Laparoscopic management of suspicious adnexal masses

OBJECTIVE: Our aim was to evaluate the feasibility and applicability of operative laparoscopy in the management of adnexal masses that do not meet the standard serum CA 125 and ultrasonographic criteria for benignity. STUDY DESIGN: One hundred thirty-eight patients underwent operative laparoscopy for removal of suspicious adnexal masses. The CA 125 level was >35 mIU/ml in 39 of 138 (28%) patients; ultrasonographic findings were abnormal in 127 of 138 (92%); masses were >10 cm in 43 of 138 (32%) of patients. RESULTS: Malignancies were discovered in 14% (19/138) of patients. Eight percent (11/138) of the procedures were converted to laparotomy, six because of inability to dissect the mass laparoscopically and five for staging or debulking of carcinoma. Operative times ranged from 25 to 210 minutes, with a mean of 86. Three major complications were encountered-an enterotomy and a lacerated vena cava, both of which were repaired laparoscopically, and a small bowel herniation through a lateral port site that required reoperation. Hospital stays ranged from 0 to 11 days, with a mean of 1.5. In two patients with "apparent" stage I adnexal carcinomas recurrence was diagnosed 6 and 38 months after surgery. CONCLUSIONS: Laparoscopic management of suspicious adnexal masses is technically feasible, with a low rate of morbidity and a short hospital stay. Adnexal carcinomas can be identified and managed appropriately with staging and complete resection as indicated. (Am J Obstet Gynecol 1996;175:1451-9.)     

Breast cancer angiogenesis — new approaches to therapy via antiangiogenesis,hypoxic activated drugs,and vascular targeting

Summary Several groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGF1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suraminin vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize.New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.     

The 24-Hour Sleep Propensity Function: Experimental Bases for Somnotypology

The present study investigated the temporal structure of sleep propensity during 48 hours using an ultrashort 7-min sleep/13-min wake cycle. Eight subjects were tested under two experimental conditions of either attempting sleep, or resisting sleep after a monitored night in the laboratory. Electrophysiological recordings were carried out during the 7-min trials. The temporal structure and the overall level of sleepiness of the 48-hour sleep propensity functions calculated from the amount of total sleep in each trial revealed a high within-subjects stability. This was found both across the two days of the study within conditions, and across conditions. Also, diurnal levels of sleepiness were systematically related to nocturnal sleep parameters. Subjects having short nocturnal sleep latencies and higher sleep efficiencies slept more during the day. It is proposed that the structure and level of the sleep propensity function can be used to characterize individuals along two dimensions of somnotypology: "morningness-eveningness" and "sleepy-alert."     

Relative pharmacokinetics of three amikacin brands in onco-hemotologic pediatric patients experiencing febrile neutropeina.

Three commercially available brands of amikacin were investigated in a parallel study design for the assessment of comparative pharmacokinetics in pediatric oncology patients with chemotherapy-induced neutropenic febrile episode. Amikacin concentration in serum samples was determined by fluorescence polarization immunoassay method using Abbott TDx system. Computer software, PK II was used for computation of pharmacokinetic parameters of amikacin. The serum concentration of all brands nonsignificantly (p > 0.05) varied at all time points, except at 1 and 2 hrs post dosing. At 1 hr post dosing, the serum concentration of brand II varied from rest of two brands. Whereas at 2 hr following I/V infusion, brands II and I were statistically different. Highest serum concentration of 38.69 +/- 1.45 microg/ml was observed in case of brand III while brands I and II showed lower but not significantly different serum concentration values, i.e., 36.30 +/- 1.65 and 37.89 +/- 1.32 microg/ml, respectively when compared with brand I. The other pharmacokinetic parameters of 3 brands found to have non-significant difference (P < 0.05) except, t(1/2)alpha and Cl of brands I and II that deviated statistically significant (p < 0.01). The relative bioavailability of brand II and III as compared with brand I, considered as standard 86.17 and 96.86%, respectively falls within the accepted limits of +/- 20% required for the bioequivalence of any two brands. Based upon findings of the present study, all these brands may be used interchangeably in oncology patients. Further studies, however are needed to determine whether the statistically elevated Cl value in brand II is of any clinical significance.     

Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo.

