What is the Significance of the Circumferential Margin in Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiotherapy?

Background

The circumferential resection margin (CRM) is highly prognostic for local recurrence in rectal cancer surgery without neoadjuvant treatment. However, its significance in the setting of long-course neoadjuvant chemoradiotherapy (nCRT) is not well defined.

Methods

Review of a single institution’s prospectively maintained database from 1998 to 2007 identified 563 patients with locally advanced rectal cancer (T3/T4 and/or N1) receiving nCRT, followed after 6 weeks by total mesorectal excision (TME). Kaplan-Meier, Cox regression, and competing risk analysis were performed.

Results

The authors noted that 75 % of all patients had stage III disease as determined by endorectal ultrasound (ERUS) and/or magnetic resonance imaging (MRI). With median follow-up of 39 months after resection, local and distant relapse were noted in 12 (2.1 %) and 98 (17.4 %) patients, respectively. On competing risk analysis, the optimal cutoff point of CRM was 1 mm for local recurrence and 2 mm for distant metastasis. Factors independently associated with local recurrence included CRM ≤1 mm, and high-grade tumor (p = 0.012 and 0.007, respectively). CRM ≤2 mm, as well as pathological, nodal, and overall tumor stage are also significant independent risk factors for distant metastasis (p = 0.025, 0.010, and <0.001, respectively).

Conclusion

In this dataset of locally advanced rectal cancer treated with nCRT followed by TME, CRM ≤1 mm is an independent risk factor for local recurrence and is considered a positive margin. CRM ≤2 mm was associated with distant recurrence, independent of pathological tumor and nodal stage.     

Diffuse axonal injury in mild traumatic brain injury: a diffusion tensor imaging study

OBJECT: Diffuse axonal injury (DAI) is a major complication of traumatic brain injury (TBI) that leads to functional and psychological deficits. Although DAI is frequently underdiagnosed by conventional imaging modalities, it can be demonstrated using diffusion tensor imaging. The aim of this study was to assess the presence and extent of DAI in patients with mild TBI. METHODS: Forty-six patients with mild TBI and 29 healthy volunteers underwent a magnetic resonance (MR) imaging protocol including: dual-spin echo, fluid-attenuated inversion recovery, T2-weighted gradient echo, and diffusion tensor imaging sequences. In 20 of the patients, MR imaging was performed at a mean of 4.05 days after injury. In the remaining 26, MR imaging was performed at a mean of 5.7 years after injury. In each case, mean diffusivity and fractional anisotropy were measured using both whole-brain histograms and regions of interest analysis. No differences in any of the histogram-derived measures were found between patients and control volunteers. Compared with controls, a significant reduction of fractional anisotropy was observed in patients' corpus callosum, internal capsule, and centrum semiovale, and there were significant increases of mean diffusivity in the corpus callosum and internal capsule. Neither histogram-derived nor regional diffusion tensor imaging metrics differed between the two groups. CONCLUSIONS: Although mean diffusivity and fractional anisotropy abnormalities in these patients with TBI were too subtle to be detected with the whole-brain histogram analysis, they are present in brain areas that are frequent sites of DAI. Because diffusion tensor imaging changes are present at both early and late time points following injury, they may represent an early indicator and a prognostic measure of subsequent brain damage.     

E-selectin binding peptide–polymer–drug conjugates and their selective cytotoxicity against vascular endothelial cells

The hypothesis that E-selectin on activated endothelial cells could be exploited to selectively target drug delivery systems to tumor vasculature was investigated. HPMA copolymer–doxorubicin (DOX) conjugates displaying the high affinity E-selectin binding peptide (Esbp, primary sequence DITWDQLWDLMK) as targeting ligand were synthesized and tested for their cytotoxicity and intracellular fate in human immortalized vascular endothelial cells (IVECs). The targeted copolymers displaying multiple copies of Esbp are bound to surface-associated E-selectin with affinity at the low nano-molar range, three orders of magnitude stronger than the free Esbp. In addition, the binding affinity of the HPMA–Esbp copolymers to E-selectin expressing IVECs was found to be 10-fold superior relative to non-targeted copolymers. Once bound, E-selectin facilitated rapid internalization and lysosomal trafficking of the copolymers. This lysosomotropism of HPMA–Esbp-bound DOX copolymers was then correlated with a 150-fold higher cytotoxicity relative to non-targeted HPMA–DOX conjugates. These findings strongly support the emerging role of E-selectin as a viable target for controlled drug delivery in cancer therapy.     

