would expect from the severity of the narrowing of the urethra that is seen in such a situation. In these patients treatment is advisable even if symptoms of voiding difficulty are not troublesome.” [Source] (Sanjeev: I’m having pain while voiding)
Urethrogram
Both “RUG/VCUG is costly and some-times logistically difficult to perform, and exposes men to radiation” [Source] These tests “show the exact site and length of the stricture and most of its potential complications” [Source]
The penis is postioned at approximately the 10 o’clock position. The round opaque structure in the distal penis is the inflated Foley balloon. The Foley catheter tip is faintly radiopaque, but can be better seen as a filling defect after administration of contrast. [Source]
The voiding urethrogram evaluates the posterior urethra. The Foley balloon is advanced into the bladder and contrast is instilled until the bladder is dilated. The bladder should be so dilated, that the patient “feels like he absolutely needs to pull off to the side of the road so he can urinate”. The Foley is then removed and the patient is encourage to urinate. Images are obtained of the open posterior urethra. As this is not a dedicated cystogram, imaging the bladder is a secondary concern. [Source]
AUGMENTED URETHROPLASTY
“If the stricture is long and/or located in the penis, the stricture may be open or removed and the area is more commonly patched or less commonly replaced with a tube, made from surrounding tissues, such as nearby skin or from tissue removed from other areas in the body such as from the inside of the cheek (buccal mucosa). ” [Source]
Urethral strictures may be dilated in this setting [when a stricture is suspected during surgery]to allow catheter insertion, and dilation over a guidewire is recommended to prevent false passage formation or rectal injury. Alternatively, DVIU may be performed, particularly if the stricture is too dense to be adequately dilated. SP cystotomy may also be performed to provide urinary drainage at the time of surgery if these initial maneuvers are unsuccessful, or when subsequent definitive treatment for urethral stricture is planned in the near future. [Source:Male Urethral Stricture: American Urological Association Guideline]
[Sanjeev: My surgeon felt something blocking the catheter during the prep for the prostatectomy. He did not do dilation or DVIU at that stage but moved on with the prostatectomy. I understand that using a large cathether is essential for such a surgery. In my case the goal of fixing the bigger issue – cancer – led to a secondary injury that is going to remain with me lifelong. EVEN IF HE HAD CONDUCTED A DVIU AT THAT STAGE, THE SITUATION I NOW HAVE WOULD HAVE BEEN UNCHANGED. Therefore, there was NO WAY to avoid what I’ve now got.]
URETHROTOMY IS GUARANTEED TO FAIL
After 1 urethrotomy Pansadoro and Emiliozzi found a 5-year stricture-free survival rate of 6%, which closely matched our 5-year stricture-free survival rate of 7%. Treatment eventually failed in all 7% of the patients by 79 months. [Source] – i.e. 100 PER CENT RECURRENCE WITHIN FIVE YEARS, WITH MOST RECURRING WITHIN 3-6 MONTHS.
The stricture-free rate after the first urethrotomy was 8% with a median time to recurrence of 7 months. For the second urethrotomy stricture-free rate was 6% with a median time to recurrence of 9 months. For the third urethrotomy stricture-free rate was 9% with a median time to recurrence of 3 months. For procedures 4 and 5 stricture-free rate was 0% with a median time to recurrence of 20 and 8 months, respectively. [Source]
RECOMMENDATION: NO MORE THAN ONE URETHROTOMY
“During the last 30 years urethroplasty has improved in efficacy and safety, while urethrotomy is increasingly considered neither cost-efficient nor effective in the long term. Urethroplasty is reported to have lifetime success rates ranging from 75% to 100%. Repeat and unsuccessful urethrotomies impose costs to the patients in the form of lost wages, unnecessary health care expenditures, decreased quality of life and unnecessary anesthesia. The fact that urethrotomy has a low success rate is a strong argument for opting for the more effective urethroplasty instead of a less effective urethrotomy.” [Source]
NOTE: THIS ISSUE IS NOT STENOSIS!
It is hard to get information on this issue from the internet. First thing to note is that it is quite different to meatal stenosis, which is a narrowing of the opening (this is how it looks). “Meatal stenosis is a common complication of circumcision.” Curing stenosis is relatively easy and is done through a surgical procedure called meatotomy during which the meatus is crushed with a straight mosquito hemostat and then divided with fine-tipped scissors. (here is a video of how it is done]
WHAT A MEATAL (or fossa navicularis) STRICTURE LOOKS LIKE?
