Samir P. Shirodkar

ANTITUMOR ACTIVITY OF HYALURONIC ACID SYNTHESIS INHIBITOR 4-METHYLUMBELLIFERONE IN PROSTATE CANCER CELLS

4-Methylumbelliferone (4-MU) is a hyaluronic acid (HA) synthesis inhibitor with anticancer properties; the mechanism of its anticancer effects is unknown. We evaluated the effects of 4-MU on prostate cancer cells. 4-MU inhibited proliferation, motility, and invasion of DU145, PC3-ML, LNCaP, C4-2B, and/or LAPC-4 cells. At IC(50) for HA synthesis (0.4 mmol/L), 4-MU induced >3-fold apoptosis in prostate cancer cells, which could be prevented by the addition of HA. 4-MU induced caspase-8, caspase-9, and caspase-3 activation, PARP cleavage, upregulation of Fas-L, Fas, FADD and DR4, and downregulation of bcl-2, phosphorylated bad, bcl-XL, phosphorylated Akt, phosphorylated IKB, phosphorylated ErbB2, and phosphorylated epidermal growth factor receptor. At IC(50), 4-MU also caused >90% inhibition of NF-kappaB reporter activity, which was prevented partially by the addition of HA. With the exception of caveolin-1, HA reversed the 4-MU-induced downregulation of HA receptors (CD44 and RHAMM), matrix-degrading enzymes (MMP-2 and MMP-9), interleukin-8, and chemokine receptors (CXCR1, CXCR4, and CXCR7) at the protein and mRNA levels. Expression of myristoylated-Akt rescued 4-MU-induced apoptosis and inhibition of cell growth and interleukin-8, RHAMM, HAS2, CD44, and MMP-9 expression. Oral administration of 4-MU significantly decreased PC3-ML tumor growth (>3-fold) when treatment was started either on the day of tumor cell injection or after the tumors became palpable, without organ toxicity, changes in serum chemistry, or body weight. Tumors from 4-MU-treated animals showed reduced microvessel density ( approximately 3-fold) and HA expression but increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells and expression of apoptosis-related molecules. Therefore, the anticancer effects of 4-MU, an orally bioavailable and relatively nontoxic agent, are primarily mediated by inhibition of HA signaling.

Renal Carcinoma With Supradiaphragmatic Tumor Thrombus: Avoiding Sternotomy and Cardiopulmonary Bypass

BACKGROUND Renal cell carcinoma with tumor thrombus extension into the inferior vena cava (IVC) is rare. Surgical resection provides the only reasonable chance for cure, but the approach poses a challenge to the surgical team. We describe our technique to safely resect these tumors through a transabdominal incision that exposes the intrapericardial IVC and right atrium (RA) transdiaphragmatically, without the use of sternotomy, cardiopulmonary bypass (CBP), or deep hypothermic circulatory arrest (DHCA). Clinical outcomes of these patients and techniques are reported. METHODS Between May 1997 and January 2009, 102 patients (mean age, 63 years) underwent resection of renal tumor extending into the IVC by techniques developed to avoid sternotomy and CBP. The tumor thrombus in 12 patients (13%) extended into the supradiaphragmatic IVC and RA. RESULTS Complete resection was successful through the transabdominal approach without CBP in all patients. Mean operative time was 8 hours 15 minutes. Estimated blood loss was 2960 mL, and a mean of 9 U of blood was transfused. Two patients died postoperatively, 1 on day 4 of arrhythmia and 1 on day 22 of multisystem organ failure. All discharged patients were alive at the last follow-up. Three patients had tumor recurrence and have been referred for adjuvant therapy. CONCLUSIONS In select cases, renal cell carcinoma extending into the IVC to the intrapericardial level and RA can be resected without sternotomy, CBP, or DHCA.

En Bloc Mobilization of the Pancreas and Spleen to Facilitate Resection of Large Tumors, Primarily Renal and Adrenal, in the Left Upper Quadrant of the Abdomen: Techniques Derived from Multivisceral Transplantation

