Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation.

Acute intermittent hypoxia elicits a form of serotonin-dependent respiratory plasticity known as phrenic long term facilitation (pLTF). Episodic spinal serotonin-2 (5-HT2) receptor activation on or near phrenic motor neurons is necessary for pLTF. A hallmark of pLTF is the requirement for serotonin-dependent synthesis of brain-derived neurotrophic factor (BDNF), and activation of its high affinity receptor, TrkB. Activation of spinal Gs protein-coupled adenosine 2A receptors (GsPCRs) elicits a unique form of long-lasting phrenic motor facilitation (PMF), but via unique mechanisms (BDNF independent TrkB trans-activation).We hypothesized that other GsPCRs elicit PMF, specifically serotonin-7 (5-HT7) receptors, which are expressed in phrenic motor neurons. Cervical spinal (C4) injections of a selective 5-HT7 receptor agonist, AS-19 (10 µM, 5 µl; 3 × 5 min), in anaesthetized, vagotomized and ventilated male Sprague-Dawley rats elicited long-lasting PMF (>120 min), an effect prevented by pretreatment with a 5-HT7 receptor antagonist (SB 269970; 5mM, 7 µl).GsPCR activation 'trans-activates'TrkB by increasing synthesis of an immature TrkB isoform. Spinal injection of a TrkB inhibitor (k252a) and siRNAs that prevent TrkB (but not BDNF) mRNA translation both blocked 5-HT7 agonist-induced PMF, confirming a requirement for TrkB synthesis and activity. k252a affected late PMF (≥ 90 min) only. Spinal inhibition of the PI3K/AKT pathway blocked 5-HT7 agonist-induced PMF, whereas MEK/ERK inhibition delayed, but did not block, PMF. An understanding of signalling mechanisms giving rise to PMF may guide development of novel therapeutic strategies to treat ventilatory control disorders associated with respiratory insufficiency, such as spinal injury and motor neuron disease.

Spinal adenosine A2(A) receptor inhibition enhances phrenic long term facilitation following acute intermittent hypoxia.

Phrenic long term facilitation (pLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia. pLTF requires spinal serotonin receptor activation, new BDNF synthesis and TrkB receptor activation. Spinal adenosine 2A (A(2A)) receptor activation also elicits phrenic motor facilitation, but by a distinct mechanism involving new TrkB synthesis. Because extracellular adenosine increases during hypoxia, we hypothesized that A(2A) receptor activation contributes to acute intermittent hypoxia (AIH)-induced pLTF. A selective A(2A) receptor antagonist (MSX-3, 8 microg kg(-1), 12 microl) was administered intrathecally (C4) to anaesthetized, vagotomized and ventilated male Sprague-Dawley rats before AIH (three 5 min episodes, 11% O(2)). Contrary to our hypothesis, pLTF was greater in MSX-3 versus vehicle (aCSF) treated rats (97 +/- 6% vs. 49 +/- 4% at 60 min post-AIH, respectively; P < 0.05). MSX-3 and aCSF treated rats did not exhibit facilitation without AIH (time controls; 7 +/- 5% and 9 +/- 9%, respectively; P > 0.05). A second A(2A) receptor antagonist (ZM2412385, 7 microg kg(11), 7 microl) enhanced pLTF (85 +/- 11%, P < 0.05), but an adenosine A(1) receptor antagonist (DPCPX, 3 microg kg(-1), 10 microl) had no effect (51% +/- 8%, P > 0.05), indicating specific A(2A) receptor effects. Intrathecal methysergide (306 microg kg(-1), 15 microl) blocked AIH-induced pLTF in both MSX-3 and aCSF treated rats, confirming that enhanced pLTF is serotonin dependent. Intravenous MSX-3 (140 microg kg(-1), 1 ml) enhanced both phrenic (104 +/- 7% vs. 57 +/- 5%, P < 0.05) and hypoglossal LTF (46 +/- 13% vs. 28 +/- 10%; P < 0.05). In conclusion, A(2A) receptors constrain the expression of serotonin-dependent phrenic and hypoglossal LTF following AIH. A(2A) receptor antagonists (such as caffeine) may exert beneficial therapeutic effects by enhancing the capacity for AIH-induced respiratory plasticity.

Necrotizing fasciitis of the vulva during chemotherapy.

A case of necrotizing fasciitis of the vulva arising in a leukemic patient during a chemotherapy nadir is presented. The nature of the process was not recognized initially, and the patient was treated with intravenous antibiotics. After clinically evident necrosis developed, prompt surgical debridement was carried out. Clinical improvement followed and the wound healed well. This case suggests that chemotherapy with its attendant immunosuppression is a predisposing factor in the development of necrotizing fasciitis and warrants a high index of suspicion.

