Metastatic Renal Cell Carcinoma:Review of Novel Therapeutic options

Renal cell carcimoma (RCC) is the third most common genitourinary cancer after prostate and bladder. Majority (80% to 85%) of kidney tumors are malignant. It is the most lethal malignancy of all urological cancers.
Unique characteristics of RCC
 lack of early warning signs,
 diverse clinical manifestations,
 resistance to radiation and chemotherapy, and
 immunogenic nature and spontaneous regressions.
RCC diagnosed early can be managed with nephron sparing or radical nephrectomy with excellent 5 year survival and prognosis. The problematic cases are those presenting as advanced disease at the initial presentation. The advanced disease includes: T4 N0 M0, or any T, any N, M1. These cases are associated with poor survival and limited treatment options. This information aims to throw some light on our current understanding of the pathogenic mechanisms, and the available treatment options for the management of advanced RCC.
Pretreatment features associated with shorter survival
There are various studies identifying the pretreatment factors associated with poor survival. These are
– Low Karnofsky performance status (< 80%)
– High lactate dehydrogenase level (> 1.5 x normal)
– Low hemoglobin level
– High serum calcium
– Absence of nephrectomy

• Nephrectomy and resection of metastases has been reported to prolong the survival. Effect is enhanced with long disease-free interval between initial nephrectomy and development of metastases.
• Survival also depends on the site of metastasis. Patients with lung metastasis only have better survival than those with other site metastasis. (Flanigan RC, et al. N Engl J Med. 2001; 345: 1655-1659.)
Available treatment modalities
Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Therefore, various biologic therapies have been evaluated. New agents, such as sorafenib and sunitinib, having anti-angiogenic effects through targeting multiple receptor kinases, and have been investigated in patients failing immunotherapy.
Role of Surgery
Palliative nephrectomy should be considered in patients with metastatic disease for alleviation of symptoms such as pain, hemorrhage, malaise. Several randomized studies are now showing improved overall survival in patients presenting with metastatic kidney cancer who have nephrectomy followed by either interferon or IL-2. If the patient has good physiological status, then nephrectomy should be performed prior to immunotherapy. There are anecdotal reports documenting regression of metastatic renal cell carcinoma after removal of the primary tumor but adjuvant nephrectomy is not recommended for inducing spontaneous regression; rather, it is performed to decrease symptoms or to decrease tumor burden for subsequent therapy in carefully controlled environments. About 25-30% of patients have metastatic disease at diagnosis, and fewer than 5% have solitary metastasis. Surgical resection is recommended in selected patients with metastatic renal carcinoma. This procedure may not be curative in all patients but may produce some long-term survivors. The possibility of disease-free survival increases after resection of primary tumor and isolated metastasis excision.
RADIATION THERAPY
Radiation therapy may be considered as the primary therapy for palliation in patients whose clinical condition precludes surgery, either because of extensive disease or poor overall condition. A dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy. Preoperative radiation therapy has not been found to yield any survival advantage. Controversies exist concerning postoperative radiation therapy, but it may be considered in patients with peri-nephric fat extension, adrenal invasion, or involved margins. A dose of 4500 cGy is delivered, with consideration of a boost. Palliative radiation therapy often is used for local or symptomatic metastatic disease, such as painful osseous lesions or brain metastasis, to halt potential neurological progression. Surgery also should be considered for solitary brain or spine lesions, followed by postoperative radiotherapy. Stereotactic radiosurgery is more effective than surgical extirpation for local control and can be performed on multiple lesions.
CHEMOTHERAPY
Renal cell carcinoma is refractory to most chemotherapeutic agents because of multidrug resistance mediated by p-glycoprotein. Normal renal proximal tubules and renal cell carcinoma both express high levels of p-glycoprotein. Calcium channel blockers or other drugs that interfere with the function of p-glycoprotein can diminish resistance to vinblastine and anthracycline in human renal cell carcinoma cell lines. A recent phase 2 trial of weekly intravenous gemcitabine (600 mg/m2 on days 1, 8, and 15) with continuous infusion 5-fluorouracil (150 mg/m2/d for 21 d in 28-d cycle) in patients with metastatic renal cell cancer produced a partial response rate of 17%. No complete responses were noted. Eighty percent of patients had multiple metastases, and 83% had received previous treatment. The mean progression-free survival duration of 28.7 weeks was significantly longer than that of historic controls. The role of chemotherapy is questionable with limited efficacy and more morbidity.
IMMUNOTHERAPY
Many immune modulators, such as interferon, interleukins (IL-2), vaccination, lymphokine-activated killer (LAK) cells plus IL-2, tumor-infiltrating lymphocytes, and non-myeloablative allogeneic peripheral blood stem-cell transplantation, have been tried.
A : Interferons -The interferons are natural glycoproteins with antiviral, anti-proliferative, and immuno-modulatory properties. They have a direct anti-proliferative effect on renal tumor cells in vitro, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules.
Interferon-alpha, which is derived from leukocytes, has an objective response rate of approximately 15% (range 0-29%). Preclinical studies have shown synergy between interferons and cytotoxic drugs. In several prospective randomized trials, combinations do not appear to provide major advantages over single-agent therapy. Many different types and preparations of interferons have been used without any difference in efficacy.
Interlukin -IL-2 is a T-cell growth factor and activator of T cells and natural killer cells. It hampers tumor growth by activating lymphoid cells in vivo without directly affecting tumor proliferation. It can be administered as high dose and low dose regimen.
A high-dose regimen (600,000-720,000 IU/kg q8h for a maximum of 14 doses) results in a 19% response rate with 5% complete responses. The majority of responses to IL-2 were durable, with median response duration of 20 months. Eighty percent of patients who responded completely to therapy with IL-2 were alive at 10 years. Most patients responded after the first cycle, and those who did not respond after the second cycle did not respond to any further treatment. Therefore, the current recommendation is to continue treatment with high-dose IL-2 to best response (up to 6 cycles) or until toxic effects become intolerable. Treatment should be discontinued after 2 cycles if the patient has had no regression. Combinations of IL-2 and interferon or other chemotherapeutic agents such as 5-FU have not been shown to be more effective than high-dose IL-2 alone. In the initial study by the National Cancer Institute, bolus intravenous infusions of high-dose IL-2 combined with LAK cells produced objective response rates of 33%. In subsequent multicenter trials, the response rate was 16%. Subsequent studies also showed that LAK cells add no therapeutic benefit and can be eliminated from the treatment. Combination HD IL-2/IFN alfa slightly has been reported to be slightly better than HD IL-2 alone (Rosenberg SA, et al. N Engl J Med. 1987;316:889-897). The interferons can be given as inpatient, subcutaneous, and home-administered regimens.