It appears this issue was very common with prostatectomies in the past (Some Common Complications After Prostatectomy, J. Cosbie Ross and L. F. Tinckler, The British Medical Journal, Vol. 2, No. 5153 (Oct. 10, 1959). The issue still occurs in around 2 per cent of the patients.
Male Urethral Stricture: American Urological Association Guideline (2017)
Male Urethral Stricture: American Urological Association Guideline (full guideline needs online journal access) says that uncomplicated urethral stricture confined to the meatus or fossa navicularis should be treated with simple dilation or meatotomy, with or without guidewire placement.
However, urethroplasty is needed for to patients with recurrent meatal or fossa navicularis strictures. Meatal and fossa navicularis strictures refractory (i.e. stubborn to) to endoscopic procedures are unlikely to respond to further endoscopic treatments (e.g. Urethrotomy).
Patients who opt for repeat endoscopic treatments or intermittent self-dilation in lieu of more definitive treatment, such as urethroplasty should be advised that success of a subsequent reconstructive procedure may be lower when following a plan of repeated endoscopic surgery and/ or intermittent self-dilation. Similar to other types of stricture, exact delineation of length and etiology is important for guiding treatment.
Dilation is a bad idea. In my case, when the stricture recurs, I should undergo urethroplasty (or whatever the term is called).
What are the Treatments for Meatal Stricture / Meatal Stenosis? [Sanjeev: these are quite different things]
Intermittent self meatal dilatation – In some men it is possible that the narrowing of your urethra may re-occur. To reduce this risk you may be taught how to perform intermittent self meatal dilatation. [Sanjeev: it appears it will recur in almost all cases, and instead, aggravate things.]
What is Meatal Dilatation? Meatal Dilatation is a procedure which involves you passing a short catheter into the end of your urethra. The catheter is passed beyond the narrow section and this helps to keep the urethra open.
What Are The Alternatives?
Meatal dilatation – If your urethra is not too narrow, it can be dilated or stretched in theatre under local anaesthetic or a general anaesthetic (when you are put completely to sleep) using catheters (soft, hollow plastic tubes) which are graduated in size.
Meatotomy – A small operation to stretch or cut through the narrow tissue in your urethra may be necessary. This is called a ‘meatotomy’. Occasionally an additional procedure called circumcision (removal of the foreskin) may be necessary if repeated infections and inflammation (balanitis) at the tip of the penis has resulted in a tight foreskin. [Sanjeev: this is – as described – ONLY meant for a stenosis; not applicable in my case]
What are the risks of Meatal Dilatation?
Pain. At first it may be a little painful or uncomfortable to pass the catheter, especially if you have had recent surgery. This, however, should improve with time and most men are able to tolerate the procedure with little discomfort.
Bleeding. You may see a little blood on the end of the catheter after performing the procedure or experience a little bleeding from the urethra. This is nothing to worry about and should soon stop. If the bleeding becomes heavy and prolonged then contact your healthcare professional. [Sanjeev: actually bleeding is a BAD thing during dilation, as it will simply aggravate scarring]
Infection. It is important to wash your hands and penis before performing meatal dilatation so that no bugs are passed up into the bladder. However, if you experience pain or burning when passing urine, notice that your urine is cloudy or smelly or, especially, if you start to feel unwell (i.e. high temperature, abdominal pain or flu like symptoms), contact your GP or healthcare professional immediately as you may have a urine infection.
Recurrent Stricture If you notice a reduction in your flow of urine or if it becomes difficult to pass the catheter into the urethra, it may be because the narrowing has re-occurred. If this happens seek advice from you healthcare professional. [Sanjeev: This is STUPID. The advice should be provided upfront, including discussion of all risks]
General Advice
For how long and how often should I perform Meatal Dilatation? As everyone is different, a personalised regime will be agreed between yourself and your healthcare professional as to how often and for how long you should perform the procedure.