Urinary ascites with pelvic urinoma presenting as ovarian neoplasm: clinical and ultrasonographic features.

BACKGROUND: The majority of ureteric injuries associated with an operation are the result of gynecologic surgery. Thus, gynecologists must be aware of this risk and appreciate that ureteric injury can present late and in an unusual manner. CASE: A 26-year-old woman presented with gross abdominal distention 4 months after total abdominal hysterectomy. Ultrasonography demonstrated a large volume of ascitic fluid and a complex cyst arising from the left ovary. Serum blood urea nitrogen and creatinine were normal. Laparotomy showed a mass of 1-2-cm cysts (urinomas) on the pelvic peritoneum and tubo-ovarian surfaces and a right hydroureter with a right ureteric fistula at the level of the ureteric tunnel. A ureteroneocystostomy was performed. CONCLUSION: Ureteroperitoneal fistula with urinary ascites is a rare complication of pelvic surgery. Intravenous urography or computed tomography scan would have helped establish the diagnosis.

Distal external iliac lymph nodes in early cervical cancer.

OBJECTIVE: To evaluate the utility of the deep circumflex iliac vein as a landmark for the caudal limit of external iliac lymphadenectomy for early cervical cancer. METHODS: During dissection of the distal (caudal), anterior (ventral) aspect of the external iliac vessels in conjunction with radical hysterectomy for carcinoma of the cervix, a careful search was made for the deep circumflex iliac vein. Lymph nodes immediately above this vein were sent as adjacent and lymph nodes caudal to the vein were sent as distal. The distance from the vein to the femoral canal was measured. RESULTS: Seventy-one women were studied over 40 months. Fifty-five had squamous cell carcinoma, 15 had adenocarcinoma, and one had adenosquamous carcinoma. The mean distance from the deep circumflex iliac vein to the femoral canal was 16 mm. Sixty-three patients had dissections distal to identified deep circumflex iliac veins and 49 (77%) of these had distal lymph nodes removed. The median number of pelvic lymph nodes removed was 24 (range nine to 68), and the median number of distal lymph nodes removed was 1.0 from each side. Lymph node metastases were found in 13 women (18%). One subject with multiple macroscopically positive nodes had a single positive distal lymph node. Thus, a small number of distal lymph nodes were found in most women with early invasive cervical cancer, and 8% of those with positive nodes had involvement of this nodal group. CONCLUSION: The deep circumflex iliac vein was an appropriate landmark for the caudal limit of external iliac lymphadenectomy.

Evaluation of the cervical canal with the endocervical brush.

OBJECTIVE: To evaluate and compare the cytologic information obtained from the endocervical brush and the histologic information obtained from the standard endocervical curettage (ECC) used to evaluate the endocervical canal in patients with an abnormal Papanicolaou test. METHODS: Three hundred eighty-eight patients underwent evaluation of an abnormal Papanicolaou test with a repeat Papanicolaou test, a separate endocervical brush test, colposcopy, directed biopsies, and ECC. The study group comprised 101 patients who subsequently underwent conization and/or hysterectomy. The brush and ECC results were evaluated against the final pathologic findings. RESULTS: Sixty-five patients had a satisfactory colposcopy and 36 had an unsatisfactory colposcopy. Results for these two groups are reported separately. For the total group, the sensitivities of the ECC and brush were 49 and 93%, respectively (P < .001); the specificities were 82 and 26% (P < .001), the positive predictive values were 69 and 52% (P = .99), and the negative predictive values were 65 and 82% (P = .004). CONCLUSION: The endocervical brush appears to be a sensitive test for disease in the endocervical canal but yields a high false-positive rate. The role of the brush in this setting will require further study. The ECC is more specific but is also a suboptimal test for identifying disease in the endocervical canal.

Cervical conization with frozen section before planned hysterectomy.

OBJECTIVE: To report our institutional experience with the accuracy and usefulness of cervical conization with frozen section before planned hysterectomy. METHODS: One hundred fifty-nine patients who planned to have hysterectomies for or with a concomitant diagnosis of cervical intraepithelial neoplasia (CIN) underwent preliminary cone biopsies with frozen section. The frozen and permanent pathologic diagnoses were compared retrospectively. Detailed analysis was directed at the indications for cone biopsy and the patients who were found to have invasive cancer. RESULTS: Among 108 patients with negative specimens or CIN, the frozen section was accurate within one degree of CIN in 106. Cone biopsy for a positive endocervical curettage, unsatisfactory colposcopy, or discrepant cytology did not contribute to the diagnosis of invasive cancer but did lead to an ultimate diagnosis of CIN III. One of 12 women with a frozen-section diagnosis of microinvasion had deeper invasion on permanent sections. CONCLUSIONS: Frozen-section evaluation of a cone biopsy carries a degree of accuracy that enables the surgeon to make an immediate decision about definitive therapy. Exact indications, use during pregnancy, and accuracy for the diagnosis of microinvasion require further study.