PURPOSE: In recent years, the incidence of cutaneous melanoma has increased more than that of any other cancer. Dacarbazine is considered the gold standard for treatment, having a response rate of 15% to 20%, but most responses are not sustained. Previously, we have shown that short exposure of primary cutaneous melanoma cells to dacarbazine resulted in the upregulation of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The purpose of the present study was to determine how long-term exposure of melanoma cells to dacarbazine would affect their tumorigenic and metastatic potential in vivo. MATERIALS AND METHODS: The primary cutaneous melanoma cell lines SB2 and MeWo were repeatedly exposed in vitro to increasing concentrations of dacarbazine, and dacarbazine-resistant cell lines SB2-D and MeWo-D were selected and examined for their ability to grow and metastasize in nude mice. RESULTS: The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo. This increase could be explained by the activation of RAF, MEK, and ERK, which led to the upregulation of IL-8 and VEGF. More IL-8, VEGF, matrix metalloproteinase-2 (MMP-2), and microvessel density (CD-31) were found in tumors produced by SB2-D and MeWo-D in vivo than in those produced by their parental counterparts. No mutations were observed in BRAF. CONCLUSION: Our results have significant clinical implications. Treatment of melanoma patients with dacarbazine could select for a more aggressive melanoma phenotype. We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine.     

Epidermal growth factor receptor tyrosine kinase inhibitor does not improve paclitaxel effect in an orthotopic mouse model of lung cancer.

PURPOSE: The purpose is to evaluate whether inhibition of epidermal growth factor receptor (EGFR) activation by PKI166, an EGFR-tyrosine kinase inhibitor, affects growth of human lung cancer implanted orthotopically into the lungs of nude mice. EXPERIMENTAL DESIGN: Lungs of mice were injected with NCI-H358 human bronchioloalveolar cancer cells. In three experiments, groups of mice (n = 10 per group) were randomized 7 days after tumor implantation to receive one of the following treatments: i.p. paclitaxel 100 or 200 microg (4 or 8 mg/kg) once per week, oral PKI166 100 or 200 mg/kg three times per week, paclitaxel plus PKI166, or i.p. saline and oral PKI166-vehicle (control) for 5 weeks. Mice were killed 6.5 to 8 weeks after tumor implantation. The experiments were repeated with PC14PE6 human lung adenocarcinoma cells to assess effect on survival. RESULTS: Immunohistochemical analyses revealed the expression and phosphorylation of EGFR in the growing tumors. Treatment with PKI166 alone or in combination with paclitaxel diminished activation of EGFR on tumor cells, yet maximal therapeutic effect was observed in mice treated with paclitaxel alone. Activated mitogen-activated protein kinase and basic fibroblast growth factor expression were similar in all treatment groups. Survival in mice treated with the combination of paclitaxel and PKI166 was shorter than in those treated with paclitaxel alone. CONCLUSIONS: Our results suggest that concurrent administration of EGFR-tyrosine kinase inhibitor and chemotherapy is equivalent and may indeed be inferior to chemotherapy alone, even if EGFR is functional and its phosphorylation effectively inhibited. Our data show that the interaction of EGFR-TKIs and chemotherapy is complex and suggest that other growth factors may activate the downstream signaling events.     

Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial

Context  The optimal antimicrobial regimen and treatment duration for acute uncomplicated pyelonephritis are unknown. Objective  To compare the efficacy and safety of a 7-day ciprofloxacin regimen and a 14-day trimethoprim-sulfamethoxazole regimen for the treatment of acute pyelonephritis in women. Design  Randomized, double-blind comparative trial conducted from October 1994 through January 1997. Setting  Twenty-five outpatient centers in the United States. Patients  Of 378 enrolled premenopausal women aged at least 18 years with clinical diagnosis of acute uncomplicated pyelonephritis, 255 were included in the analysis. Other individuals were excluded for no baseline causative organism, inadequate receipt of study drug, loss to follow-up, no appropriate cultures, and other reasons. Interventions  Patients were randomized to oral ciprofloxacin, 500 mg twice per day for 7 days (with or without an initial 400-mg intravenous dose) followed by placebo for 7 days (n = 128 included in analysis) vs trimethoprim-sulfamethoxazole, 160/800 mg twice per day for 14 days (with or without intravenous ceftriaxone, 1 g) (n = 127 included in the analysis). Main Outcome Measure  Continued bacteriologic and clinical cure, such that alternative antimicrobial drugs were not required, among evaluable patients through the 4- to 11-day posttherapy visit, compared by treatment group. Results  At 4 to 11 days posttherapy, bacteriologic cure rates were 99% (112 of 113) for the ciprofloxacin regimen and 89% (90 of 101) for the trimethoprim-sulfamethoxazole regimen (95% confidence interval [CI] for difference, 0.04-0.16; P = .004). Clinical cure rates were 96% (109 of 113) for the ciprofloxacin regimen and 83% (92 of 111) for the trimethoprim-sulfamethoxazole regimen (95% CI, 0.06-0.22; P = .002). Escherichia coli, which caused more than 90% of infections, was more frequently resistant to trimethoprim-sulfamethoxazole (18%) than to ciprofloxacin (0%; P<.001). Among trimethoprim-sulfamethoxazole–treated patients, drug resistance was associated with greater bacteriologic and clinical failure rates (P<.001 for both). Drug-related adverse events occurred in 24% of 191 ciprofloxacin-treated patients and in 33% of 187 trimethoprim-sulfamethoxazole–treated patients, respectively (95% CI, -0.001 to 0.2). Conclusions  In our study of outpatient treatment of acute uncomplicated pyelonephritis in women, a 7-day ciprofloxacin regimen was associated with greater bacteriologic and clinical cure rates than a 14-day trimethoprim-sulfamethoxazole regimen, especially in patients infected with trimethoprim-sulfamethoxazole–resistant strains.      

