Cetuximab potentiates oxaliplatin cytotoxic effect through a defect in NER and DNA replication initiation.

Preclinical studies have demonstrated that the chemotherapeutic action of oxaliplatin, a third generation platinum derivative, is improved when combined with cetuximab, a monoclonal antibody inhibitor of epidermal growth factor receptors. To explore the mechanism of this synergistic benefit, we used HCT-8 and HCT-116, two human colon cancer cell lines, respectively, responsive and non-responsive to the oxaliplatin/cetuximab combination. We examined the effect of drug exposure on glutathione-S-transferase-mediated oxaliplatin detoxification, DNA-platinum adducts formation, cell cycle distribution, apoptosis, and the expression of multiple targets involved in DNA replication, recombination, and repair. The major changes we found in HCT-8 were a stimulation of oxaliplatin-DNA adduct formation associated with reduced expression of the key enzyme (excision repair cross complementation group1: ERCC1) in the key repair process of oxaliplatin-DNA platinum adduct, the nucleotide excision repair (NER), both at the mRNA and protein levels. We also observed a reduced expression of factors involved in DNA replication initiation, which correlates with an enrichment of cells in the G1 phase of the cell cycle as well as an acceleration of apoptosis. None of these changes occurred in the non-responsive HCT-116 cell that we used as a negative control. These findings support the fact that cetuximab potentiates the oxaliplatin-mediated cytotoxic effect as the result of inhibition of NER and also DNA replication initiation.

Term delivery following conservative treatment for villoglandular papillary adenocarcinoma of the uterine cervix: report of a case and analysis of the literature.

BACKGROUND: Villoglandularpapillary adenocarcinoma (VPA) of the cervix is often indolent, and surgical treatment has a favorable outlook. Risk factors include depth of invasion, lymphovascular invasion, and the presence of other histologic types of cancer. CASE: An amputation of the cervical portio was required to satisfactorily resect a 2.5-cm ectocervical lesion in a 28-year-old nulligravida. A diagnosis of pure VPA with a depth of invasion less than 2 mm was established. During a subsequent pregnancy, second trimester ultrasound showed extreme effacement of her cervix and an abdominal cerclage was placed. The pregnancy continued until delivery of a healthy infant at 36 weeks. CONCLUSIONS: In cases of tumor invasion less than 3 mm, and in the absence of lymphovascular space involvement, extrauterine spread of pure VPA has not been described. When conservative treatment is planned, amputation of the cervical portio may be better suited than conization to the achievement of an adequate margin of resection. Cervical cerclage may be needed to offset the extensive cervical surgery.

In vitro fertilization following conservative management of stage 3 serous borderline tumor of the ovary.

Among patients with advanced stage serous borderline tumors of the ovary, those with micropapillary architecture or invasive implants have the greatest risk of malignant transformation. In the absence of these patterns, consideration can be given to preservation of reproductive function. A 28-year-old, nulliparous patient presented with symptoms mimicking advanced ovarian cancer. Histology showed a serous borderline tumor with a hierarchical branching pattern. Surgery was able to remove all visible disease but still preserve the uterus and a portion of one ovary. She subsequently underwent in vitro fertilization and delivered a full-term infant.

Pharmacological therapy of Helicobacter pylori infection.

Helicobacter pylori has been associated with several diseases including peptic ulcer disease and gastric cancer. Eradication of H pylori not only results in ulcer healing, but reduces recurrences essentially curing peptic ulcer disease. Eradicating H pylori can be difficult. There are several reasons for antimicrobial failure, and the resistance rates for several antibiotics are increasing. The most common drugs used to treat this infection include amoxicillin, clarithromycin, tetracycline, bismuth, and omeprazole and lansoprazole. Dual therapy using a proton pump inhibitor and a single antibiotic gives a suboptimal eradication rate. Triple therapy using at least two antibiotics and either bismuth or a proton pump inhibitor gives satisfactory eradication rates of 90%. However, these regimens are complicated and have significant side effects and compliance problems. The ideal regimen has yet to be developed. In the future, we will prevent infection with immunization. Several vaccines are being developed.

Rabbit and ferret parietal cell inhibition by Helicobacter species.