BACKGROUND The left upper quadrant of the abdomen may be occupied by a wide range of urologic pathology. When these lesions are large, safely resecting them often presents a significant technical challenge, with the possibility of resultant morbidity and mortality. OBJECTIVE We describe a technique derived from our experience with multivisceral transplant and organ procurement, which provides excellent exposure of this anatomic region. DESIGN, SETTING, AND PARTICIPANTS From May 1999 to April 2006, 70 patients underwent en bloc mobilization of the spleen and the pancreas and, as necessary, the stomach for masses in the left upper retroperitoneum. Pathology included malignant and benign lesions, including renal cell carcinoma (RCC) with or without inferior vena cava (IVC) involvement, adrenal tumors, retrocrural lymphadenopathy from testicular cancer, and transitional cell carcinoma of the renal pelvis. SURGICAL PROCEDURE An extended subcostal transabdominal approach was used to resect large tumors in the left upper abdomen. This approach offers significant advantages over conventional approaches, including a flank, thoracoabdominal, or midline transabdominal incision with reflection of the descending colon. MEASUREMENTS Intraoperative variables, including operative time, blood loss, transfusion rate, and extent of mobilization were recorded. Postoperative complications, including prolonged intubation, ileus, and deep venous thrombosis were also noted. RESULTS AND LIMITATIONS Mean estimated blood loss during surgery was 973 ml. There were no perioperative deaths. No patients had pancreatitis or acute renal failure. Deep venous thrombosis was not seen. Cardiopulmonary bypass was used in one patient with an atrial thrombus. At a median follow-up of 42 mo, two patients died due to metastasis. CONCLUSIONS Techniques acquired from organ harvesting as well as our experience at multivisceral transplant, such as en bloc mobilization of the spleen, pancreas, and stomach, can be utilized safely and effectively to gain excellent exposure to the left upper retroperitoneum via an extended subcostal incision with no additional morbidity for the patient.

Molecular characterization of kidney cancer: Association of hyaluronic acid family with histological subtypes and metastasis

Molecular profiling of renal cell carcinomas (RCCs) may improve the distinction between oncocytoma and malignant RCC subtypes and aid in early detection of metastasis. The hyaluronic acid (HA) family includes HA synthases (HAS1, HAS2, HAS3), hyaluronidases (HYAL‐1, HYAL‐2, HYAL‐3, HYAL‐4, PH20, HYAL‐P1), and HA receptors (CD44s, CD44v, RHAMM). HA family members promote tumor growth and metastasis. The authors evaluated the expression of HA family members in kidney specimens.

Vascular Stapling of the Inferior Vena Cava: Further Refinement of Techniques for the Excision of Extensive Renal Cell Carcinoma With Unresectable Vena-caval Involvement

OBJECTIVES To present our experience with a novel technique of tumor removal: en bloc resection of the tumor, thrombus, and inferior vena cava (IVC) via vascular staple ligation and excision, and to excise all tumor, which may include a portion of the IVC when invasion is present. Management of renal cell carcinoma (RCC) with IVC thrombus presents a challenge. Options for tumor excision include thrombectomy with or without cardiopulmonary bypass, replacement of the cava with synthetic or venous graft, or caval excision without replacement. METHODS Six patients with extensive RCC with IVC thrombus were evaluated. All patients underwent preoperative imaging that depicted completely obstructing IVC thrombus of varying cranial extension with apparent invasion of the caval wall. None had lower extremity edema. Patients underwent IVC staple ligation and en bloc resection of tumor and thrombus. Pre-, intra-, and postoperative as well as pathological factors were measured. These included estimated blood loss, transfusions, and procedure length. Inpatient factors including duration of intubation, length of intensive care unit stay, and overall length of stay were recorded. Tumor-free status was evaluated. RESULTS All patients had Fuhrman Grade 4 RCC. No perioperative deaths occurred. Mean estimated blood loss was 6350 mL (range 900-25 000). Length of intubation averaged 1.5 days. Mean intensive care unit stay was 4.3 days. Overall length of stay averaged 9.3 days. CONCLUSIONS Complete excision of a portion of the IVC, using a vascular stapler in conjunction with radical nephrectomy is a satisfactory method to remove RCC with IVC invasion. Sufficient collateral circulation exists for venous return from the lower extremities.

Bladder tumor markers: From hematuria to molecular diagnostics - Where do we stand?

Bladder cancer is a common malignancy in the USA. Currently, the detection of initial tumors and recurrent disease is based on evaluation of voided urinary specimens, often followed by cystoscopy. With the high rate of recurrence, cystoscopies are regularly repeated with the aim of halting progression of the disease. For patients, this process is fraught with anxiety, pain and high cost. As a result, intense work is being done in the field of bladder tumor markers with the goal of identifying bladder cancer earlier, both in the initial diagnosis and in recurrences of known tumor. The possibility of identifying a marker that could noninvasively differentiate benign and malignant causes of hematuria, and identify recurrences prior to their pathologic progression is the objective of this area of research. Currently, a large number of tumor markers exist, each scrutinized in both the laboratory and in clinical trials. Here we present many of the most widely used and tested markers. Background details are provided as to the mechanism of detection of malignant cells, the results of recent trials and future directions of study. Some novel modalities for tumor detection are also presented. The next few years will no doubt bring newer markers and lead to the elimination of others. Studies continue to refine the role of these markers in clinical practice, but their ultimate efficacy will need to be borne out in large-scale clinical trials in a multitude of settings.

