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Biomedical subjects

Mani Menon

Publications and source records attributed to Mani Menon.

At least 19 recordsLinked to original sources
PubMed2006

Calmodulin-androgen receptor (AR) interaction: calcium-dependent, calpain-mediated breakdown of AR in LNCaP prostate cancer cells.

Chemotherapy of prostate cancer targets androgen receptor (AR) by androgen ablation or antiandrogens, but unfortunately, it is not curative. Our attack on prostate cancer envisions the proteolytic elimination of AR, which requires a fuller understanding of AR turnover. We showed previously that calmodulin (CaM) binds to AR with important consequences for AR stability and function. To examine the involvement of Ca(2+)/CaM in the proteolytic breakdown of AR, we analyzed LNCaP cell extracts that bind to a CaM affinity column for the presence of low molecular weight forms of AR (intact AR size, approximately 114 kDa). Using an antibody directed against the NH(2)-terminal domain (ATD) of AR on Western blots, we identified approximately 76-kDa, approximately 50-kDa, and 34/31-kDa polypeptides in eluates of CaM affinity columns, suggesting the presence of CaM-binding sites within the 31/34-kDa ATD of AR. Under cell-free conditions in the presence of phenylmethylsulfonyl fluoride, AR underwent Ca(2+)-dependent degradation. AR degradation was inhibited by N-acetyl-leu-leu-norleu, an inhibitor of thiol proteases, suggesting the involvement of calpain. In intact cells, AR breakdown was accelerated by raising intracellular Ca(2+) using calcimycin, and increased AR breakdown was reversed with the cell-permeable Ca(2+) chelator bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra-(acetoxymethyl)-ester. In CaM affinity chromatography studies, the Ca(2+)-dependent protease calpain was bound to and eluted from the CaM-agarose column along with AR. Caspase-3, which plays a role in AR turnover under stress conditions, did not bind to the CaM column and was present in the proenzyme form. Similarly, AR immunoprecipitates prepared from whole-cell extracts of exponentially growing LNCaP cells contained both calpain and calpastatin. Nuclear levels of calpain and calpastatin (its endogenous inhibitor) changed in a reciprocal fashion as synchronized LNCaP cells progressed from G(1) to S phase. These reciprocal changes correlated with changes in AR level, which increased in late G(1) phase and decreased as S phase progressed. Taken together, these observations suggest potential involvement of AR-bound CaM in calcium-controlled, calpain-mediated breakdown of AR in prostate cancer cells.

Androgen Antagonists↗
PubMed2006

Vattikuti Institute prostatectomy: contemporary technique and analysis of results.

OBJECTIVES: Contemporary techniques of radical prostatectomy achieve excellent oncologic outcomes; erectile dysfunction is the most common adverse effect. We have modified our technique of robotic radical prostatectomy (Vattikuti Institute prostatectomy [VIP]) in an attempt to minimize decrease of erectile function while maintaining the excellent oncologic outcomes achieved by the radical retropubic prostatectomy. We present our current technique of VIP with preservation of the lateral prostatic fascia ("veil of Aphrodite"). METHODS: A total of 2652 patients with localized carcinoma prostate underwent VIP. The salient features of our current technique are early transection of the bladder neck, preservation of the prostatic fascia, and control of the dorsal vein complex after dissection of the prostatic apex. Oncologic and functional outcomes were obtained through a questionnaire collected by a third party not involved in patient care. RESULTS: Complete follow-up information was obtained in 1142 patients with a minimum follow-up of 12 mo (range: 12-66 mo; median: 36 mo). The actuarial 5-yr biochemical recurrence rate was 8.4% and the actual biochemical recurrence rate was 2.3%. Median duration of incontinence was 4 wk; 0.8% patients had total incontinence at 12 mo. The intercourse rate was 93% in men with no preoperative erectile dysfunction undergoing veil nerve-sparing surgery, although only 51% returned to baseline function. CONCLUSIONS: VIP with veil nerve sparing offers oncologic and continence results that are comparable to the results of conventional nerve-sparing radical prostatectomy. Early potency results are encouraging.

Adult↗
PubMed2006

Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer.