Toxicity is dose dependent. Most common dose dependant toxicity is hypotension requiring vasopressors. Also malaise, diarrhea, pyrexia, and rashes are commonly reported toxicities.
Approved for treatment of patients with metastatic RCC.
Durability of response: Approximately 60% of CRs remain disease free at > 10 yrs follow-up[3]
Prognostic factors for favorable response with IL-2 and IFN alfa therapy
ECOG performance status (0 vs ≥ 1)
Time from diagnosis to treatment (≤ 12 mos)
Number of metastatic sites (1 vs ≥ 2)
(Canobbio L, et al. J Cancer Res Clin Oncol. 1995;121:753-756
B: cG250 THERAPY:
Immunotherapy targeting for the induction of a T-cell-mediated antitumor response in patients with RCC appears to hold significant promise. G250, a widely expressed RCC associated antigen; and granulocyte/macrophage-colony stimulating factor (GM-CSF), an immunomodulatory factor for antigen-presenting cells. The G250-GM-CSF fusion gene was constructed and expressed in Sf9 cells using a baculovirus expression vector system. The purified FP retains GM-CSF bioactivity, which is comparable, on a molar basis, to that of recombinant GM-CSF when tested in a GM-CSF-dependent cell line. When combined with interleukin 4, it induced differentiation of monocytes (CD14+) into dendritic cells (DCs) expressing surface markers characteristic for antigen-presenting cells. Up-regulation of mature DCs with enhanced expression of HLA class I and class II antigens was detected in FP-cultured DCs as compared with DCs cultured with recombinant GM-CSF. Treatment of peripheral blood mononuclear cells (PBMCs) with FP alone (2.7 microg/10(7) cells) augments both T-cell helper 1 (Th1) and Th2 cytokine mRNA expression (IL-2, IL-4, GM-CSF, IFN-gamma, and tumor necrosis factor-alpha). Comparison of various immune manipulation strategies in parallel, bulk PBMCs treated with FP (0.34 microg/ml) plus IL-4 (1000 units/ml) for 1 week and restimulated weekly with FP plus IL-2 (20 IU/ml) induced maximal growth expansion of active T cells expressing the T-cell receptor and specific anti-RCC cytotoxicity, which could be blocked by the addition of anti-HLA class I, anti-CD3, or anti-CD8 antibodies. In one tested patient, an augmented cytotoxicity against lymph node-derived RCC target was determined as compared to that against primary tumor targets, which corresponded to an 8-fold higher G250 mRNA expression in lymph node tumor as compared with primary tumor. The replacement of FP with recombinant GM-CSF as an immunostimulant completely abrogated the selection of RCC-specific killer cells in peripheral blood mononuclear cell cultures. All FP-modulated peripheral blood mononuclear cell cultures with antitumor activity showed an up-regulated CD3+CD4+ cell population. These results suggest that GM-CSF-G250 FP is a potent immunostimulant with the capacity for activating immunomodulatory DCs and inducing a T-helper cell-supported, G250-targeted, and CD8+-mediated antitumor response. These findings may have important implications for the use of GM-CSF-G250 FP as a tumor vaccine for the treatment of patients with advanced kidney cancer
.
Anti-angiogenic agents
With the better understanding of molecular biology of the tumor and the mechanisms of tissue invasion and metastasis, various agents targeting the angiogenesis have been tried in the treatment of metastatic RCC.
A: NEOVASTAT(Marketed in India as Requar Powder)
Neovastat is a naturally occurring anti-angiogenic compound, extracted from shark cartilage, with multiple anti-angiogenic mechanisms of action that provide broad therapeutic potential for a number of diseases. It is currently in international Phase III trials for renal cell carcinoma and non-small-cell lung cancer. Neovastat is administered orally and can be used alone or in combination with other therapies.
Anti-angiogenic mechanisms of Neovastat
1. Blocking VEGF binding.
Studies reveal that Neovastat contains a component that specifically prevents the binding of VEGF (Vascular Endothelial Growth Factor) to its receptors. The prevention of the binding of VEGF to its receptors is an important factor in the prevention and containment of tumor growth. .
2. Inhibiting MMP’s.
Results of studies reveal strong inhibition of gelatinolytic and elastinolytic activities for MMP-2, MMP-9, and MMP-12. The MMP's are often over expressed in tumors and play an important role in the degradation of the matrix that surrounds the cell (extracellular matrix), which allows tumor growth and invasion (metastasis).
3. Induction of endothelial cell specific apoptosis.
Induction of apoptosis (programmed cell death) is an additional Anti angiogenic activity found in Neovastat. The induction of endothelial cell apoptosis by Neovastat may thus prevent the formation of new blood vessels.
4. Increase in the level and the activity of tissue-type plasminogen activator (t-PA).
Data from an experimental study (glioblastoma) shows that Neovastat is capable of increasing the level and activity of t-PA from endothelial cells present within the tumor. The t-PA may induce the disintegration of blood vessels present inside the tumor.
5. Anti-metastatic properties:
Results of animal studies of the effect of Neovastat on lung metastasis show a significant decrease in the number of lung nodules when Neovastat was used alone or in combination with Cisplatin. Neovastat was also shown to decrease bone metastasis in mice.
Anti-tumor properties:
Studies performed with a mouse model of breast cancer (DA3 adenocarcinoma) demonstrates that oral administration of Neovastat for 54 days inhibits the progression of tumor volume by 60% compared to the control group. In experimental glioblastoma implanted in the brain, Neovastat was shown to significantly increase mice survival.
Neovastat has shown a consistently excellent safety and tolerability profile in clinical studies involving more than 850 patients. Some patients have been receiving treatment for almost four years.
Clinical experience:
Survival benefit in patients with renal cell carcinoma (RCC): Among the patients included in a Phase II open-label trial, a prospective survival analysis was performed in 22 patients with metastatic RCC refractory to standard therapies or for whom no treatment was available. Patients were treated with 60 ml/day (8 patients) or 240 ml/day (14 patients). Median survival time in patients receiving 240 ml/day has been found significantly longer as compared to the median survival time in patients receiving 60 ml/day (16.3 vs 7.1 months; p=0.01)
B: THALIDOMIDE:
Thalidomide is reported to suppress levels of several cytokines, angiogenic growth factors including TNF- , basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The resulting anti-angiogenic, immunomodulatory and growth suppressive effects form the rationale for investigating thalidomide in the treatment of malignancies. Studies have been carried out where high dose thalidomide have been administered to the patients with renal cell carcinoma (600 mg daily).Thalidomide has been given to patient s who are refractory to the immunotherapy. The partial response occurs in 9-10% patients with 30-50% patients show stable disease for a period ranging from 6 -12 months.