We tested sonicates of Helicobacter pylori, H. mustelae, and H. felis for inhibition of acid secretion in rabbit and ferret isolated gastric glands. Three H. pylori strains, two of three H. mustelae strains, and two H. felis strains significantly inhibited acid secretion in rabbit cells by 95.2-93.3%, 55.9% and 96.4%, and 83.4-96%, respectively. All Helicobacter strains examined inhibited acid secretion by ferret cells by 65.3-76.8%, 89.1-97.6%, and 85.8-92.8%. H. pylori inhibited acid secretion after stimulation with histamine and isobutylmethylxanthine or with 8-bromo-cyclic adenosine monophosphate (P < 0.05 for all tests). These findings demonstrate that acid inhibition is a property common to the three Helicobacter species tested. It occurs independently of the mammalian origin of the parietal cell, and it does not involve blockade of histamine-2 receptors.

Changes in cell cycle-associated gene expression in a model of impaired liver regeneration.

Following partial hepatectomy (PH) there is compensatory regeneration of the remnant liver which eventually restores hepatic mass and function. The response to PH was studied in normal BALB/c and athymic nude mice, a model of impaired liver regeneration. Following PH, nude mice demonstrated diminished peak hepatic [3H]thymidine uptake and delayed liver mass restoration through 60 h post-PH. However, between 72-120 h there was no significant difference in mass restoration between the groups. The expression of genes associated with different stages of the cell cycle was evaluated in both models. In nude mice, there was an increase in peak expression of c-jun transcripts, while c-myc transcript expression was moderately attenuated. Thymidine kinase (TK) and cyclin-dependent kinase 1 (CDK1) mRNA expression was also diminished in athymic nude mice. The results suggest that while the defect in the regenerative response of the nude mouse after PH affects events in several phases of the cell cycle, mass restoration of the liver is only delayed and not attenuated.

Placental site trophoblastic tumor: a report of radiologic, surgical, and pathologic methods of evaluating the extent of disease.

A dramatic vaginal hemorrhage occurred 1 year after a normal vaginal delivery. A curettage showed placental site trophoblastic tumor. Magnetic resonance imaging and color flow Doppler documented a marked increase in uterine vascularity, as well as an abnormal endomyometrial appearance. Surgery included total abdominal hysterectomy and pelvic lymph node dissection. This confirmed the extensive uterine tumor and also showed an extremely small focus of tumor cells in one lymph node. Immunohistochemical staining for human placental lactogen and for cytokeratin confirmed the histologic finding. After surgery, we gave adjuvant chemotherapy with the EMACO regimen. The radiologic, surgical, and pathologic procedures utilized in this case provided a more complete understanding of the extent of her disease. These techniques may be helpful in making therapeutic decisions for other women with this rare disorder.

Primary biliary carcinoma with metastasis to the ovary.

The ovary is a relatively frequent site of metastasis from malignant neoplasia arising elsewhere in the body, the majority of these originating from the GI tract. The best known tumor of this type is signet-ring cell adenocarcinoma (Krukenberg tumor) of gastric origin. The gall bladder and bile ducts are rare sources of these metastases. Asymptomatic carcinoma of the cystic duct metastasizing to the ovary is extremely rare. We are reporting such a case in which the patient presented with no GI or hepatic symptoms. The cystic duct carcinoma was an incidental finding from routine and careful examination of the abdominal viscera.

Immature teratoma of the ovary.

