Prognostic factors in 677 patients in Singapore with nondisseminated nasopharyngeal carcinoma

BACKGROUND: The objective of the current study was to describe the survival of nasopharyngeal carcinoma (NPC) patients in Singapore, verify the prognostic value of the revised 1997 TNM staging system, and develop a multivariate prognostic model for NPC. In addition, the authors also examined the prognostic value of characteristics of lymph node spread and parapharyngeal involvement. METHODS: A prospectively maintained database containing clinical and computed tomography scan data was used to reclassify 677 NPC patients treated between 1992 and 1994 according to the new staging system. Records were linked with the death registry to ascertain the patient's vital status and date of death. Overall and stage specific survival were analyzed using the Kaplan-Meier method and the log rank test. Univariate and multivariate Cox proportional hazards regression analysis were used to obtain prognostic models. RESULTS: Two hundred seventy-four deaths (40.5%) occurred. The 5-year survival rate was 56.6% (95% confidence interval [95% CI], 52.3%, 60.7%). The stage specific 5-year survival rates were: Stage I, 88%; Stage IIA, 75%; Stage IIB, 74%; Stage III, 60%; Stage IVA, 35%; and Stage IVB, 28%. TNM stage was found to be a statistically significant prognostic factor (P < 0.0001). Cranial nerve (hazard ratio [HR]: 2.77), orbit (HR: 5.71), and intracranial involvement (HR: 2.46) conferred a particularly bad prognosis in univariate analysis. Independently significant prognostic factors were age; lymph node status; and paraoropharyngeal, cranial nerve, orbit, and nasal involvement. Among lymph node positive patients, independently significant prognostic lymph node characteristics were Ho level and laterality. Although parapharyngeal involvement appeared to be prognostically unimportant, paraoropharyngeal involvement distinguished a subgroup with a poorer prognosis (HR: 1.84; 95% CI, 1.45, 2.34; P < 0.0001). Lateral spread to the medial infratemporal fossa and beyond also was found to confer a poorer prognosis. CONCLUSIONS: The results of the current study show that the revised 1997 TNM staging system is prognostically useful. Subdivision into paraoropharyngeal involvement and using the medial infratemporal fossa to delineate prognostically significant lateral spread should be considered in future revisions.     

Outpatient 5-fluorouracil, folinic acid and cisplatin in patients with advanced esophageal carcinoma

In a multicenter phase II study, 30 patients with unresectable, locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were treated with folinic acid 200 mg/m²/d, 5-FU 300 mg/m²/d, and cisplatin 20 mg/m²/d intravenously for 5 days every 4 weeks. Two of 13 patients with squamous cell carcinoma (SCC) had a complete response (CR), but one died of pneumonia after 9 months while still in CR, and the other still in CR after more than 5 years. Six other patients (3 SCC, 2 of 16 with adenocarcinoma, 1 mixed histology) had a partial response with a median duration of 9 months (range 5 to 57+months) for an overall response rate of 27%. A further 6 patients (20%) had stable disease. Grade 4 neutropenia occurred in 6 patients (20%), with 5 requiring antibiotics for associated fever. Other grade 4 toxicities were nausea and vomiting (1), anemia (1), and thrombocytopenia (1); there were three early deaths (emphysema, cardiac arrest, pulmonary embolism). This combination appears to be an active, convenient regimen for advanced esophageal cancer, resulting in prolonged remission and survival in some patients.     

Alexithymia and psychotherapy.

Alexithymia represents a disturbance in affective and cognitive function which overlaps diagnostic categories. Emotions are not differential, and are poor verbalized. Imagination related to drive fulfillment is limited. These and other problems seriously interfere with the patients' capacity to benefit from dynamic, uncovering or "anxiety-producing" psychotherapy. In order to consider possible remediation of the problem, we must explore the nature and causes of this disturbance.     

Intraoperative cell salvage in metastatic spine tumour surgery reduces potential for reinfusion of viable cancer cells

Purpose

This study aimed at evaluating our hypothesis that tumour cells, which pass through the intraoperative cell salvage (IOCS) machine, lose viability due to possible injury to the cell membrane during centrifugation and filtration, enabling safe reinfusion even without filtration.

Methods

Thirteen patients who underwent metastatic spine tumour surgery (MSTS) at our institution were recruited. Blood samples (5 ml each) were collected at five different stages during surgery, namely, stage A and B: from patients’ vein during induction and at the time of maximum tumour manipulation; stage C, D and E: from the operative blood prior to IOCS processing, after IOCS processing and after IOCS-LDF (leucocyte depletion filter) processing, respectively. The samples were then analysed for viability of tumour cells using microwell-based culture.

Results

The median age of the patients was 65 years (range 37–77 years). The most common primary tumour was lung, followed by breast, hepatocellular and renal cell carcinoma. The median blood loss was 680 ml (range 300–1500 ml). Analysis of cultured blood samples showed that CTC-containing clusters were developed from some samples before IOCS-LDF processing (stage A: three patients, stage B: three patients and stage C: one patient). None of the samples from stages D and E generated clusters after culture, suggesting the absence of viable cancer cells after IOCS processing.