Other experimental approaches
Other therapies which hold promise include immunomodulatory allogeneic peripheral blood stem-cell drugs, vaccines, and nonmyeloablative transplantation.
The immunomodulator, lenalidomide (Revlimid), a derivative of thalidomide, inhibits VEGF, stimulates T and NK cells, and inhibits inflammatory cytokines. It has been evaluated extensively in hematologic malignancies and recently was reported to demonstrate efficacy in RCC regression and delayed time to progression in a phase 2 study of metastatic RCC.
Vaccines:
Vaccine trials are in early stages of development. Few antigens have been identified that induce T-cell responses from renal cell carcinoma. One example of vaccine strategy is to induce the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) into autologous cultured renal cell cancer lines by retroviral transduction. Patients then are immunized with irradiated tumor cells secreting large amounts of GM-CSF and are evaluated for immune responses and clinical tumor regression. Other approaches to vaccination include tumor lysates and dendritic cells. Autologous vaccine therapy is now being tried in combination with cytokine therapy. Several tumorcell and dendritic cell based vaccines are in clinical trials now-a-days. Potential DC activators include HSP (Heat Shock Protein), dead cells, bacterial products etc. HSPPC-96(HSP-peptide complex -96) is currently in phase 3 trials.
Another strategy to augment the immune system include using anti-CTLA-4 (cytotoxic T-lymphocyte associated antigen-4) to block the suppression of the lymphocyte activity. Gene modified autologous tumor cell expressing B-7-1(CD-80), a T-cell co-stimulatory molecule, combined with systemic IL-2 also represent a safe and active biological approach. Due to its critical role in RCC biology CA-9 has been exploited as a potential target for immunotherapy. CA-9 based vaccine strategy is currently being developed, including granulocyte-macrophage colony stimulating factor-CA 9 fusion protein vaccine in an attempt to enhance immunogenic activity of CA-9.
Nonmyeloablative allogeneic stem-cell transplantation is another research approach. This can induce sustained regression of metastatic renal cell carcinoma in patients who have had no response to conventional immunotherapy. In one recent trial, 19 patients with refractory metastatic renal cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of peripheral blood stem cells from a human leukocyte antigen (HLA)-identical sibling or a sibling with a mismatch of a single HLA antigen. Patients with no response received as many as 3 infusions of donor lymphocytes. Two patients died of transplantation-related causes, and 8 died from progressive disease. In 10 patients (53%), metastatic disease regressed; 3 patients had a complete response, and 7 had a partial response. The durations of these responses continue to be assessed. Further trials are needed to confirm these findings and to evaluate long-term benefits.
Multiple studies have been conducted using megestrol (Megace) in the treatment of renal cell carcinoma. No benefit has been shown except for appetite stimulation, so megestrol currently is not recommended. Antiestrogens such as tamoxifen (100 mg/m2/d or more) and toremifene (300 mg/d) also have been tried, with a response rate as low as that of most chemotherapeutic agents.
Binding antibodies to the VEGF protein
Bevacizumab
VEGF receptor inhibitors
Sunitinib
Sorafenib
Others under investigation (eg, valatinib, axitinib)



Bevacizumab:
A recombinant anti-VEGF antibody created by transferring the VEGF-binding regions of the murine antibody to a humanized IgG1 framework (93% human, 7% murine). Produces a humanized IgG. Mediates blockade of VEGF protein (ligand). Binds and neutralizes all biologically active isoforms of VEGF.

Multi-kinase inhibitors
Advanced and metastatic renal cell cancer (RCC) is resistant to conventional chemotherapy. Only a very small number of patients survive long term after immunotherapy. However, any effect of interleukin-2 (IL-2) and/or interferon on median overall survival is small, and treatment-associated toxicities may be severe. The disease is therefore an area of high unmet medical need. Activation of the VEGF and EGF/RAS/RAF/MAP kinase pathways is frequent in solid tumours such as RCC. Such activation is implicated in tumour angiogenesis and proliferation. VEGF and EGF receptors and molecules (such as RAF kinase) involved in downstream signalling are therefore potential appropriate targets for drug therapy. Several antibodies and low molecular weight tyrosine kinase inhibitors (TKIs) have completed phase II clinical trials. Phase II studies of multitargeted agents, which include inhibition of VEGFR tyrosine kinase in their repertoire (sorafenib, sunitinib and AG 013736), show clear second-line activity in metastatic RCC. The same is true of the anti-VEGF antibody, bevacizumab. In a randomised phase III comparison against placebo in pretreated patients, sorafenib doubled median progression free survival (24 versus 12 weeks). Studies now in progress will determine whether benefits seen second-line will also be evident first-line, and whether the activity of novel agents can be increased by combining them with each other, with cytokines, or with chemotherapy
Sorafenib. A small molecule Raf kinase and VEGF multi-receptor kinase inhibitor, for the treatment of patients with advanced renal cell carcinoma. This indication is based on the demonstration of improved progression-free survival in a large, multinational, randomized double-blind, placebo-controlled phase 3 study and a supportive phase 2 study. Overall survival results from the phase 3 study are preliminary at this time. The median progression-free survival was 167 days in the sorafenib group versus 84 days in the placebo control group (HR 0.44; 95% CI for HR: 0.35-0.55), logrank p < 0.000001). Time-to-progression was similarly improved. Tumor response was determined by independent radiologic review according to RECIST criteria. Overall, of 672 patients who were able to be evaluated for response, 7 (2%) sorafenib patients and 0 (0%) placebo patients had confirmed partialresponses. The recommended dose is 400 mg (two 200 mg tab) twice daily taken either 1 hour before or 2 hours after meals. Adverse events were accommodated by temporary dose interruptions or reductions to 400 mg once daily or 400 mg every other day. Sorafenib targets serine/threonine and receptor tyrosine kinases, including those of RAF, VEGFR-2,3, PDGFR-, KIT, FLT-3, and RET. Further clinical studies evaluating the role of sorafenib in the first-line setting, in combination with other immunomodulators, are underway. Preliminary results appear promising.

