Mono-galloyl glucose derivatives are potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors and partially reduce PARP-1-dependent cell death.

BACKGROUND AND PURPOSE: Maintenance of poly(ADP-ribose) (PAR) polymers at homoeostatic levels by PAR glycohydrolase (PARG) is central in cell functioning and survival. Yet the pharmacological relevance of PARG inhibitors is still debated. Gallotannin, a complex mixture of hydrolysable tannins from oak gall, inhibits PARG but which of its constituents is responsible for the inhibition and whether the pharmacodynamic properties are due to its antioxidant properties, has not yet been established. EXPERIMENTAL APPROACH: A structure-activity relationship study was conducted on different natural and synthetic tannins/galloyl derivatives as potential PARG inhibitors, using a novel in vitro enzymic assay. Cytotoxicity was assayed in cultured HeLa cells. KEY RESULTS: Mono-galloyl glucose compounds were potent inhibitors of PARG, with activities similar to that of ADP-(hydroxymethyl) pyrrolidinediol, the most potent PARG inhibitor yet identified. When tested on HeLa cells exposed to the PAR polymerase (PARP)-1-activating compound 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), 3-galloyl glucose weakly inhibited PAR degradation. Conversely, the more lipophilic, 3-galloyl-1,2-O-isopropylidene glucose, despite being inactive on the pure enzyme, efficiently prolonged the half-life of the polymers in intact HeLa cells. Also, PARG inhibitors, but not radical scavengers, reduced, in part, cell death caused by MNNG. CONCLUSIONS AND IMPLICATIONS: Taken together, our findings identify mono-galloyl glucose derivatives as potent PARG inhibitors, and emphasize the active function of this enzyme in cell death.

[Histopathologic examination of the intervertebral lumbar disk. Evaluation of its usefulness and limitations]. / L'esame istopatologico del disco intervertebrale lombare. Valutazione dell'utilità e dei limiti.

A retrospective clinical-pathological review of 192 lumbar intervertebral discs removed via an interlaminar approach or percutaneous nucleotomy from patients suffering from sciatic pain was carried out in order to assess if routine examination is useful. Only for a case of our series, which showed ill defined features at preoperative neuroradiologic imaging, an intraoperative pathologic examination was necessary. Immunohistochemical study was never required. A routine examination with a hematoxilin-eosin stain was sufficient also to recognize postoperative scar in patients reoperated. In conclusion we think that routine examination of the intervertebral disc is a procedure which is not expensive and useful to assess the nature of the lesion in reoperated patients and in rare cases showing unclear radiologic pattern.

Calf pseudohypertrophy in a patient with double neurogenic pathology.

A pseudohypertrophy of the calf can be rarely associated with neurogenic pathologies as S-1 radiculopathy, poliomyelitis, spinal muscular atrophy, traumatic lesions of peripheral nerves, intraspinal neurinoma. The causes of this particular phenomenon are unknown. The authors present the case of a 52-year-old man with an enlargement of the left calf suffering from a mild form of spinal paralytic poliomyelitis in the early childhood and episodes of severe left sciatica in the last four years. Electromyography demonstrated a pattern of denervation in both legs and an H-reflex absent when the left tibial nerve was stimulated. An open muscle biopsy of the left calf was performed. Light microscopic and ultrastructural examination of the muscle confirmed the presence of a pattern of "neurogenic type" pseudohypertrophy. Our results could be interesting for the understanding of the mechanism of neurogenic pseudohypertrophy. This case suggests that timing of stimulus or "dose" of denervation may be important factors in such a phenomenon.

Safety of transvaginal fine needle puncture of gynecologic masses: a report after 500 consecutive procedures.

Transvaginal sonographically guided puncture may be used for diagnostic and therapeutic purpose in general gynecology and in oncology. To define the complication rate of this technique, 500 consecutive procedures were reviewed; 289 procedures were on cystic masses, 146 on solid tumors, 34 on mixed tumors, and 31 on other lesions. No life-threatening complications occurred. Early mild and self-limited complications developed in eight procedures (1.6%). Short-term complications occurred in four cases (0.8%; two infections, one pelvic pain, one hemorrhage); two of these required surgery. Transvaginal sonographically guided puncture is safe and does not entail a higher risk of infection than transabdominal punctures.

Salvage therapy with ifosfamide and mitoxantrone in advanced ovarian cancer.

OBJECTIVE: To evaluate the anti-tumour activity and toxicity of ifosfamide (5 g/m2 continuous infusion) and mitoxantrone (10 mg/m2) given in combination every 3 weeks in patients with ovarian cancer resistant to at least two previous regimens which included platinum. PATIENTS AND METHODS: Additional eligibility criteria were an ECOG performance status < or = 2 and measurable disease. Of 47 patients entered in the study, 8 were defined as platinum-resistant and 39 as potentially sensitive according to Markman's criteria. Thirty-five patients had also received paclitaxel as last treatment before entering this study. Tumour response was evaluated every three cycles. RESULTS: One complete and 11 partial responses were reported, for an overall response rate of 25% (95% CI: 14%-40%). Three of the partial responders were resistant to platinum. None of the 7 partial responders pretreated with taxol had responded to it. The overall median survival was 11 months. Neutropenia G4 was reported in 18 patients (42%) with hospitalisation because of febrile neutropenia in 3 of them. CONCLUSIONS: In patients with ovarian cancer failing at least 2 previous therapies including platinum, the combination of ifosfamide and mitoxantrone has shown an antitumour activity comparable to that of paclitaxel, with acceptable toxicity. Objective responses were reported also in patients failing paclitaxel, suggesting a lack of cross resistance.