Atrial natriuretic factor in gynecologic malignancy.

OBJECTIVE: To determine whether plasma atrial natriuretic factor (ANF) levels are different in patients with gynecologic malignancy compared with those in healthy, nonpregnant women, and if differences do exist, whether chemotherapy plays a role. METHODS: We compared the plasma levels of ANF in nonpregnant women free of malignancy (group 1, n = 25) and in patients with malignancy receiving at least one course of platinum-based chemotherapy (group 2, n = 32). To differentiate the contributory role of chemotherapy, another group of patients (group 3, n = 18) was studied before the initiation of chemotherapy. RESULTS: The ANF values (mean +/- standard error [SE]) in groups 1, 2, and 3 were 7.3 +/- 0.3, 13.8 +/- 0.8, and 14.6 +/- 1.8 fmol/mL of plasma, respectively. Significant differences (P < or = .001) occurred between groups 1 and 2 and 1 and 3, but not between 2 and 3. In comparing groups 2 and 3 for a specific type of cancer, there were no significant differences. The respective values (mean +/- SE) for endometrial, ovarian, and cervical cancer before chemotherapy were 9.9 +/- 1.7, 15.05 +/- 2.6, and 18.5 +/- 4.3 fmol/mL. After chemotherapy, the values remained at 9.3 +/- 1.5, 15.03 +/- 1.06, and 14.6 +/- 2.2 fmol/mL, respectively. CONCLUSION: Plasma ANF levels in gynecologic cancer patients were significantly higher than those in healthy, nonpregnant women. Levels were higher before chemotherapy started, thus negating the idea that chemotherapy may initiate the production and release of ANF.

The management of diaphragmatic lesions in ovarian carcinoma.

Cytoreduction is currently an essential feature of the treatment of carcinoma of the ovary. Occasionally, optimal reduction is achieved except for localized diaphragmatic lesions. Two patients who were treated with primary cytoreduction for epithelial ovarian carcinoma had localized full-thickness diaphragmatic metastasis. Often resection is avoided because of concern about pneumothorax. A safe and easy method is described for removing peritoneal and diaphragmatic muscular metastasis without the need for a thoracostomy tube. These patients were cytoreduced without morbidity. The first patient is currently free of disease at 17 months after surgery. The second patient had a 13-month disease-free interval before her abdominal recurrence.

Percutaneous nephrostomy and ureteral stenting in gynecologic malignancies.

OBJECTIVE: To identify the indications, complications, and efficacy of percutaneous nephrostomies and ureteral stents in women with gynecologic cancer. METHODS: In a retrospective study, 40 women underwent urinary diversion with percutaneous nephrostomy and ureteral stents. Nine had ureteral stenosis on initial presentation, 18 had persistent or recurrent cancer, nine had no evidence of disease, and four had operative ureteral damage. Of the nine who were without disease, seven had a urinary conduit. RESULTS: Thirty-five patients had ureteral stenosis, which was bilateral in 24, and five had a ureteral fistula. Sixteen had a unilateral and 22 had bilateral percutaneous nephrostomies, with two cases having stents only. The most common complication was hematuria. Thirteen women were later hospitalized for pyelonephritis. Twenty-nine (72.5%) had ureteral stents, which were bilateral in 12. Renal function was abnormal in 26, but improved in 14 and returned to normal in six. Five fistulas were managed with ureteral stents alone and four were closed. The median time to death (N = 22) was 5.5 months, 12 months in primary cases versus 5.5 months in recurrent cases. Twelve of the remaining 18 were alive without evidence of disease at a median of 38 months, five were alive with disease at a median of 16 months, and one was lost to follow-up. CONCLUSIONS: These techniques are safe and often improve renal function. The procedures have different roles in women with primary and recurrent gynecologic cancer, in those without evidence of recurrent disease, and in those with urinary conduits.

Accuracy of lymph node palpation to determine need for lymphadenectomy in gynecologic malignancies.