Sunitinib (Sutent) Sunitinib is another multi-kinase inhibitor approved by the FDA in January 2006 for the treatment of metastatic kidney cancer that has progressed after a trial of immunotherapy. The approval was based on the high response rate (40% partial responses) and a median time to progression of 8.7 months and an overall survival of 16.4 months. The receptor tyrosine kinases inhibited by sunitinib include VEGFR 1-3 and PDGFR  and . Major toxicities (grade II or higher) include fatigue (38%), diarrhea (24%), nausea (19%), dyspepsia (16%), stomatitis (19%), and decline in cardiac ejection fraction (11%). Dermatitis occurred in 8%, and hypertension occurred in 5% of patients. A recent phase 3 study evaluating sunitinib in the first-line setting, compared against IFN-, in patients with metastatic RCC demonstrated significant improvement in PFS and response rates compared against the control arm. These results are considered to be preliminary, and longer-term follow-up is necessary for conclusive results.

Other multi-kinase inhibitors undergoing investigation for RCC
Lapatinib is an EGFR and ErbB-2 dual tyrosine kinase inhibitor, which appears to have efficacy in the treatment of tumors, including RCC, which overexpress EGFR. This was recently reported in a phase 3 study in advanced RCC evaluating lapatinib against hormonal therapy in patients who had failed prior therapy.RAD001 (Everolimus) is a serine-threonine kinase inhibitor of mTOR, an important regulatory protein in cell signaling. A recent phase 2 trial in patients with metastatic RCC demonstrated promising preliminary clinical results

CONSERVATIVE MANAGEMENT OF STRESS URINARY INCONTINENCE

Conservative management of Stress Urinary Incontinence

1. An involuntary loss of urine during coughing, or physical exertion
2. Evident as leakage of urine on increased abdominal pressure without change in detrusor pressure (VLPP) during filling phase on UDS(SPECIALISED PRESSURE MANOMETRY)
It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners.

Usual cause of stress urinary incontinence
1. Vaginal delivery--multiple vaginal births(unattended deliveries common in ESPECIALLY in villages)
2. Aging
3. Estrogen deficiency(Some woman leak one week before menstrual period.The lowered estrogen levels that particular time may lead to lower muscular pressure around the urethra, increasing chances of leakage. The incidence of stress incontinence increases following menopause, similarly because of lowered estrogen levels)
4. Neurological disease(especially diabetes)
5. In female high-level athletes, effort incontinence occurs in all sports involving abrupt repeated increases in intra-abdominal pressure that may exceed perineal floor resistance


As In India; multiple vaginal births are a common scenario and there is cultural taboo so incontinence is very high in prevalence but majority of household women suffer from it silently.Many of them avoid mingling in social occasions for fear of leakage preferring to remain aloof.The urine leakage is equally annoying to their sex partners which may severely affect sex life and adversely affect married life.There are certain myths in society about stress urinary leakage:
1. Urinary incontinence/prolapse is a natural part of aging
2. Nothing can be done about it
3. Surgery is the only solution(phobia for doctors;thinking that they will invariably suggest surgery for the disease)


Prevalence:
Reported prevalence rates range from 4.5% to 53%
Our Hopsital Statistics shows:
1. 50 Patients of stress/mixed incontinence / 6 months
2. 10 Undergo UDS/ 6months
3. 3-4 Undergo surgical intervention

Can we do something to remove doctor phobia especially in Indian society?
Can Nurse led continence service of any use?

A study was conducted by Matharu et al in 2004 where women aged ≥40 yrs with LUTS (n= 2421) were randomly allocated to a nurse-led continence service.Out of them , 450 underwent urodynamic study.The results showed women with OAB, 79.1% were correctly allocated anticholinergics & 64.8% were allocated pelvic floor training protocol(PFT).Of all women with urodynamic SUI, 88.8% were allocated PFT.This shows that nurse led continence service fairly treat women and this type of service can be initiated by Government of India to avoid urine leakage misery.

Management of tress urinary incontinence:
Continence and micturition involve a balance between urethral closure and detrusor muscle activity. Urethral pressure normally exceeds bladder pressure, resulting in urine remaining in the bladder. The proximal urethra and bladder are both within the pelvis. Intraabdominal pressure increases (from coughing and sneezing) are transmitted to both urethra and bladder equally, leaving the pressure differential unchanged, resulting in continence. Normal voiding is the result of changes in both of these pressure factors:urethral pressure falls and bladder pressure rises. SUI is due essentially to insufficient strength of the pelvic floor muscles. It is the loss of small amounts of urine associated with coughing, laughing, sneezing, exercising or other movements that increase intra-abdominal pressure and thus increase pressure on the bladder. The urethra is supported by fascia of the pelvic floor. If this support is insufficient, the urethra can move downward at times of increased abdominal pressure, allowing urine to pass.
So the basic aim of the treatment is Aim: To improve urethral resistance.These are the conservative measures:

1.Weight loss
A study published in The New England Journal of Medicine on January 29, 2009, demonstrated that weight loss in overweight women reduced stress incontinence. The study included women with a Body Mass Index (BMI) over 25 and at least 10 episodes of urinary incontinence per week. The results demonstrated that with exercise and restricted diet they had a 70% or greater reduction in overall incontinence episodes.So weigth loss should be the first thing a woman ahould follow for reduction in incontinence.
2. Absorbent products
Absorbent products include, undergarments, protective underwear, briefs, diapers and underpads.There are some assist devices used like vaginal pessaries,femsoft catheter as physical barrier for prevention of urinary leakage.
4. Exercises
One of the most common treatment recommendations includes exercising the muscles of the pelvis. Kegel exercises to strengthen or retrain pelvic floor muscles and sphincter muscles can reduce stress leakage.
Role of pelvic floor training:
The Cochrane Incontinence Group Specialized Trials Register included One arm comprised PFT, the other either no treatment, placebo, sham treatment. A total 13 trials involving 714 women were included.They concluded that PFT be included in first-line conservative management programs.Basically suffering woman should Identify the pubococcygeus muscle first with the help of urologist and then Exercise the muscle (10 s contraction followed by 10 s relaxation) 30 to 80 times /day.This Increases muscle support of the pelvic viscera &increased closing force on the urethra and the benefits may be seen in 2 to 6 weeks.
An alternative or adjunct to PME is exercises the pelvic muscles by holding small weights inside the vagina for up to 15 minutes bid.Successiely the weights can be increased I ncreasing the capacity of the pubococcygeus muscle contraction.Success rate up to 70% to 80%. A recent Cochrane Review shows no advantage to combining PFT with biofeedback over the use of well-done PFT alone.Atleast 3 months of pelvic floor exercises are necessary.
Biofeedback:
Biofeedback uses measuring devices to help the patient become aware of his or her body's functioning. By using electronic devices or diaries to track when the bladder and urethral muscles contract, the patient can gain control over these muscles. Biofeedback can be used with pelvic muscle exercises
RESULTS OF PELVIC FLOOR TRAINING:
There was a trial
1. 76 women underwent a 3-month exercise program & followed for 1 year.
2. 30% of subjects were cured &17% were improved.
3. Subjects with severe incontinence did not benefit from the therapy

Medications
Medications can reduce many types of leakage. Drugs with a-adrenergic activity to increase bladder outlet resistance.For Example ..phenylpropanolamine 25-75 mg bid &imipramine10-25 mg qd-tid.These medicines have been taken off from the U.S. market because of concerns about hemorrhagic strokes in young women.A new nedicine has been tried in SUI:duloxetene :called drug which kills three birds in one stone. It is Combined serotonin and nor-epinephrine re-uptake inhibitor.Its actions are :
o Increases tone of external urethral sphincter
o In an integrated analysis of 4 randomised controlled trials, it significantly decreased incontinence episode frequency by 51.5%
A study by Drutz et al revealed In a subgroup of women with severe SUI awaiting surgery, duloxetine was found to be effective.Incontinence decreased by 46% or their Incontinence Quality of Life (I-QOL) score improved by 6.3 points.

Vaginal oestrogens:
Vaginal oestrogens are used in SUI especially in aging population.The basis behind is
• Common embryonic origin of bladder urethra & vagina
• High concentration of estrogen receptors in pelvic tissues
• General collagen deficiency state (falconer et al., 1994)
• Urethral coaptation affected by loss of estrogen

The oestrogen cream can improve the mucosal integrity and suppleness of the urethra and the vagina thereby take care of the urethral coaptation.These medicines can produce harmful side effects if used for long periods. There is an increased risk of cancers of the breast and endometrium (lining of the uterus). A patient should talk to a doctor about the risks and benefits of long-term use of medications.
When should doctor send the patient for surgery?(Vague indicators)
1. Severe SUI(≥ 2 PADS /DAY)
2. Duration of symptoms> 5 years
3. VLPP≤80 cm H2O-Urdynamic parameters
Apart from that:
1. Pt with significant associated prolapse that may be corrected at the same time
2. High levels of physical stress owing to lifestyle or occupation-models,athletes,stage performers
Summary:
a) SUI needs to be treated with conservative measures initially: simple, inexpensive and without complications
b) No need of UDS prior to conservative measures
c) Duloxetine helpful in noncompliant pt.

Varicocele:Andrological point of view

Varicoceles:
Varicocele has been most controversial topic as to what is significant varicocele,how should it be diagnosed and how should it be operated.The dilemma still persists amongst health care professionals especially Gynecologists whether Varicocele surgery really helps in infertility.Below is a list of common questions cropped up in minds of health care professionals as well as common men and we are trying to give simple and scientific answers as follows..
1. What is varicocele?
2. What are the symptoms?
3. How to diagnose the condition?
4. Does it need surgery?
5. Basis of the treatment
6. What surgery is the best?
7. What should the patient expect post-operatively?
8. Any other modalities for the management?

What is varicocele?:
Varicoceles develop as a result of dilatation and tortuosity of veins of the pampiniform plexus secondary to retrograde flow into the internal spermatic vein (ISV).It may sometimes give feel of bag of worms in the hemiscrotum.
The incidence of varicocele in general population is as high as 15% so surgical selection of the case should be scrupulous.


What are the symptoms:
the common symptoms are dragging sensations in the hemiscrotum,contstant dull pain,testicular atrophy.




How to diagnose:
Clinical Examination in standing position and with Valsalva is all that is necessary although in obese patient sometimes Colour Doppler Ultrasound is needed to prove the diagnosis.


Colour Doppler should only be offered for obese or previously operated groins
Does it need surgery?
• Clinically detectable varicoceles associated with abnormal semen parameters normal female partner or female partner with potentially curable infertility problem. IVF with or without ICSI can be considered to be first-line treatment in the presence of an independent female infertility factor requiring the use of these techniques.
Certain factors predict good outcome like:
 Grade 3 varicocele
 Lack of testiculat atrophy
 Normal FSH
 Motility >60% and motile sperm count >5 ×106


• Palpable varicoceles in adolescent boys when accompanied by ipsilateral testicular atrophy. Adolescents with normal testicular size should be offered follow-up with annual measurement.



REDUCTION IN SIZE OF THE TESTES AS SEEN BY PRADERS ORCHIDOMETER
• Debilitating testicular pain. But unfortunately, 10-15% has either persistent or worsening symptoms.