A randomized prospective study on the effect of short and long Buserelin treatment in women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response

Fifty four women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response to stimulation with human menopausal gonadotropins (hMG) participated in this study. They were randomized to receive either gonadotropin releasing hormone agonist (GNRHa), Buserelin, prior to and during induction of ovulation by hMG (Group I—long protocol), or GnRHa starting on the first day of the cycle together with induction of ovulation by hMG (Group II—short protocol). Mean follicular phase serum luteinizing hormone (LH) and progesterone (P) levels were significantly lower in Group I than in Group II (P<0.01). Cancellation rate was significantly lower in Group I than in Group II (P<0.01). The long GNRHa protocol resulted in statistically significant lower cancellation rates, more oocytes per pickup (OPU), more embryos trans-ferred per patient, and a higher pregnancy rate. Significantly more hMG ampoules and more treatments days were required in the long GNRHa protocol. Our data demonstrate that the use of GNRHa prior to and during ovarian stimulation with hMG offers a very good alternative for patients with repetitive unsuccessful IVF cycles due to inadequate response.     

The influence of transient hyperprolactinemia on hormonal parameters,oocyte recovery,and fertilization rates in in vitro fertilization

A detrimental effect of transient elevation of plasma prolactin (PRL) during in vitro fertilization (IVF) has not been proven; however, treatment with a dopamine agonist has been suggested. The present study was undertaken to determine if transient, midcycle hyperprolactinemia exerted a deleterious effect on the number of oocytes retrieved or on fertilization of oocytes in vitro. Fifty-three infertile patients with midcycle hyperprolactinemia (PRL>20 g/liter) during ovarian hyperstimulation for IVF were compared with 53 matched controls who remained normoprolactinemic. Mean (±SE) serum PRL levels on the day after hCG were significantly higher in the study group (29.5±1 g/liter) than in the control (13.1±0.5 g/liter) (P<0.0005), whereas the mean estradiol (E₂) concentrations on the same day were not significanily different (4822±287 and 4492±269 pmol/liters, respectively). Fertilization rates (72±4 and 70±4%, respectively) and the mean number of oocytes recovered (4.2±0.3 and 3.7±0.3, respectively) did not differ between the two groups. No correlation was observed between serum PRL and E₂ levels, fertilization rates, or the number of oocytes retrieved in either group. Eleven patients with elevated PRL levels as a result of ovarian hyperstimulation were treated with 2.5 mg bromocriptine daily during the next IVF cycle. Serum PRL levels were significantly lower in the treated (5.6±1.8 g/liter) than in the untreated cycles (35.6±3.1 g/liter) (P<0.0005), whereas serum E₂ concentrations did not differ. Although the mean number of oocytes recovered was significantly higher in the treated (6.2±1.1) than in the untreated (4.7±0.7) (P<0.02) cycles, the fertilization rates were significantly lower when the patients were treated with bromocriptine compared with the previous untreated cycle (55±8.0 and 76.5±7.0%, respectively;P<0.05). Our data demonstrate that a transient elevation of PRL during ovarian stimulation for IVF does not adversely affect the endocrine response, number of oocytes retrieved, or fertilization rates. No improvement in these parameters was observed in bromocriptine-treated cycles. These results do not support the treatment of transient hyperprolactinemia with dopamine agonists in IVF patients.     

Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF)

The texture and the thickness of the endometrium as assessed by transvaginal sonography were prospectively evaluated in 123 patients undergoing IVF treatment. Three different types of endometrial patterns could be distinguished: (A) an entirely homogeneous, hyperechogenic endometrium; (B) an intermediate type characterized by the same reflectivity of ultrasound as the myometrium, with a nonprominent or absent central echogenic line; and (C) a multilayered endometrium consisting of prominent outer and midline hyperechogenic lines and inner hypoechogenic regions. On the day before oocyte retrieval, endometrial thickness was significantly greater in the group of patients who achieved pregnancy than in the group who did not (8.7±0.4 vs 7.5±0.2 mm, respectively; P<0.01) and significantly more patients had multilayered, pattern C, endometrium (75% in pregnant women vs 42.4% in nonpregnant women; P<0.01). No pregnancy occurred when the endometrial thickness was less than 6 mm. When type C endometrium >-6 mm thick was seen, the pregnancy rate per embryo transfer was 39%. When type A or B endometrial pattern was seen, the negative predictive value for the occurrence of pregnancy was 90.5%. Our results suggest that transvaginal sonographic evaluation of endometrial texture and thickness may be an indicator of the likelihood of achieving pregnancy.     

Effect of irrigation or intravenous antibiotic prophylaxis on infectious morbidity at cesarean section

The efficacy of intraoperative irrigation with cefamandole nafate at cesarean section was evaluated in a prospective, randomized double-blind study. Two hundred and eight patients were treated with antibiotic irrigation and intravenous placebo or with perioperative intravenous cefamandole and irrigated with normal saline. The rate of endometritis was 10.9% in the irrigation group and 14% in the intravenous group, but the difference was not statistically significant. The rate of any infection, the number of days with fever, additional hospitalization days, and number of antibiotics used for treatment were similar in the two groups. It thus was concluded that irrigation with antibiotic is equal but not superior to perioperative intravenous antibiotics.     

Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase

BACKGROUND: Replication-competent herpes simplex virus-1 (HSV-1) mutants have an oncolytic effect on human and animal cancers. The aim of this study was to determine whether G207, an HSV-1 mutant, can be combined with ionizing radiation (IR) to increase antitumor activity while decreasing treatment-associated toxicity. METHODS: This study was performed by using G207, a replication-competent HSV-1 mutant deficient in viral ribonucleotide reductase (RR) and the gamma(1)34.5 neurovirulence protein. The antitumor activity of G207 or IR was tested against HCT-8 human colorectal cancer cells in vitro and in an in vivo mouse subcutaneous tumor model. RESULTS: We demonstrated that G207 has significant oncolytic effect on HCT-8 cells in vitro in a cytotoxicity assay and in vivo in a mouse flank tumor model and that these effects are improved with low-dose IR. We further illustrated that the increased tumoricidal effect is dependent on the up-regulation of cellular RR by IR measured by a functional bioassay for RR activity. Chemical inhibition of RR by hydroxyurea abrogates the enhanced effect. In contrast to G207, R3616, the parent virus of G207 that expresses functional RR, does not exhibit enhanced oncolysis when combined with IR. CONCLUSIONS: These data encourage clinical investigation of combination radiation therapy and HSV oncolytic therapy.     

Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade

OBJECTIVE: To assess the nature of changes in the field of hepatic resectional surgery and their impact on perioperative outcome. METHODS: Demographics, extent of resection, concomitant major procedures, operative and transfusion data, complications, and hospital stay were analyzed for 1,803 consecutive patients undergoing hepatic resection from December 1991 to September 2001 at Memorial Sloan-Kettering Cancer Center. Factors associated with morbidity and mortality and trends in operative and perioperative variables over the period of study were analyzed. RESULTS: Malignant disease was the most common diagnosis (1,642 patients, 91%); of these cases, metastatic colorectal cancer accounted for 62% (n = 1,021). Three hundred seventy-five resections (21%) were performed for primary hepatic or biliary cancers and 161 (9%) for benign disease. Anatomical resections were performed in 1,568 patients (87%) and included 544 extended hepatectomies, 483 hepatectomies, and 526 segmental resections. Sixty-two percent of patients had three or more segments resected, 42% had bilobar resections, and 37% had concomitant additional major procedures. The median blood loss was 600 mL and 49% of patients were transfused at any time during the index admission. Median hospital stay was 8 days, morbidity was 45%, and operative mortality was 3.1%. Over the study period, there was a significant increase in the use of parenchymal-sparing segmental resections and a decrease in the number of hepatic segments resected. In parallel with this, there was a significant decline in blood loss, the use of blood products, and hospital stay. Despite an increase in concomitant major procedures, operative mortality decreased from approximately 4% in the first 5 years of the study to 1.3% in the last 2 years, with 0 operative deaths in the last 184 consecutive cases. On multivariate analysis, the number of hepatic segments resected and operative blood loss were the only independent predictors of both perioperative morbidity and mortality. CONCLUSIONS: Over the past decade, the use of parenchymal-sparing segmental resections has increased significantly. The number of hepatic segments resected and operative blood loss were the only predictors of both perioperative morbidity and mortality, and reductions in both are largely responsible for the decrease in perioperative mortality, which has occurred despite an increase in concomitant major procedures.     

Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism

Impairment in social reciprocity is a central component of autism. In preclinical studies, arginine vasopressin (AVP) has been shown to increase a range of social behaviors, including affiliation and attachment, via the V(1a) receptor (AVPR1A) in the brain. Both the behavioral effects of AVP and the neural distribution of the V1a receptor vary greatly across mammalian species. This difference in regional receptor expression as well as differences in social behavior may result from a highly variable repetitive sequence in the 5' flanking region of the V1a gene (AVPR1A). Given this comparative evidence for a role in inter-species variation in social behavior, we explored whether within our own species, variation in the human AVPR1A may contribute to individual variations in social behavior, with autism representing an extreme form of social impairment. We genotyped two microsatellite polymorphisms from the 5' flanking region of AVPR1A for 115 autism trios and found nominally significant transmission disequilibrium between autism and one of the microsatellite markers by Multiallelic Transmission/Disequilibrium test (MTDT) that was not significant after Bonferroni correction. We also screened approximately 2 kb of the 5' flanking region and the coding region and identified 10 single nucleotide polymorphisms.