Intravesical Methylene Blue Facilitates Precise Identification of the Diverticular Neck During Robot-Assisted Laparoscopic Bladder Diverticulectomy

BACKGROUND The aim of this report is to describe our surgical technique for robot-assisted laparoscopic bladder diverticulectomy. In this technique, methylene blue is instilled into the bladder to aid in intra-abdominal identification of the diverticular neck. SUBJECTS AND METHODS We retrospectively reviewed the records of patients who underwent robot-assisted bladder diverticulectomy by a single surgeon. RESULTS Between September 2008 and January 2011, 5 patients successfully underwent robot-assisted laparoscopic bladder diverticulectomy using 1% intravesical methylene blue. All cases were completed without intraoperative complication or need for open conversion. Mean operative time was 216 minutes, with a mean estimated blood loss of 45 mL. Patients were discharged 1-2 days following surgery. No patient experienced a perioperative complication. CONCLUSIONS The robot-assisted approach for bladder diverticulectomy is a viable alternative to both open and laparoscopic surgery. The use of intravesical methylene blue greatly aids in identification of the diverticular neck during this procedure.

Modified Surgical Technique for the Management of Renal Cell Carcinoma With Level I or II Tumor Thrombus

OBJECTIVE To describe a modified open surgical technique for the resection of renal cell carcinoma with level I or II tumor thrombus. METHOD In our modified technique, the renal artery is ligated early and the tumor thrombus is secured ahead of kidney mobilization by either milking into the renal vein or with extirpation from the inferior vena cava. We retrospectively studied patients who were managed with this technique. RESULTS Between September 2006 and June 2010, 20 patients with a median age of 65 years underwent surgery for renal cell carcinoma with level I (n=15) or II (n=5) tumor thrombus using the modified technique. Median blood loss was 275 mL with 75% of patients requiring at least 1 transfused unit of blood. No case was complicated by an intraoperative tumor embolism. Following surgery, patients stayed a median of 5 days in the hospital and none experienced a perioperative complication. CONCLUSION The described surgical technique allows for the safe and effective resection of renal cell carcinoma with level I or II tumor thrombus. This technique enables vascular control of the inferior vena cava with a minimal risk of tumor embolization.

Technical Modification for Laparoscopic Donor Nephrectomy to Minimize Testicular Pain: A Complication with Significant Morbidity

The laparoscopic approach to donor nephrectomy is becoming increasingly common. While it is felt that the recovery from laparoscopic nephrectomy is quicker and less painful, a number of complications have been reported. A rarely reported on complication in the literature with significant morbidity is ipsilateral orchalgia. From 1998 to 2008, 257 hand‐assisted laparoscopic donor nephrectomies were performed at our institution. Eight of 129 (6.2%) men complained of de novo ipsilateral orchalgia postoperatively. The average duration of pain was 402 days. Patients reported significant morbidity related to this complication. None, however, required further treatment. Three patients reported that they would reconsider organ donation as a result of testicular pain. Our technique originally included dissection and ligation of the gonadal vein en bloc with the ureter at the level of the left common iliac artery. Since recognizing this complication, we have adopted a gonadal vein sparing approach so as not to disturb the vessel below its point of ligation at the renal vein. To date, 50 patients have undergone the modified technique without experiencing orchalgia. In conclusion, ipsilateral testicular pan is a relatively frequent complication of laparoscopic donor nephrectomy and may be a source of significant morbidity. Using a modified surgical technique, this complication can be reduced or eradicated.

Budd-Chiari syndrome in urology: Impact on nephrectomy for advanced renal cell carcinoma

Objectives: Budd-Chiari syndrome (BCS) is a poorly understood entity in urology. It results from obstruction of the hepatic veins and the subsequent complications. It has been infrequently reported to be secondary to hepatic venous obstruction from invasion by an inferior vena cava (IVC) tumor thrombus in renal cell carcinoma (RCC). We report the largest known series of patients with RCC and BCS. Patients and Methods: Ten patients presented to a tertiary hospital with locally advanced RCC with IVC tumor thrombus. All were evaluated and had clinical or radiographic evidence of BCS. All underwent nephrectomy, IVC thrombectomy or ligation, and tumor removal from the hepatic veins. The perioperative and pathological factors were measured. These included estimated blood loss (EBL) and transfusions. Inpatient factors including duration of intubation, length of intensive care unit (ICU) stay, and overall length of stay (LOS) were recorded. The tumor-free status was evaluated. Results: The average age was 59 years. No intraoperative deaths occurred. Two intraoperative complications were noted. The mean EBL was 4244 cc; mean surgery length was 8 hours 12 minutes; and the mean ICU stay was nine days. The overall LOS averaged 13.25 days. One patient died postoperatively of sepsis and multisystem organ failure. One patient required reoperation for an abdominal wall hematoma caused by subcutaneous enoxaparin administration. Average follow-up was 28 months. Five patients are alive with no evidence of disease. Conclusions: Budd-Chiari syndrome is a rare entity in urology, with a potential for significant morbidity and mortality. Surgical excision of the primary tumor along with thrombectomy results in alleviation of BCS and improvement in the patient.