The effect of intensive care on in-hospital survival

Intensive Care Units (ICU) are one of the most powerful and expensive technologies within inpatient care. However, its effect on survival is still an issue under discussion. The objective of this paper is to assess the effect of General ICU on in-hospital survival. We assessed the effect of ICU on survival using Linear and Probit regressions. Since admission to IC is not random and depends on unobserved (to the researcher) heterogeneity, we reassessed the IC effect by Instrumental Variables (IV) and Bivariate Probit techniques, using crowding in the IC unit as an instrument. The results show that a simple Probit of the IC effect on survival is 7–10 percentage-points (pts). The IV estimate of the IC effect on survival is 21–34 pts, and the Bivariate Probit estimate is 17–21 pts. We conclude that although admitted patients are at lower risk of death, as determined by their observable (to the researcher) characteristics, controlling for observable differences, those with a higher unobserved risk of mortality are more likely to be admitted. The implications for an optimal admission policy are discussed.     

Feedback and feedforward adaptation to visuomotor delay during reaching and slicing movements

It has been suggested that the brain and in particular the cerebellum and motor cortex adapt to represent the environment during reaching movements under various visuomotor perturbations. It is well known that significant delay is present in neural conductance and processing; however, the possible representation of delay and adaptation to delayed visual feedback has been largely overlooked. Here we investigated the control of reaching movements in human subjects during an imposed visuomotor delay in a virtual reality environment. In the first experiment, when visual feedback was unexpectedly delayed, the hand movement overshot the end‐point target, indicating a vision‐based feedback control. Over the ensuing trials, movements gradually adapted and became accurate. When the delay was removed unexpectedly, movements systematically undershot the target, demonstrating that adaptation occurred within the vision‐based feedback control mechanism. In a second experiment designed to broaden our understanding of the underlying mechanisms, we revealed similar after‐effects for rhythmic reversal (out‐and‐back) movements. We present a computational model accounting for these results based on two adapted forward models, each tuned for a specific modality delay (proprioception or vision), and a third feedforward controller. The computational model, along with the experimental results, refutes delay representation in a pure forward vision‐based predictor and suggests that adaptation occurred in the forward vision‐based predictor, and concurrently in the state‐based feedforward controller. Understanding how the brain compensates for conductance and processing delays is essential for understanding certain impairments concerning these neural delays as well as for the development of brain–machine interfaces.     

Intrahepatic cholangiocarcinoma: current management and emerging therapies

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with an increasing incidence and a high-case fatality. While surgery offers the best hope at long-term survival, only one-third of tumors are amenable to surgical resection at the time of the diagnosis. Unfortunately, conventional chemotherapy offers limited survival benefit in the management of unresectable or metastatic disease. Recent advances in understanding the molecular pathogenesis of iCCA and the use of next-generation sequencing techniques have provided a chance to identify ‘target-able’ molecular aberrations. These novel molecular therapies offer the promise to personalize therapy for patients with iCCA and, in turn, improve the outcomes of patients.

Area covered: We herein review the current management options for iCCA with a focus on defining both established and emerging therapies.

Expert commentary: Surgical resection remains as an only hope for cure in iCCA patients. However, frequently the diagnosis is delayed till advanced stages when surgery cannot be offered; signifying the urge for specific diagnostic tumor biomarkers and targeted therapies. New advances in genomic profiling have contributed to a better understanding of the landscape of molecular alterations in iCCA and offer hope for the development of novel diagnostic biomarkers and targeted therapies.