Prostate cancer cells rely on androgen receptor (AR) for proliferation and survival. Therefore, curing prostate cancer will require elimination of AR. Although androgen is the natural ligand that activates AR, AR activity is also subject to regulation by growth factor/growth factor receptor-stimulated signaling pathways that control the cell cycle. Cell cycle regulatory proteins and protein kinases in signaling pathways affected by growth factors can lead to AR activation in the absence of androgen. While downstream signaling proteins such as cyclins, cyclin-dependent kinases (CDKs), and pRB can modulate AR activity, upstream signaling pathways involving protein kinases such as mitogen-activated protein kinases, protein kinase A, and protein kinase B/Akt can affect post-translational modification of AR to affect not only AR function but also AR stability. Calcium and calmodulin (CaM), essential for proliferation and viability of a number of cells, including prostate cancer cells, play an important role in AR expression, stability, and function. CaM affects AR partly by interacting directly with AR and partly by activating protein kinases such as Akt and DNA-PK that can phosphorylate AR. The ubiquitin/26S proteasome pathway responsible for timely destruction of cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex. Maspin, a serine protease inhibitor that is known mostly for its role as a tumor suppressor can also regulate AR intracellular localization and function by competing with AR for binding to the chaperone protein Hsp90 and co-repressor HDAC1, respectively. This perspective reviews the experimental evidence implicating these diverse cellular processes in AR expression, stability, and/or function, and presents a rationale for disrupting these cellular processes as a viable option for the treatment of both the hormone-sensitive and the hormone-insensitive prostate cancer.

Calcium↗
PubMed2006

da Vinci-assisted robotic partial nephrectomy: technique and results at a mean of 15 months of follow-up.

OBJECTIVE: Laparoscopic partial nephrectomy is gaining acceptance as an alternative to open surgery for small renal tumours, although technical difficulty of intracorporeal suturing and concerns over warm ischemia time are limitations. Previous work has demonstrated that suturing with the robotic system is easier compared with laparoscopy. We believe the robot has an application and we report our initial experience in 10 patients undergoing robotic partial nephrectomy. METHODS: Ten patients with small exophytic renal masses underwent intraperitoneal robotic partial nephrectomy. Principles of traditional open surgery were followed and intraoperative ultrasound was used to define resection margins. The renal artery was clamped with laparoscopic bulldog clamps and indigo carmine was administered intravenously to detect entry into collecting system. Suture closure and FLOSEAL were used for hemostasis. Frozen sections were obtained in all patients. RESULTS: Seven men and three women, mean age 59 yr, underwent robotic partial nephrectomy. Mean tumour size was 2 cm. Mean console and warm ischemia time were 158 min and 21 min, respectively. The median hospital stay was 1.5 d. Pathology revealed renal cell carcinoma in eight, oncocytoma in one, and lipoma in one. All resection margins were negative. Follow-up ranged from 6 to 28 mo. CONCLUSIONS: Robotic partial nephrectomy is a viable alternative to open or laparoscopic partial nephrectomy in carefully selected patients with small renal tumours. The advantages of the robotic system must be weighed against its cost. Further studies will determine if reduction in procedure complexity warrants the expense of such technology.

Adult↗
PubMed2006

Robotic radical prostatectomy: evolution from conventional to VIP.

Following the popularization of Vattikuti Institute Prostatectomy technique of robotic radical prostatectomy (RARP) by Menon et al., RARP has been gaining steady acceptance as a preferred alternative to both open and laparoscopic radical prostatectomy (LRP). Up until now, radical retropubic prostatectomy has been considered the gold standard for treatment of organ confined prostate cancer. Despite significant improvements in intraoperative blood loss and functional outcomes, driven primarily by the description of anatomical radical prostatectomy by Walsh, the perioperative morbidity, analgesic requirement, and recovery times have remained disadvantages of the open approach. LRP has been unable to gain widespread acceptance because of technical difficulty and a steep learning curve. The da Vinci assisted approach incorporates the advantages of minimally invasive approach while improving upon the results of the open approach. This paper traces the evolution of RARP and describes technical modifications incorporated at the Vattikuti Urology Institute including operative data, complications, and functional outcomes.

Humans↗
PubMed2006

Robotic extended pyelolithotomy for treatment of renal calculi: a feasibility study.