Twenty-five cases of patients with pure immature teratoma of the ovary, accrued from the Connecticut Tumor Registry from 1969 to 1984, were reviewed. Two patients had grade 1 tumors, twelve had grade 2 tumors, and eleven had grade 3 tumors. The majority of patients (23) were stage I at the time of initial surgery. Twenty-one of the twenty-three patients were treated with some form of unilateral adnexal surgery with or without adjuvant combination chemotherapy (VAC). Two of the twenty-three patients were treated with total abdominal hysterectomy/bilateral salpingo-oophorectomy (TAH/BSO) with the addition of either VAC chemotherapy or radiation therapy. Recurrence occurred in two patients, both of whom had grade 3 tumors and were subsequently treated with surgical resection plus VAC chemotherapy. One patient, who recurred after initial therapy with unilateral salpingo-oophorectomy (USO) plus VAC chemotherapy, was successfully treated with surgical resection and further chemotherapy. Two patients were stage III at the time of initial surgery, one of whom was treated with USO plus adjuvant combination chemotherapy and radio-therapy. The other patient was treated with TAH/BSO plus VAC chemotherapy. In our series, no patient died from immature teratoma (one patient died from advanced breast carcinoma). It is reasonable to withhold chemotherapy from patients with stage I, grade 1 and 2, immature teratoma which may be treated initially with conservative surgery. The risk of recurrence in patients with grade 3 tumors warrants the addition of further chemotherapy.

Tolerance during long-term administration of intrathecal morphine.

We studied the time course of development of tolerance in four terminally ill cancer patients who were treated for intractable pain by intrathecal morphine administered by an implanted catheter and pump. The duration of treatment varied from 1.8 to 10.5 months. Our study shows that with disease progression, there was a constant patient-specific time rate of increase in the morphine dose requirements. Hence, for any given patient, the slope of the dose v time curve is effectively a constant over long periods. We also found that patients tolerate very high doses of intrathecal morphine without serious side effects.

Dysgerminoma: a study of 13 cases from the Connecticut Tumor Registry.

Thirteen cases of patients with dysgerminoma of the ovary, accrued from the Connecticut Tumor Registry from 1974-84, were reviewed. Seven of the 13 patients were stage I at the time of initial surgery. Two of these patients had a diagnosis of dysgerminoma arising within a gonadoblastoma. Five of the seven patients were treated with some form of adnexal surgery; one patient received adjuvant combination chemotherapy consisting of vincristine, dactinomycin, and cyclophosphamide (VAC) and another received radiation therapy. Two of the seven patients were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) plus radiation therapy. One patient, whose tumor recurred after initial therapy with unilateral oophorectomy, was successfully treated with radiation therapy. Six patients had advanced disease at the time of initial surgery. One patient with stage II disease and three patients with stage III disease were treated with TAH/BSO plus radiation therapy. One patient with stage III disease was treated with unilateral adnexectomy plus combination chemotherapy consisting of vinblastine, bleomycin, dactinomycin, cyclophosphamide, and cisplatin (VAB-VI). One patient with stage IV disease was treated with decompressive laminectomy with tumor resection, removal of left pelvic mass, radiation therapy and adjuvant combination chemotherapy (VAC). In our series, no patient died from dysgerminoma (one patient died of an apparently unrelated cause). The role of radiation therapy in the treatment of advanced and recurrent dysgerminoma has been demonstrated. However, the use of combination chemotherapy has been playing an increasingly important role in patients treated with conservative surgery in which preservation of fertility is a concern.

Molar pregnancy coexisting with a normal fetus: a case report.

Molar pregnancy with a coexisting live fetus is a rare occurrence. We present morphologic and cytogenetic analysis of a recent case. Cytogenetic studies revealed a 46, XX karyotype for the fetus, the normal placenta, and the abnormal placenta. Chromosome banding studies confirmed the presence of maternal and paternal chromosomes in all three tissues. These studies favored the possibility that both tumor and fetus arose from a single gestation. Subsequently, the patient required chemotherapy for low-risk, metastatic trophoblastic disease.

Percutaneous epidural catheterization for intractable pain in terminal cancer patients.

We examined the effects of long-term percutaneous epidural catheterization for pain relief in nine terminally ill gynecologic cancer patients. All patients were free of side-effects such as respiratory depression, nausea, vomiting, urinary retention, or pruritus. Analgesia was excellent in six patients. Puncture-site skin inflammation occurred in four patients. Catheter dislodgement occurred in three patients. Although percutaneous epidural catheters were well tolerated in a few patients for an extended period of time, the frequency of catheter problems demonstrate that other methods such as catheter tunneling or implantable systems should be considered for long-term epidural administration of narcotics. This method appears to be most effective in patients suffering from pain due to nerve root involvement.

Central nervous system lesions and advanced ovarian cancer.