Ultrasound-guided aspiration of endometriomas: possible applications and limitations.

OBJECTIVES: To evaluate the role of needle aspiration in the management of endometriomas. DESIGN: Retrospective evaluation of the activity of the section of interventional ultrasound in a single tertiary care institution. SETTING: Department of Obstetrics and Gynecology, Ospedale S. Gerardo, Monza, University of Milan, Italy. PATIENTS: Two hundred nine premenopausal patients underwent aspiration for diagnostic purpose (n = 166), for relief of symptoms (n = 25), or with therapeutic intent (n = 18). RESULTS: Adequate material was obtained by all punctures. Early complications (self-limiting vagal symptoms or pain) occurred in eight cases. Short-term complications consisted of acute abdominal pain in three cases and infection in one. Three women required surgical treatment of the complication. At first examination after aspiration, persistence of the cyst was observed in all but four cases, including all cases who had undergone therapeutic aspiration. Nine patients reported relief of symptoms but six other patients referred onset or worsening of pelvic discomfort after aspiration. CONCLUSIONS: Ultrasound-guided aspiration of endometriomas is feasible. The transvaginal route reduces early complication but implies a risk of infection of 1.3%. However, drainage alone is ineffective as a therapeutic procedure and the applications of aspiration of endometriomas appear limited to some cases with diagnostic intent.

Central nervous system metastases in patients with ovarian carcinoma. A report of 23 cases and a literature review.

BACKGROUND: Central nervous system (CNS) involvement by ovarian carcinoma is rare. PATIENTS AND METHODS: From September 1982 to September 1994, 23 patients with CNS metastases from ovarian carcinoma were observed in our institution. RESULTS: Their median age at the time of CNS metastasis diagnosis was 59 years, and the median interval between diagnosis of ovarian cancer and documentation of the metastasis was 35 months. The most common symptoms related to CNS involvement were motor weakness, headache, seizures, dizziness and visual disturbances. One patient had meningeal carcinomatosis; 22 had parenchymal lesions (18 cerebral and 4 cerebellar). Nine patients had a single CNS lesion, and 13 had multiple metastatic sites. CNS was the only site of disease in 9 patients, while 8 had concomitant extraperitoneal dissemination. The median survival (MS) from diagnosis of cerebral metastases for the entire series was five months. Four patients were not treated (MS 3 months); 14 received radiotherapy (MS 5.5 months), and five underwent surgical resection of solitary metastases followed by radiotherapy (MS 17 months). Number of CNS lesions, extent of the disease at the time of CNS metastasis and treatment were the only factors which significantly affected survival CONCLUSIONS: The prognosis of patients with CNS metastasis from ovarian carcinoma appears poor. However, early diagnosis followed by multimodal treatment may result in significant palliation and improve overall survival in a selected group of patients.

Transvaginal ultrasound-guided fine needle sampling of deep cancer recurrences in the pelvis: usefulness and limitations.

The usefulness of fine needle sampling (FNS) under transvaginal ultrasound guidance in gynecologic oncology patients is evaluated in this study. Between 1990 and 1993, 101 FNS under transvaginal ultrasound guidance were performed in 88 sessions. All targets were located deep in the pelvis and their median diameter was 30 mm. All procedures were performed on an outpatient basis. Sampling consisted of 46 cytologic aspirates and 55 biopsies. No false-positive result was obtained when cytologic results were correlated with both clinical outcome and surgical biopsy. For aspirates and biopsies, sensitivity was respectively 76 and 91%, while accuracy was 83 and 91%. Inadequate results were recorded in 11 aspirates and in 9 biopsies. In 7 of 12 sessions where both aspiration and biopsy were performed, false-negative or inadequate cytologic result was overcome by true-positive biopsies. No moderate or severe complication was observed. FNS under transvaginal ultrasound guidance is a safe procedure with limited invasiveness and extremely high specificity even when performed on small targets. Whenever possible, biopsies should be preferred. A negative FNS obtained from a clinically suspicious lesion requires a repeat sampling.

Ultrasound in the follow-up of young patients with malignant ovarian tumors after conservative surgery.