Percutaneous nephrolithotomy (PCNL) remains the treatment of choice for staghorn renal calculi. Many reports suggest that laparoscopy can be an alternative treatment for large renal stones. We wished to evaluate the role and feasibility of laparoscopic extended pyelolithotomy (REP) for treatment of staghorn calculi. Thirteen patients underwent REP for treatment of staghorn calculi over a 12-day period. Twelve patients had partial staghorn stones and one had a complete staghorn stone. All patients had pre-operative and post-operative imaging including KUB and computed tomography. All procedures were completed robotically without conversion to laparoscopy or open surgery. Mean operative time was 158 min and mean robotic console time was 108 min. Complete stone removal was accomplished in all patients except the one with a complete staghorn calculus. Estimated blood loss was 100 cc, and no patient required post-operative transfusion. REP is an effective treatment alternative to PCNL in some patients with staghorn calculi. However, patients with complete staghorn stones are not suitable candidates for this particular technique.

Adult↗
PubMed2006

Robotic radical prostatectomy: the Vattikuti Urology Institute training experience.

Robotic radical prostatectomy is increasingly becoming a popular surgical treatment modality for men with clinically localized prostate cancer. Establishing a robotic prostatectomy program is a tremendous undertaking for any institution requiring both financial support and a dedicated operating room team. A structured approach to learning robotics is paramount in order to successfully start a program while optimizing the learning curve to master the technique and minimize peri-operative complications. We describe our own experience in establishing a robotics program to accomplish a safe and effective operation. In addition, we describe the steps utilized in order to teach our structured approach to other practitioners and institutions around the world. Robotic surgery can be taught to experienced open, as well as, laparoscopic surgeons, and incorporated into residency and fellowship training using this structured approach to learning.

Clinical Competence↗
PubMed2006

Robotic radical prostatectomy with the "Veil of Aphrodite" technique: histologic evidence of enhanced nerve sparing.

OBJECTIVE: We have recently described a modification (Veil of Aphrodite) designed to preserve the lateral prostatic fascia (LPF) during robotic prostatectomy. Here, we histologically compare the Veil of Aphrodite technique (VT) and standard nerve-sparing technique (ST). METHODS: Thirty-six consecutive prostatectomies performed by a single surgeon were processed by the whole-mount method. The right and left anterolateral (AL) zones of each prostate were independently evaluated for LPF, plane of excision, capsular incision/margin status, margin clearance, and quantitative analysis of periprostatic nerve bundles using S100 immunostain. RESULTS: There were 42 AL zones with ST and 30 with VT. In all 42 ST zones, the plane of excision was outside the prostate and a rim of LPF was present. The mean margin clearance was 1.4 mm (0.6-2.8 mm) and the mean nerve bundle count was 10 (3-19). Capsular incision and margin status were negative in all 42. For VT, 24 of 30 zones lacked LPF and the plane of excision ran just by the prostatic edge. The mean margin clearance was 0.3 mm (0-1.7 mm) and the mean nerve bundle count was two (0-11). Two VT AL zones revealed capsular incision; the margin was negative for tumour in all 30. Differences in the margin clearances and nerve bundle counts between ST and VT were statistically significant (p < 0.0001). CONCLUSIONS: The LPF contains nerve bundles that run along the surface of the AL zones. The VT is a safe procedure that effectively preserves the LPF and appears to provide enhanced nerve sparing as compared to the ST.

Aged↗
PubMed2006

Learning curve using robotic surgery.

The da Vinci (Intuitive Surgical, Inc., Sunnyvale, CA) surgical system is being used by an increasing number of surgeons across several surgical specialties. The robotic interface is different not only to open surgery, but also to laparoscopy because it involves remote surgical control, stereoscopic vision, and lack of haptic feedback. As the transition is made from traditional open to robotic surgery, factors such as learning of robotic skills, assessment of proficiency in robotics, and structured training for urologists in practice and residents assumes importance. Understanding how the robotic surgical technique is learned and how such learning can be best assessed will enable us to define protocols for training and set standards for proficiency. Learning curve and surgical dexterity are two parameters that are used to compare surgical learning and training. This article presents the current gold standard for assessing skill training and compares surgical skill acquisition and proficiency using conventional laparoscopy and robotic interfaces.

Clinical Competence↗
PubMed2006

Long-term survival probability in men with clinically localized prostate cancer treated either conservatively or with definitive treatment (radiotherapy or radical prostatectomy).