Over the past 5 years we have seen seven cases of central nervous system tumors in patients with advanced or recurrent ovarian carcinoma. These have ranged in location from the conus medullaris to the brain and have varied in time of occurrence from the time of cancer diagnosis to 63 months following surgery. A diagnosis of metastatic ovarian carcinoma was established in six of the cases, while one patient had a second primary malignancy. All cases had prodromal and localizing neurologic symptoms which led to the suspicion of central nervous system involvement. The critical diagnostic studies were myelography and computed tomography of the brain and spine. We have reviewed our approach to diagnosis and therapy.

The role of second-look laparotomy in treatment of epithelial ovarian cancer.

Forty-two patients underwent a second-look laparotomy to assess response to systemic chemotherapy for epithelial ovarian cancer. In 20 cases the operation showed no histologic evidence of disease. None of these cases received additional treatment at the time of negative second-look laparotomy. There has only been one recurrence noted in an average follow-up interval of 38.5 months. The remaining 22 cases did have residual carcinoma and 16 have developed progressive carcinoma despite secondary treatment. We found second-look laparotomy to be a safe and reliable assessment tool. However, we could not demonstrate a medical benefit from the procedure.

Amyloidogenesis. One serum amyloid A isotype is selectively removed from the circulation.

The deposits of fibrils found in amyloidosis of the A type are derived from only one of the three serum amyloid A (SAA) gene products, namely SAA2. In order to explore the mechanism of SAA isotype-specific amyloid protein AA deposition, the molecular kinetics of the serum amyloid proteins were examined in CBA mice during casein induction of amyloidosis. The presence of SAA mRNA in spleen was searched for; hepatic SAA1 and SAA2 mRNA levels, rates of specific protein synthesis and secretion by hepatocytes, and serum levels were measured during a 20-d period of amyloid induction. We observed the following: small amounts of amyloid substance appeared in the spleen by day 5 and increased steadily over the ensuing 15 d to occupy nearly 30% of splenic volume by day 20. No SAA mRNA was detected in spleen at any time during induction of amyloid formation. Total serum SAA levels peaked 1 d after we began casein treatment, and thereafter declined. This decline was accounted for entirely by a dramatic fall in SAA2, while SAA1 levels remained nearly constant throughout. The ratios of hepatic SAA2:SAA1 mRNA, as determined by in vitro translation, remained constant during the 20-d period, as did amounts of SAA1 and SAA2 synthesized and secreted by freshly isolated hepatocytes. These data indicate that the deposition of amyloid A protein derived from SAA2 is not due to local SAA production in spleen, nor excessive SAA2 production compared with SAA1, but involves the selective and accelerated removal of SAA2 from the circulating pool of both SAA1 and SAA2.

Prognostic significance of groin lymph node metastases in squamous carcinoma of the vulva.

A retrospective review of the clinical and histologic findings in 48 cases of stages I, II, and III (excluding T3) squamous carcinoma of the vulva with positive groin nodes reveals the prognostic significance of the size and number of the nodal metastases. Other factors such as the morphology of the lymph nodes and the histologic features of the primary neoplasm are not nearly as significant. Patients with only one or two small nodal metastases have an excellent outlook for survival providing that adequate margins can be obtained around the primary tumor and that thorough groin node dissections can be performed. These patients do not appear to need adjuvant radiation or pelvic node dissection. A further finding is that patients with unilateral labial carcinomas do not have metastases to the opposite groin in the absence of ipsilateral groin metastases, although six of 21 patients had metastases to both groins.

Microinvasive squamous carcinoma of the vulva: search for a definition.

All cases of stage I squamous cell carcinoma of the vulva from the University of Michigan Tumor Registry from 1935 to 1981 were reviewed. Seventeen of 90 (19%) patients had nodal metastases. All had a depth of invasion of more than 2 mm and all exhibited histologic confluence. The risk of nodal metastases varied with depth of invasion, size of lesion, and histologic grade, although the association with grade was not statistically significant. The size of the lesion influenced the incidence of nodal metastases only in that it was associated with the depth of invasion. Lymphovascular invasion was present in only four patients, but three of them had nodal metastases, including one patient with only 3 mm depth of invasion.