OBJECTIVE: To assess the accuracy of intraoperative lymph node palpation for identifying lymph node metastasis in gynecologic malignancies. METHODS: We prospectively evaluated 126 women who had lymphadenectomies for staging of various gynecologic malignancies from August 1995 to June 1997. Surgeries were done by obstetrician-gynecologists with subspecialty certification in gynecologic oncology from the American Board of Obstetrics and Gynecology, who had practiced gynecologic oncology for at least 5 years. Data were collected on gynecologic oncologists' opinions of lymph node status by palpation. Nodes believed to be positive were sent separately. We recorded operating time for lymphadenectomies, and intraoperative and postoperative complications. RESULTS: Mean (range) patient age was 55 (18-83) years. Mean (range) operating time was 188 (85-435) minutes. The mean (range) lymphadenectomy time was 46 (5-150) minutes. The total number of lymph nodes dissected was 2138. One hundred seven of 2138 (5%) nodes were positive for malignancy. Thirty-eight of 107 (36%) positive lymph nodes were missed by palpation. Fifty-six of 2031 (3%) negative lymph nodes were selected as positive. Sixty-nine of 107 (64%) positive lymph nodes were identified correctly. Sensitivity and specificity of palpation were 72% and 81%, respectively. The positive and negative predictive values of lymph node palpation were 56% and 89%, respectively. CONCLUSION: Intraoperative lymph node palpation has low sensitivity and positive predictive value even when done by experienced board-certified gynecologic oncologists.

Congenital duplication of the tricuspid valve presenting as a circumscribed obstructive mass in the right ventricular outflow tract.

Congenital duplication of the tricuspid valve is a rare condition. We present a case of a 32-year-old man with an increase in intensity of a long-standing heart murmur and intermittent palpitations. The murmur was evaluated by transthoracic and transesophageal echocardiography that identified a mass in the right ventricle and right ventricular outflow tract resulting in partial obstruction of the right ventricular outflow tract. This mass was determined to be congenital duplication of the tricuspid valve by histologic examination after surgical excision.

Recent modifications in the treatment of invasive squamous cell carcinoma of the vulva.

The curative potential of therapy should not be sacrificed. However, an effort must be made to determine methods that will reduce the morbidity while at least retaining the curative potential. Modifications which potentially may reduce the morbidity of regional nodal management include deletion of the inguinal lymphadenectomy or use of superficial inguinal lymphadenectomy in selected early lesions, the use of separate groin incisions, the selected use of unilateral inguinal lymphadenectomy, and the use of primary radiation therapy to the inguinal and/or pelvic nodal areas. Modifications which potentially may reduce the morbidity of the primary tumor management include wide local excision for superficial lesions, modified radical vulvectomy for regionalized lesions, the use of skin flaps in selected cases, the development of more sophisticated plastic surgical procedures for the management of posterior lesions, and the use of combined treatment modalities in the management of locally advanced disease.

Isolated skin bridge metastasis following modified radical vulvectomy and bilateral inguinofemoral lymphadenectomy.

Separate vulvar and groin incisions have significantly reduced the morbidity of vulvar cancer surgery. We describe a patient with FIGO stage II squamous vulvar cancer, who developed an ipsilateral tumor recurrence in the skin bridge between the vulva and the groin within 7 months of modified radical vulvectomy and bilateral inguinofemoral lymphadenectomy, using triple incisions. The recurrence was treated by wide local excision alone and she remains free of disease 2 years later. Although rare, the potential for failing to excise tumor emboli in the lymphatics of the skin bridge must be recognized when the triple incision technique is used in the surgical treatment of vulvar cancer.

Ultraradical surgery for advanced carcinoma of the vulva: an update.

From July 1, 1955 to March 31, 1989 24 patients with locally advanced vulvar cancer underwent ultraradical resection. Three patients had received prior radiotherapy. Seventeen of the 24 patients underwent posterior exenteration, four underwent anterior exenteration, and the remaining three required a total pelvic exenteration. One patient died 3 months postoperatively of fulminating infection considered to be a complication of the operation. Three other patients experienced serious complications, including postoperative hemorrhage, severe urinary sepsis, and colostomy stoma necrosis. Eleven (46%) of the 24 patients have remained alive without evidence of recurrent cancer for at least 3 years. Of the 10 patients known to have died of recurrent cancer, nine had positive lymph nodes at the time of surgery. It may be reasonable to utilize ultraradical surgery in patients with clearly resectable lesions who have negative or perhaps 1 or 2 microscopically positive regional lymph nodes.

Does ligation of the hypogastric artery at the time of radical hysterectomy and lymphadenectomy decrease blood loss? Results of a prospective randomized trial.