Basis of the treatment:
• Infertile men with varicocele, were found to have an increased number of abnormal forms, decreased motility and lower mean sperm counts (‘stress pattern'. Varicocelectomy results in significantly improved semen parameters in 60% to 80% of men).
• A multi-center WHO study on the influence of varicocele on fertility parameters demonstrated that the mean Testosterone level of men older than 30 years of age with varicoceles was significantly lower than that of younger patients with varicoceles which was correctable after the surgery.
• Only two randomized, prospective, controlled studies have been performed to show cause and effect relationship between varicocelectomy and improvement in pregnancy rate. Nieschlag et al found that semen parameters improved significantly in the treatment groups but pregnancy rates were no different. Most of the varicoceles in that study were Grade I and a microsurgical; artery sparing technique was not applied. A second study by Madgar, et al. employed a cross over design. In that study, pregnancy rates were 6 times higher in the men undergoing immediate varicocelectomy compared to those in the observation group (60% vs. 10% respectively) over the first year.
• Varicocelectomy can be effective even in men with azoospermia. Matthews and Goldstein recently reported that 55% of azoospermic men had motile sperm observed in their ejaculate after repair.
What is the best modality of treatment:
Surgical repair may be accomplished by various surgical approaches like inguinal (Ivanissevich), subinguinal and retroperitoneal approaches (Palomo), Most experts perform inguinal or subinguinal surgical repair employing loupes or an operating microscope for optical magnification. Techniques using optical magnification help in reliable identification and preservation of the testicular artery or arteries, cremasteric artery and lymphatic channels and reliable identification of all internal spermatic veins and gubernacular veins reducing the risk of persistence or recurrence of varicocele. The introduction of microsurgical technique to varicocelectomy has resulted in a substantial reduction in the incidence of postoperative hydrocele formation and testicular atrophy. The use of magnification enhances the ability to identify and preserves the 0.5 - 1.5-mm testicular arteries, thus avoiding the complications of azoospermia.
Microsurgery only should be the choice for varicocele patient

Laparoscopy has been used for varicocele repair but this approach carries the risk of major intraperitoneal complications, such as injury to bowel, bladder and major blood vessels and also risk of leaving some tributaries especially above level of L4 vertebra.
In general; laparoscopy should not be assorted for varicocele treatment.
The Gold standard of varicocelectomy is Microsurgical Varicocele Ligation.
What should the patient expect post-operatively?

The semen count will take a while to improve so semen analysis should be repeated after an interval of 3 months. Adjuvant medicines such as L carnitine, CoQ 10,Selenium and zinc may facilitate further recovery of sperm count.

Any other modality of tretament:
Some treatments like applying cold water, Typical Yoga postures like Sarvangasan and sheershasan(relieving pressure off the veins) and avoiding sleeping prone are said to ease the varicocele but yet to be proved.

Vaginal Health:Problems with hypo-oestrogenism

A 56-year-old postmenopausal woman presented with a history of incontinence and weak micturition. The incontinence was continuous with intermittent normal voiding. The urine culture was sterile. General physical examination was within normal limits. Pelvic examination demonstrated extreme labial fusion with only a pinhole opening. Conservative management in the form of local estrogen cream application was instituted without improvement. The woman underwent labial separation under spinal anesthesia. There were also vaginal synechiae and urethral stenosis which were lysed and dilated with Hegar’s dilators. Postoperatively the patient was instructed to apply estrogen cream locally. She presented in the interim period twice with loose fibrinous adhesions for which gentle separation and Hegars dilatation under local anesthesia sufficed. She has till now not needed major procedure for treatment.
Adhesions of the labia are rare in the adult population.It presents with vulvodynia,pruritus ,dyspareunia etc.Labial fusion presentation with pseudoincontinence is still rarer. The etiology of labial adhesions probably relates to vaginal inflammation or irritation. Once the superficial epithelium of the labia is denuded subsequent healing leads to fibrous adhesions between the labia. Etiological factors for labial fusion in adult women are senile vaginitis, hypoestrogenism, lack of sexual activity, local trauma, vaginal laceration following childbirth, female genital cutting(practice prevalent in some communities) and recurrent urinary tract infections( and /or STDs). In the present case, pseudoincontinence was caused by collection of urine in the space behind the fused labia.
Treatment is most often conservative in the form of estrogen cream for hypoestrogenism and atrophic mucosa. Labial separation should be employed when this treatment fails; but as the labia are often tender the separation may need to be done under anesthesia. In addition, the presence of vaginal synechiae or urethral stenosis can make regional or general anesthesia essential. Postoperatively estrogen or steroid cream should help to prevent recurrence of the problem.
Labial fusion is a rare condition in adults, most often caused by hypoestrogenism. While conservative topical estrogen therapy is sufficient in most cases, labial fusion may persist and require surgical intervention.In our case; even after the surgical separation and local oestrogen therapy fusion recurred albeit the adhesion was filmsy and did not need anaesthesia.
In some refractory cases advancement flap surgery will be needed to cover the raw area.