Ultrasound examinations were performed us a step in the follow-up of 62 patients previously treated with conservative surgery for malignant ovarian tumors. With a minimal follow-up period of 36 months (range 36-129) 12 recurrences of disease were observed in nine patients. When compared to other routine follow-up procedures, ultrasound examination proved to be the most effective procedure in the monitoring of these patients, correctly detecting ten recurrences. Physical and gynecological examinations detected seven, tumor marker measurements detected six and chest X-rays detected one. Ultrasound examination was 83% sensitive, 99% specific and 99% accurate in the detection of recurrent disease. In four recurrences leading to death, the diameters of the tumors at first detection were 25, 50, 50 and 100 mm, significantly higher (p = 0.03) than in seven recurrences followed by complete response of the tumor (range 15-35 mm, median 30 mm). Ultrasound appears to be superior to physical and gynecological examination in early detection of recurrence; considering that smaller burdens of tumor at the time of recurrence seem to imply a better prognosis, ultrasound should be considered us a useful additional procedure in the follow-up of these patients.

Early and short-term complications after US-guided puncture of gynecologic lesions: evaluation after 1,000 consecutive cases.

PURPOSE: To ascertain the complication rate associated with ultrasound (US)-guided puncture of gynecologic lesions. MATERIALS AND METHODS: Between 1986 and 1992, 878 transabdominal and 122 transvaginal US-guided punctures of gynecologic lesions were performed in 893 patients. Most of the procedures were performed in adnexal cysts (n = 838); the rest, in solid tumors (n = 66), mixed tumors (n = 56), or lymphoceles, abscesses, or fluid collections (n = 40). No anesthesia or antibiotic prophylaxis was routinely used. RESULTS: No life-threatening complication was recorded. Early complications (defined as complications that occurred within 24 hours after puncture) were recorded in 31 patients and consisted mainly of transient vagal symptoms or pain. Short-term complications (within 5 days after puncture) were recorded in 10 patients, six of whom required surgery. CONCLUSION: US-guided puncture of gynecologic lesions is safe in selected patients. Complication rates depend on the type of lesion and are very high in dermoid cysts, which should not be punctured, and extremely low in serous cysts, solid tumors, and mixed tumors.

Cisplatin-induced peripheral neurotoxicity is dependent on total-dose intensity and single-dose intensity.

The authors prospectively evaluated the effects of three different schedules of cisplatin (DDP) administration in 60 patients with advanced epithelial ovarian cancer. The individual total dose of DDP was 450 mg/m2 in all three groups, and the anti-cancer response at the end of treatment was similar for the different regimens. The clinical and neurophysiologic results confirmed that axonal sensory neuropathy occurred after the standard administration of DDP (75 mg/m2 in 3-week cycles) and probably not only the peripheral, but also the central sensory pathway, was involved. Although the total dose of the drug was identical, the two less conventional schedules were less neurotoxic. These results suggest that not only the total-dose intensity, but also the single-dose intensity are relevant in the onset of DDP-induced sensory neuropathy; therefore, the use of less neurotoxic schedules may prevent or reduce sensory nerve damage.

The incidence and course of paraneoplastic neuropathy in women with epithelial ovarian cancer.

Sensorimotor polyneuropathy is the most common of the paraneoplastic syndromes involving the nervous system. Its incidence is high (more than 50%) in the patients undergoing neurophysiological investigation, and it is considered to be more frequent in subjects with lung and breast cancers. In this study we evaluated a series of 58 women with epithelial ovarian cancer at FIGO stages I and III. The aim of the study was to assess the incidence and characteristics of peripheral nerve involvement during the course of the disease both clinically and neurophysiologically. Our results suggest that in women with epithelial ovarian cancer (1) the incidence of subclinical polyneuropathy is high; (2) sensory involvement is predominant in stage I, but motor involvement is frequent in stage III; and (3) the incidence of peripheral nerve involvement increases with progression of the cancer.

Alpha-fetoprotein in the management of germ cell tumors of the ovary.

From 1982 to 1989 positive alpha-fetoprotein (AFP) levels were detected after surgery in 3 patients with pure immature teratoma, 7 patients with mixed germ cell tumors and 16 patients with pure endodermal sinus tumor (EST) of the ovary. In the three patients with pure immature teratoma, AFP serum levels became spontaneously undetectable in one month without chemotherapy. The marker was thereafter negative, despite the persistence of tumor in 2 patients, and a relapse in the third one. The serum levels of AFP did not correlate with the stage of EST and mixed germ cell tumors. The monitoring of AFP serum levels during treatment correlated with response to chemotherapy: of the 16 patients with pure EST, 14 achieved a serological complete response and did not undergo second look surgery; two patients had a serological partial response. One of them reached a serological complete response after further chemotherapy. The other patient with liver extragonadic tumor underwent liver lobectomy with negative histology. Among 7 patients with mixed germ cell tumor, 6 achieved a serological and pathologic complete response. The 7th patient had a serological complete response, but microscopic residual tumor at second look laparotomy. The decrement curve of AFP was not predictive for recurrence. However, AFP monitoring was useful for an early diagnosis of relapse in 4 patients. AFP is a reliable marker for the diagnosis, treatment evaluation and follow-up of patients with pure EST and a useful marker in the clinical management of mixed germ cell tumors of the ovary.