Dilatation catheters
These are usually sterile hydrophilic coated single use catheters with NO drainage eyes. They are used for keeping the urethra patent in patients with strictures or who have had surgery to the urethra. Dilatation catheters will not drain the bladder. Shorter length meatal dilators are available for men who need only to dilate the meatus to avoid meatal stenosis, or to dilate a sub-meatal stricture. If the stricture is higher in the urethra then a full length dilatation catheter (40cm) will be needed. [Source: Trust Guideline for the Management of Teaching Clean Intermittent Self-catheterisation (CISC)]
DILATION IS NOT A GREAT IDEA
Treatment approach to pre-TURP urethral strictures:
– Meatal/sub-meatal stricuture: Do a formal meatotomy instead of excess dilation
“For urethral strictures in the penile urethra to the bulbar urethra, dilation is not recommended.” [Source]
CAN DILATION WORK IN SOME CASES? – UNLIKELY
It is said in the Male Urethral Stricture: American Urological Association Guideline that stricture recurrence is significantly lower among patients performing self-catheterization. Data suggests that performing self-catheterization for greater than four months after DVIU reduced recurrence rates compared to performing self-catheterization for less than three months. [Sanjeev: I find this hard to believe – given the study which showed that RECURRENCE IS GUARANTEED WITH DVIU – seethis study].
TREATMENT OPTION 2: MEATOPLASTY/ URETHROPLASTY – fixes 90 per cent of the time
URETHROPLASTY CAN FAIL IF YOUR SURGEON IS NOT EXTRAORDINARLY COMPETENT
” the success of open urethroplasty is very dependent on the surgical technique and the expertise of the surgeon. When urethral surgery is not properly performed, early recurrence of the stricture is a very common complication. … Although stricture recurrence is always a possibility, even when the surgery is performed by a qualified experienced specialist, recurrences more commonly occur when surgery is performed by urologists not exclusively specialized in male urethral and penile reconstructive surgery. When the surgery is not properly performed, failure is an expected outcome.” [Source]
ONE-STAGE MEATOPLASTY IS POTENTIALLY AN OPTION IN MY CASE
SUB-MEATAL STRICTURE SOMETIMES REQUIRES TWO STAGE SURGERY
“For the most complex strictures of the anterior urethra, including the urethral meatus, a staged surgical approach is adopted, removing the stricture then placing a graft in the open space. This is allowed to heal open to the air for a period of 6-12 months, before it is “re-tubularized” into a urethra. This is usually reserved for individuals with strictures in the pendulous urethra, very scarred strictures, repeated failures, and very long strictures.” [Source]
A TEN PERCENT RECURRENCE RATE EXISTS EVEN FOR URETHROPLASTY
“Like all surgical procedures, the results of urethroplasty are not 100%. A recurrence urethral stricture rate of 10 % can be expected long-term. Patients with pelvic fracture associated urethral stricture and prostate involvement associated strictures have the highest recurrence rate.” [Source]
The surgical technique of Meatoplasty is generally suggested in patients with meatal urethral strictures. There are three basic types of Meatoplasty [Source] This is perhaps the best description.
Meatoplasty using skin flap. Using this technique, the urethral meatus is augmented using a penile skin flap (figure 1).
Meatoplasty with oral mucosal graft. Using this technique, the urethral meatus is augmented by a transplant of an oral graft (figure 2).
Meatoplasty with skin graft.Using this technique, the urethral meatus is augmented by a transplant of a skin graft.
Glanular/meatal stricture can be seen as an isolated problem or as part of more extensive urethral stricture disease. Various treatment options are available, including penile flap and buccal mucosa, for the treatment of stricture at this location
This is an amazing advance in science – BUT THERE IS A RISK THAT STEM CELL THERAPY MIGHT MULTIPLY ANY RESIDUAL CANCER CELLS THAT ARE LEFT BEHIND AFTER SURGERY.
“Decades ago, researchers discovered that a particular type of stem cell — mesenchymal stem cells — in bone marrow could generate new bone, cartilage, and fat. In 2001 researchers discovered that mesenchymal cells are even more plentiful in body fat…. Injured and inflamed cells send out an SOS signal; new stem cells pick it up. “The stem cells are so smart, all you have to do is turn them loose,” he offers. “They float around to different areas of the body and fix them.”…you’ll find a significant number of unhappy people who’ve paid thousands of dollars at clinics and have not seen any results. ?” [Source]
“Stem cells are able to be derived from a number of sources: embryonic stems cells (ESCs) and mesenchymal stem cells (MSCs) , which include: placental or amniotic fluid stem cells (AFPSCs), muscle-derived stem cells (MDSC) , adipose-derived stem cells (ADSC) , bone-marrow-derived stem cells, and even urinary-derived stem cells (USC).” [Urinary Continence and Sexual Function After Robotic Radical Prostatectomy]
Human trials in stress urinary incontinence have been ongoing for a number of years. Carr et al. reported on a patient population of 38 women with stress urinary incontinence who underwent muscle-derived stem cell injections into the sphincter. The women were also offered a second injection 3 months later. Ninety percent of the treated women had over a 50 % decrease in pad weight and only 50 % reported leaks. Adverse events were essentially absent [ 38 ].