OBJECTIVES: To report the long-term survival probability in more than 3000 men with localized prostate cancer treated either conservatively or by definitive treatment (radiotherapy or radical prostatectomy). METHODS: We studied 3159 men with biopsy-confirmed, clinically localized prostate cancer diagnosed from 1980 to 1997. We restricted our analysis to men 75 years of age or younger. The extent of comorbid disease was measured using the Charlson score. The Cox proportional hazards regression model was used to compare long-term survival in patients who were treated conservatively versus survival in patients treated with either radiotherapy or radical prostatectomy. RESULTS: After adjusting for age, race, tumor grade, comorbid disease, income status, and year of diagnosis, the overall survival rate at 15 years was 35% for conservative management, 50% for radiotherapy, and 65% for radical prostatectomy. The corresponding prostate cancer-specific survival rates were 79%, 87%, and 92%. Patients undergoing radiotherapy or radical prostatectomy had lower overall mortality than patients undergoing conservative management (adjusted relative risk 0.67 for radiotherapy and 0.41 for prostatectomy; P <0.001). The increase in the survival duration was 4.6 years with radiotherapy and 8.6 years with radical prostatectomy. CONCLUSIONS: The results of this study have shown that compared with conservative management, both radiotherapy and radical prostatectomy increase survival for men with localized prostate cancer.

Aged↗
PubMed2006

Functional outcomes and oncological efficacy of Vattikuti Institute prostatectomy with Veil of Aphrodite nerve-sparing: an analysis of 154 consecutive patients.

OBJECTIVES: To report updated results, at 1 year of follow-up, of a modified nerve-sparing robotic radical prostatectomy that preserves the lateral prostatic fascia (Veil of Aphrodite). PATIENTS AND METHODS: From January to December 2003, 154 consecutive men had a Vattikuti Institute prostatectomy with Veil of Aphrodite nerve-sparing by one surgeon. A prospective database recorded patient demographics, intraoperative, peri-operative, and pathological variables. Peri-operative complications were recorded using the Clavien classification. Patients had serum prostate-specific antigen (PSA) levels measured every 3 months and self-administered the International Prostate Symptom Score and Sexual Health Inventory for Male questionnaires before and at 1 year after surgery. RESULTS: The men had a mean age of 57.4 years, a mean body mass index of 27.2 kg/m(2), and a mean PSA level before surgery of 5.11 ng/mL. The mean operative duration was 122 min. At 1 year, 96% of the men reported having had intercourse and 71% had recovered normal erectile function. One man had a Clavien grade II complication, 4.6% of men with organ-confined disease had positive surgical margins, and no patient had a PSA recurrence at 12 months; 97% of the men were continent at 1 year, and the median time to continence was 14 days. CONCLUSION: Veil of Aphrodite nerve-sparing surgery provides better recovery of sexual function at 1 year than in contemporary series from centres of excellence, without compromising cancer control and urinary function.

Adult↗
PubMed2005

Effect of GGC (glycine) repeat length polymorphism in the human androgen receptor on androgen action.

BACKGROUND: The human androgen receptor (AR) contains glutamine (CAG) and glycine (GGC) repeat length polymorphisms. Normal glutamine repeat length affects androgen action, but an effect of normal glycine repeat length has not been studied. METHODS: To determine whether glycine/GGC repeat length affects AR function, we constructed AR cDNA expression vectors with different GGC repeat lengths in the physiological range (13-17 GGCs). AR constructs were transfected into AR-negative DU145 human prostate cancer cells along with an androgen-responsive reporter plasmid (PSA-firefly luciferase) and a transfection efficiency control plasmid (Renilla luciferase). RESULTS: Glycine repeat length had no significant effect on androgen-dependent AR transactivation activity expressed as firefly luciferase per unit amount of AR protein. However, AR protein levels (normalized for transfection efficiency) were inversely affected by glycine repeat length (P < 0.001; r = -0.9; e.g., GGC13 yielded 2.7 times more AR protein than did GGC17). Therefore, the net amount of AR activity per cell would be higher in cells expressing AR with a short glycine repeat. Based on programs that predict structure from RNA sequence, the GGC repeat can form a hairpin structure, the free energy of which decreases (i.e., hairpin stability increases) as a function of increasing repeat length. This suggests that hairpin stability may interfere with translation, accounting for the inverse effect of GGC repeat length on AR protein yields. CONCLUSIONS: The ability of a short GGC repeat to enhance androgen action provides a biologically plausible mechanism to account for reports that a short GGC repeat in the AR gene is a risk factor for prostate cancer.