Vaginismus-Cause of Infertility

A 34 year old gentleman presented to us with PRIMARY INFERTILITY.The Couple were trying for 5 years for conception.The investigation profile revealed moderate oligospermia.After having tried all medicines (both multivitamins,anti-ostrogens and alternative medicines) there was no fruitful outcome.The couple had almost given up.On presentation to us; we came across a very important finding which was failure of penetration of the male organ on account of vaginal pain (Vaginismus).The husband perse could never deposit semen in the vagina.
The presence of bordrline sperm count had almost driven the focus of attention from this important condition(vaginismus) to treatment of sperm count(? For years).
We were quite surprised as 5 years had elapsed since marriage and the marriage was uncosummated.
In our society majority of the couples entering into arranged marriage are virgins with little knowledge about sexual anatomy of themselves leave apart understanding the anatomy of the partner.No sexual experience and scanty sexual knowledge leads to vast majority of couples presenting to sexologist with inability to consummate.
Many couples are GUIDED by elderly members of the society that ‘things will work out’ especially after first childbirth as the vaginal canal will dilate.Ther poor couple was waiting for the first child to arrive without finishing the first essential formality of proper deposition of the sperms in the vaginal canal.
vaginismus, is a involuntary tightening of the vaginal muscle, which prevents penis-vagina intercourse. If a man pushes hard trying to enter, it can cause the woman intense pain. In other cases, vaginismus is due to a medical condition that causes pain in the vulvar area, inside the vagina, or elsewhere in the pelvic region. Tightening the pelvic muscles is an unconscious reflex effort to prevent further pain.
In some cases, vaginismus is caused by fear or aversion to sex. For women who experienced sexual abuse, rape or other trauma, this may be an effort to protect themselves from further violation or pain. Many women who are fearful or aversive to sex have no history of trauma, but may have heard scary stories about sex, learned negative sexual attitudes, or have frightening images relating to sex.
So basic sex counselling to correct misconceptions,allay the fears and teach the right technique of the intercourse.The lubricating non-spermicidal jellys can be used for decreasing the pain of penetration.All efforts should be focussed towards encouraging interpersonal relationship between husband and the wife.
Any underlying pelvic diseases should be treated with help of gynecologist.If still the problem persist then the women must be taught vaginal self dilatation.Gradually larger dilator can be accomodated and the fear of penetration will decrease.Vaginal self dilatation works in women with a tough hymen also without need of surgical hymenectomy.
One very useful adjust in such cases is pelvic relaxation exercise and Kegels exercise.This can wok wonders with self dilatation at least in 80% cases.










LUBRICATING JELLY AND SERIAL DILATORS FOR GENTLE PROGRESSIVE SELF DILATATION OF THE VAGINA

LASER prostatectomy in high risk old patient

A 90 year old gentleman presented to us with refractory retention and overflow incontinence. He had history of chronic subdural hematoma which was drained in the month of January 2010.On evaluation, he had grade 3 prostatomegaly.The Ultrasound examination revelaed 96 gm prostate and bilateral hydroureteronephrosis. Renal Function Tests revelaed mildly lelevated creatinine levels(1.8 mg%).
After initial stabilisation of creatinine with indwelling catheter(after subsidence of the bilateral hydro-ureteronephrosis) he was taken for LASER Prostatectomy.He was cleared by physician with moderate risk because of sub-optimal (45%)ejection fraction.

The Prostatectomy was done with Continuous wave Thulium Laser and took 40 minutes for the enucleation.The procedure was completed with morcellation.A 18-Fr Foleys catheter was kept in the bladder.The catheter was removed the very next day and the patient was discharged.The patient is voiding well with good amount void.
The Thulium LASER causes fast and clean cut without vibration because of continuous wave Technology.It causes rapid vaporization of both glandular and fibrous prostate.As the Laser is absorbed by cellular water –it is useful for both fibrous and glandular prostate.The depth of penetration of the Laser therefore is shallow and there is minimal chance of secondary hemorrhages as there is no necrotic tissue in the prostatic bed.This technology is very safe and effective in vessel sealing of both arteries and veins.

We used Richard Wolf 22.5 F Continuous Flow Scope so the rate of the urethral stricture is comparitively less than the other endoscopic methods.
This technology can be offered to old frail patients with cardiac risk and even on anticoagulants and platelet aggregate inhibitors.



Thulium LASER machine



Procedure being carried out

Urological problems in old age

The extension of life expectancy is one of the most dramatic achievements of the 20th century. Elderly population, over 65 years, is the fastest growing age group. Rcent Census shows how the age pyramid is showing increase in old age population.






The typical general problems in elderly population are:
• Change in dexterity, decreased mobility : because age related tremors or Parkinsonism/stroke etc.
• Altered Mentation, Sleep pattern: because of age related amnesia
• Comorbidity: HTN, stroke, diabetes, Alzheimer's etc
• Concomitant drug intake: multiple comorbidities
The typical urological problems along with abovesaid general geratric problems are:
• Aging Bladder: Prostatic enlargement& Bladder instability- causing frequency of urination,weak stream ,urgency,nocturia.Nocturia and urgency can be dangerous as the old frail people can have falls and fractures adding to their woes while rushing to the toilets in the night time.Many of Prostatic problems can be treated with medicines avoding the agony.Those people who have severe problems can be easily ttreated surgically with LASER.LASER prostatectomy can offer effective treatment in elderly people with co-morbidities without complications as in routine conventional surgeries.
• Hormonal alterations (age related decline in androgen production):Many people experience erectile dysfunction which they ignore or feel shy to express to doctors passing off as age related problem.Testosterone supplemenation with or without PDE-5 inhibitors help in restoring manhood in may such people.
• Tendency to excrete more water during night: causing nocturnal trips to toilets disturbing a sound sleep.There are nasal sprays available to decrease nocturnal excretion of extra urine.
• Malignancy: Carcinoma prostate : Many western countries have successfully started screening programme(Digital Rectal Examination and Sr PSA) in aged popultation which might result in early detection of cancer and resultant less morbidity.
• Incontinence:Overactive Bladder or weak sphicters because of aging /multiple vaginal births/bladder changes can cause miserable life in females leading to social embarassment. Medications to decrease overactivity or increasing the bladder capacity may reduce the incontinence.Ostrogen topical supplementation in elderly females may enhance local defense mechanism
• Urinary tract infections :Old people may not exhibit same symptoms like dysuria, fever,LUTS like young adults instead they present with lethargy, confusion, weakness or new onset incontinence. Unabated infections if not treated early :may lead to urospepsis with high mortality so Appropriate antibiotics with or without Foley catheterisation/Intermittent catheterisation is the treatment in many patients.Caution has to be exercised when giving antibiotics as the tolerance to antibiotics is always not like young adults.
These are the common urological problems in geriatric population.Many simple measures such as medications for prostate enlargement, antibiotics for infection ,anti-incontinence medications for urine leakage can solve the majority of the issues.Testosterone supplemenation in properly screened aging population can restore not only the erectile dysfunction but feeling of general well being,muscle mass,hemoglobin etc.Challenges in old age are limited mental & functional ability which interferes with learning, motivation, and cooperation needed for successful treatment.So may elderly people suffer in silence.Apart from curing the specific illesses strategies are needed that help to address these psychosocial issues and needs in older patients. As the proportion of elderly people is on the rise, special emphasis should be laid down on the their needs and suitability to treatment.