A prospective, randomized study of patients undergoing radical hysterectomy for gynecologic malignancies was undertaken from 10/95 to 11/96 to determine if ligation of the hypogastric arteries at the time of radical hysterectomy decreases blood loss. Patients were randomized to either ligation of the hypogastric artery (Group 1) or no ligation (Group 2) prior to a standard Piver type III radical hysterectomy. Surgeries were performed by Board certified gynecologic oncologists with gynecologic oncology fellows and/or OB/GYN residents. Patients were analyzed for demographic characteristics and intraoperative and postoperative parameters. Statistical analysis was performed with independent samples t-test, Mann-Whitney rank sum test, Chi square and Fisher exact test. Twenty-one patients were randomized to group 1 and 22 to group 2. Groups were similar with respect to demographics and preoperative parameters except for age. There were no differences among the groups with respect to intraoperative and postoperative parameters. The mean estimated blood loss for group 1 was 600 ml and 550 ml for group 2 (P = NS). Hypogastric artery ligation (HAL) at the time of radical hysterectomy for gynecologic malignancy does not reduce blood loss.

Use of local flaps in the preservation of fecal continence following resection of perianal neoplasias.

The feasibility of achieving curative resection of perianal pre-invasive and invasive lesions with preservation of fecal continence was studied prospectively. Resection of these lesions involved excision of as much as the anterior third of the external anal sphincter. Twenty-two patients had invasive cancer and nine had extensive carcinoma in situ suspicious for invasive disease on preoperative assessment. Anal reconstruction consisted of plication of the external anal sphincter and plication of the puborectalis muscles. The perianal/perineal defects were closed using bilateral rhomboid flaps in 21 patients, unilateral rhomboid flaps in five patients and local advancement flaps in five patients. Twenty-eight patients were ultimately continent of feces, although two required further surgery for incontinence. Two of the three incontinent patients had fecal incontinence before surgery. Two patients had recurrence of invasive cancer, neither of which was perineal or perianal. Curative surgery of selected perianal lesions with preservation of fecal continence can be achieved with local resection and reconstruction with the use of local full thickness skin flaps.

Diagnosis and management of vulvar and vaginal intraepithelial neoplasia.

Vulvar intraepithelial neoplasia and VAIN present unique challenges to the practicing gynecologist. VIN may produce distressing symptoms and undergo malignant conversion. A high index of suspicion and liberal use of biopsy are required to make the diagnosis. The approach to therapy for VIN has been reviewed. Treatment should be tailored to each individual patient and may include a period of expectant observation. Variations and combinations are used whenever necessary to preserve normal function and anatomy. Frequent surveillance is a must because recurrence rates are high, especially with multifocal disease in young women. Although VAIN accounts for less than 0.5% of lower genital tract neoplasia, the frequency of its detection is increasing, especially in younger patients. These lesions are most commonly found in the upper third of the vagina and are often multifocal in nature. The close proximity of the upper vagina to the rectum, bladder, and ureters makes treatment difficult. The occult invasion rate may be as high as 28%, and a wide variety of therapies are available. As is true for VIN, recurrence is not uncommon.

Primary esophageal lymphoma in AIDS.

Primary esophageal lymphomas are extremely rare. We report a primary esophageal T cell lymphoma of the diffuse large cell type in a patient with AIDS and review other published data. Although rare, the diagnosis should be considered in patients with dysphagia, weight loss (with or without hematemesis), and endoscopic findings of masses, polyps, or ulcerations that are especially unresponsive to antifungal therapy or antiviral therapy or both. Repeat endoscopy with biopsy may be needed to establish the diagnosis properly.

Transvestibular retropubic bladder neck suspension. A pilot study.

A pilot study was conducted assessing the operative feasibility, complications and results of a retropubic bladder neck suspension performed through a transvestibular approach. This study extended from July 1, 1990, to June 30, 1991, and included patients who planned to undergo primary surgical correction of stress urinary incontinence. Through a transvestibular incision, a bladder neck suspension was performed by suturing the adjacent area of the vagina to the back of the pubic symphysis or the puborectalis muscle near the pubic bone. Ten women were entered into the study. There was one notable complication, a hematoma in the space of Retzius. One patient described worsening of her incontinence and underwent a Marshall-Marchetti-Krantz procedure three months postoperatively. The mean follow-up for the remaining nine patients was 27 months (range, 13-31). At this writing, 6 patients were completely continent, 1 was improved, and 2 had some degree of bladder instability with associated incontinence. Overall, the transvestibular procedure was thought to be technically difficult. Based on very limited data, the results of the study have discouraged our continued use of this procedure. The transvestibular approach may be applicable occasionally on selected patients.