Androgens↗
PubMed2005

Androgen receptor regulates Cdc6 in synchronized LNCaP cells progressing from G1 to S phase.

We have shown previously that androgen receptor (AR) activity is required for the progression of cells from G(1) to S phase. In an attempt to elucidate the mechanism of androgen- and androgen-receptor-mediated proliferation of prostate cancer cells, we studied the effect of anti-androgen bicalutamide (Casodex) on the expression of cell-cycle regulatory genes in synchronized LNCaP cells progressing from G(1) to S phase. LNCaP cells were synchronized by isoleucine-deprivation. Expression of cell-cycle regulatory genes in S phase control cells versus Casodex-treated cells that fail to enter S phase was studied using a microarray containing cDNA probes for 111 cell-cycle specific genes. RT-PCR and Western-blots were used to validate microarray data. Casodex blocked synchronized LNCaP cells from entering S phase. Microarrays revealed downregulation of eight genes in cells prevented from entering into S phase by Casodex. Of these eight genes, only Cdc6, cyclin A, and cyclin B were downregulated at both the mRNA and protein level in Casodex treated cells as compared to control cells. The mRNA and protein levels of Cdc6 increased as synchronized LNCaP cells progressed from G(1) to S phase, and were attenuated in Casodex-treated cells failed to enter S phase. Cyclins A and B were detected when cells entered S phase, but not when they were in G(1) phase. Like Cdc6, the levels of both cyclins A and B were attenuated in Casodex-treated cells. AR may play an important role in the onset of DNA synthesis in prostate cancer cells by regulating the expression and stability of Cdc6, which is critically required for the assembly of the pre-replication complex(pre-RC).

Androgen Antagonists↗
PubMed2005

The window sign: an aid in laparoscopic and robotic radical prostatectomy.

AIM: Certain steps of laparoscopic radical prostatectomy (LRP) and robotic radical prostatectomy (RRP), such as identification of seminal vesicles, bladder neck and retroprostatic dissections are technically challenging specially during initial experience. We describe an important land mark -- "Window sign", which helps significantly during the procedure. METHODS: The seminal vesicles can be dissected either through the transperitoneal, subperitoneal or extraperitoneal approach. In transperitoneal approach the vas deferens, seminal vesicles and Denonvillier's fascia are dissected posteriorly, and this plane is re-entered after division of the prostate from the posterior bladder neck, and with division of the Denonvillier's fascia. The communication between the anteriorly and posteriorly dissected planes in the retrovesical and retroprostatic space is termed "the window." Alternatively, in the RRP technique, bladder neck is divided anteriorly and posteriorly and vas deferens and seminal vesicle pulled out through this window. We have found that this window in transperitoneal, subperitoneal or extraperitoneal approach whether done during laparoscopic or robotic radical prostatectomy, allows to retract the vas deferens and seminal vesicles to elevate the prostate, facilitates control of the prostatic pedicles, helps in dissection of the prostate and assists in the identification and careful avoidance of the neurovascular bundles. RESULTS: This window sign was identified on the basis of our experience of over 450 cases of laparoscopic and robotic anatomical radical prostatectomies. We have followed this step in all of the cases by either technique. CONCLUSION: The "window sign" is an important aid while performing laparoscopic and robotic radical prostatectomy. This technique helps the surgeon to achieve both the anatomic and oncologic goals of the nerve sparing, during anatomic radical prostatectomy.

Humans↗
PubMed2005

Robotic radical prostatectomy: a minimally invasive therapy for prostate cancer.

The robotic radical prostatectomy technique involves the use of the da Vinci surgical robot (Intuitive Surgical, Sunnyvale, CA) assistance with three-dimensional stereoscopic visualization and ergonomic multijointed instruments. This article presents our results after treating 750 patients with robot-assisted radical prostatectomy at the Vattikuti Institute of Urology.

Adult↗
PubMed2005

Robot-assisted radical cystectomy and urinary diversion.

Radical cystectomy remains the standard for muscle-invasive, organ-confined urothelial carcinoma of the bladder. With the emergence of minimally invasive approaches for the treatment of urologic cancers, technologic advances using laparoscopy have led to the development of robotic assistance to increase the feasibility of performing this formidable operation. In this article, we describe the procedure of robotic-assisted laparoscopic radical cystectomy with urinary diversion and review the pertinent literature.

Carcinoma, Transitional Cell↗