Penile stress test:window to hearts of men

Many people are hesitant to consult for erectile dysfunction(ED) in their mid 50 s.They think it is a part of ageing.But erectile dysfunction in middle ages can be because of generalised endothelial dysfunction.It could be a presursor of future heart problems.That is the reason many andrologist would call erectile dysfunction as a “wake up call” to coronary artery disease.It has been found that after adjustment for age, ED correlated with the presence of heart disease, hypertension, Diabetes Mellitus, smoking and inversely with protective Lipids(HDL).

Penile erection is caused by a series of actions: relaxation of cavernosal arteries and cavernosal sinuses leads to increased blood flow into the penis, pooling of blood in the sinuses, and an increase in corpus cavernosum pressure.The same NO-cGMP pathway that is critical to erectile function was discovered years earlier as a key endothelium derived dilator of arteries in the systemic, coronary, and
pulmonary vasculatures.In the clinical setting, loss of endothelial NO occurs in the earliest stages of atherosclerosis. In fact, it has been linked to each of the known atherogenic risk factors, such as various forms of dyslipidemia, hypertension, diabetes, cigarette smoking, aging, menopause, hyperhomocystinemia, and a family history of premature atherosclerosis.Although atherosclerosis in its early stages tends to be focal, preferentially localizing to sites of abnormal hemodynamic stresses, loss of endothelium-derived NO in the setting of risk factors is much more generalized and affects nearly all arterial beds, including the arterial blood supply to the penis and the endothelium lining cavernosal sinuses.
Because the arteries supplying penis are smaller than the coronary arteries.So the process causing decereased flow in penile arteries is an harbinger of decreased flow in heart and brain vessels in the future.
So, 57% of men undergoing coronary artery bypass grafting and 64% of men with acute myocardial infarction had preceding ED of some duration. Interestingly, subjects with ED have evidence of endothelial dysfunction in systemic arteries, and an impairment in the NO-cGMP pathway is present before any other evidence of atherosclerotic process is detectable by sophisticated testing. It has been suggested that a deficiency of NO manifests early as ED because erection requires a comparatively large, perhaps 80%, dilation of penile arteries, and hence, this system can ill-afford a loss of NO.Thus, ED, just as endothelial dysfunction, appears to be a sensitive forerunner of atherosclerosis and its complications.

Patient With Multiple Renal And Ureteric Calculi

A 38 year old patient presented with pain in the left flank and fever of 15 days duration.He was a known case of renal stone disease having undergone Percutaneous Nephrolithotomy(PCNL) 5 years back on the same side.

On investigations there were with multiple left renal calculi bulk mainly in lower and middle calyceal groups and multiple lower ureteric stones .He was treated with suitable antibiotic medications till his Urine culture became sterile.
He was then taken up for Ureteroscopy first in view of making him free of ureteric obstruction.With Holmium LASER lithotripsy all stones were pulverised and a 5.5 Fr DJ stent was placed.

Ater a period of 2 days; he was taken up for conventional PCNL.The access was done through posterior-inferior calyx and middle posterior calyx. The complete fluoroscopic and endosocpic clearance was achieved with the use of LASER lithotripsy.

With availability of Holmium LASER as energy medium for stone pulverisation the dwell time in ureter and pelvi-calyceal system has been reduced greatly.It gives us freedom for initially going for Ureteroscopy and rapid stone clearance instead of PCN placement which is done conventionally in Febrile UTI with stones.Thus many complicated stone patients can be tackled in minimun possible sittings without compromising on safety.

Mini PCNL

A 50 year old lady presented with pain in the right flank of 2 years duration.
On investigations there was with right sided staghorn calulcus.



She was taken up for Mini-PCNL.The access was done through posterior-inferior calyx. A J-tip PTFE guide wire was placed in the system.Serial dilatation was done till 15 Fr and 15 Fr Sheath was introduced. The sheath has a offshoot Luer-Lock outflow for reduction of intra-pelvic pressure so as to reduce the incidence of sepsis.A wide angle straight forward telescope 12 ° with angled eyepiece (Karl Storz, Tuttingen, Germany) was used as nephrosocpe.Holmium LASER energy was used as energy for stone dis-integration.









The procedure took 60 minutes and the procedure was completed with the intoduction of small bore nephrostomy tube .The post-operative X-ray showed near total clearance of the calculus.



Stones of the renal pelvis can be treated either by extracorporeal shock wave lithotripsy (SWL) or percutaneous nephrolithotomy (PCNL). As a low-risk procedure with a longer treatment period, SWL often leads to persistent residual stone fragments, whereas conventional PCNL achieves a higher stone-free rate and allows a shorter treatment period albeit with a somewhat higher surgical risk. To reduce the invasiveness of conventional PCNL, the application of a miniaturised instrument for PCNL (MPCNL) has come in vogue.
Miniature percutaneous (mini-perc) access was first described in the pediatric population by Jackman et al (1997) as an alternative to standard PCNL. Generally, it consists of downsizing to smaller percutaneous access sheaths with the intention of decreasing blood loss, postoperative pain, and the hospital stay in patients undergoing nephroscopic procedures. Feng et al (2001) found that PCNL performed via the mini-perc technique was disadvantageous with regard to visibility and optics compared with PCNL performed through the standard access diameter. Deane and Clayman (2007) published a review on PCNL and concluded that PCNL performed via the mini-perc technique appears to have little value, except in children.
In our experience we have found that mini-PCNL with Holmium LASER application can complete the procedure even in larger stone burden in a reasonable time.The bleeding has been remarkably less than the conventional PCNL.In some cases we can always stage the procedure in the safety of the patient.The post-operative pain and the requirements of the analgesia has been less.As far as visibility is concerned ;as the shearing of renal parenchyma is less during dilatation,the tract bleeding is less so the pelvi-calyceal system most-often is clear.This clarity of vision allows s to use gretaer power Holmium for stone pulverisation and the clearance is rapid.We are a referral centre here in Hyderabad and most often get difficult stagorn calculi but in most of the cases we could clear stones with miniature PCNL without having to resort to a large 28 or 30 Fr tract.