Gotoh treated 11 men with persistent stress urinary incontinence 1 year after prostate surgery and demonstrated a 60 % decrease in urinary leakage volume on pads weighed by the patients. One of the 11 achieved complete return of urinary control. Functional urethral leak and urethral closing pressures were also increased compared to pretreatment levels. No adverse events were reported [39 ].
Currently, there is a large multicenter ongoing trial phase 3 trial in the United States with muscle-derived stem cells in women with stress urinary incontinence and a phase 1, 2 trial using muscle-derived stem cell in postpros-tatectomy incontinence (ClinicalTrials.gov Identifier: NCT01893138 and NCT02291432).
Although stem cells derived from any source are not yet ready for clinical use in men with stress urinary incontinence after radical retropubic prostatectomy, the future appears to hold promise. Nonetheless, ethical and regulatory issues remain of concern and may present hurdles to widespread clinical adoption [40 ].
The early ethical concerns surrounding the use of fetal embryonic stem cells have by and large been resolved by the development of so many other sources for multipotent stem cells. Nonetheless, the recent classification of stem cells as a “drug” places them under the purview of the FDA and now regulatory hurdles may enhance or impede the science and usefulness of these agents.
Finally, the fears of the development of secondary cancers or causing early recurrences/failures of cancers if stems cells are released into the operative field to and in early functional recovery are very real. Well-structured trials need to be carried out to address these questions and the questions of which (if any) of the currently available products might be best used in men undergoing prostatectomy. Nonetheless, the future of stem cells use in our patients undergoing prostatectomy appears bright. [Urinary Continence and Sexual Function After Robotic Radical Prostatectomy]
Male Incontinence and Cell Surgical Network is using Stromal Vascular Fraction with adipose derived adult mesenchymal stem cells to treat post prostatectomy incontinence. The SVF and a small amount of condensed fat matrix is injected with a telescope directly into a deficient sphincter under local anesthetic. Based on experience from Nagoya University, Japan where Stromal Vascular Fraction has been used successfully for male incontinence, we believe that the external sphincter may be regenerated to some extent to provide bladder control. can provide access to the same technology through our investigatory protocol. [Source]
“In the past five years, the number of U.S. stem cell clinics has mushroomed from 25 to 570, according to a recent report published in the journal Cell Stem Cell…. the costly procedures are still unapproved by the FDA, leaving an open gate for medical charlatans and hucksters.” [Source – including analysis]
“the FDA warns that stem cells can migrate to the wrong site or turn into tumors.” [source]
Stem Cell Injections Ease Incontinence (2007) [“Endoscopic injections of human umbilical cord blood stem cells may be a safe treatment option for women with stress urinary incontinence (SUI), according to findings presented here at the American Urological Association annual meeting.”]
Stem Cell Therapy for Incontinence: Where Are We Now? (2011) What is the Realistic Potential?
Charuspong Dissaranan, Michelle A. Cruz, Bruna M. Couri, Howard B. Goldman, and Margot S. Damaser [” the future of this therapy looks promising”]
Stem Cell Therapy for Male Urinary Incontinence – Giberti C. · Gallo F. · Schenone M. · Cortese P. · Ninotta G. [“Regarding animal studies, bone marrow-, muscle- and adipose-derived stem cells have been widely studied, showing regeneration of the urethral sphincter and recovery of the damaged pelvic nerves. With regard to human studies, only four papers are available in the literature using muscle- and adipose-derived stem cells which reported a significant improvement in sphincteric function and incontinence with no severe side effects.”]
The potential role of stem cells in the treatment of urinary incontinence (2015) Christine Tran and Margot S. Damas [“Early clinical trials using stem cells for the treatment of stress urinary incontinence in both male and female patients have also achieved promising functional results with minimal adverse effects.”]