Conclusions

The salvaged blood may contain some tumour cells after processing with IOCS machine, but these cells are damaged and hence unable to replicate and unlikely to metastasise. The results of this study support the hypothesis that salvaged blood in MSTS is safe for transfusion.

     

Incontinence medication response relates to the female urinary microbiota

Introduction and hypothesis

Many adult women have resident urinary bacteria (urinary microbiome/microbiota). In adult women affected by urinary urgency incontinence (UUI), the etiologic and/or therapeutic role of the urinary microbiome/microbiota remains unknown. We hypothesized that microbiome/microbiota characteristics would relate to clinically relevant treatment response to UUI medication per os.

Methods

Adult women initiating medication treatment orally for UUI and a comparator group of unaffected women were recruited in a tertiary care health-care system. All participants provided baseline clinical data and urine samples. Women with UUI were given 5 mg solifenacin, with potential dose escalation to 10 mg for inadequate UUI symptom control at 4 weeks. Additional data and urine samples were collected from women with UUI at 4 and 12 weeks. The samples were assessed using 16S ribosomal RNA (rRNA) gene sequencing and enhanced quantitative urine culturing. The primary outcome was treatment response as measured by the validated Patient Global Symptom Control (PGSC) questionnaire. Clinically relevant UUI symptom control was defined as a 4 or 5 score on the PGSC.

Results

Diversity and composition of the urinary microbiome/microbiota of women with and without UUI differed at baseline. Women with UUI had more bacteria and a more diverse microbiome/microbiota. The clinical response to solifenacin in UUI participants was related to baseline microbiome/microbiota, with responders more likely to have fewer bacteria and a less diverse community at baseline. Nonresponders had a more diverse community that often included bacteria not typically found in responders.

Conclusions

Knowledge of an individual’s urinary microbiome/microbiota may help refine UUI treatment. Complementary tools, DNA sequencing, and expanded urine culture provide information about bacteria that appear to be related to UUI incontinence status and treatment response in this population of adult women.

     

Effects of Repeated Anesthesia Containing Urethane on Tumor Formation and Health Scores in Male C57BL/6J Mice

Repeated injection of urethane (ethyl carbamate) is carcinogenic in susceptible strains of mice. Most recent cancer studies involving urethane-induced tumor formation use p53^+/– mice, which lack one copy of the p53 tumor suppressor gene. In contrast, the same protocol elicits at most a single tumor in wildtype C57BL/6 mice. The effect of repeatedly injecting urethane as a component of a ketamine–xylazine anesthetic mixture in the highly prevalent mouse strain C57BL/6 is unknown. Male C57BL/6J mice (n = 30; age, 3 mo) were anesthetized once monthly for 4 mo by using 560 mg/kg urethane, 28 mg/kg ketamine, and 5.6 mg/kg xylazine. The physical health of the mice was evaluated according to 2 published scoring systems. The average body condition score (scale, 1 to 5; normal, 3) was 3.3, 3.3, and 3.4 after the 2nd, 3rd, and 4th injections, respectively. The visual assessment score was 0 (that is, normal) at all time points examined. Within 1 wk after the 4th injection, the mice were euthanized, necropsied, and evaluated histopathologically. No histopathologic findings were noteworthy. We conclude that repeated monthly injection with urethane as a component of an anesthetic cocktail does not cause clinically detectable abnormalities or induce neoplasia in C57BL/6J mice. These findings are important because urethane combined with low-dose ketamine, unlike other anesthetic regimens, allows for accurate recording of neuronal activity in both the brain and retina. Longitudinal neuronal recordings minimize the number of mice needed and improve the analysis of disease progression and potential therapeutic interventions.Abbreviations: ERG, electroretinogram; VEP, visual evoked potentialUrethane is classified as a chemical carcinogen¹⁵ and is used by many laboratories to induce tumor formation in mice. Critical parameters affecting urethane-induced tumor formation in mice include the mouse strain, urethane dose, and frequency of administration. For example, urethane induces tumors in albino strain A mice, which are naturally susceptible to tumor formation.^11,17,22 The delivery of urethane to Swiss or C57BL1 mice induces the formation of skin and lung tumors but only when a tumor-promoting agent, such as croton oil or X-ray irradiation, is given concurrently.^2-4,10,12,24 Within these strains, young mice appear to be more susceptible than are adults.^9,17One of the mouse lines most resistant to urethane-induced tumor formation is also the strain used most often in research studies: C57BL/6.²¹ Weekly injections of 1000 mg/kg urethane for 10 wk are required to induce tumor formation in this strain.²¹ The tumors typically induced in this model are pulmonary adenomas and hepatic hemangiomas or hemangiosarcomas.^8,9,11,13 Furthermore, 5 mo after the first injection, only half of the mice injected had developed tumors, at an average of 0.63 tumors per mouse.²¹ Another study showed that the strain variability may be due to genetic alterations at 3 separate loci.¹⁹ Despite the existence of more susceptible mouse strains, many studies use p53^+/– mice on a C57BL/6 background to obtain reliable and consistent results.⁸ Although these mice are inherently susceptible to tumor formation due to the lack of one copy of the p53 tumor suppressor gene, they still have to be injected repeatedly with high doses of urethane to induce tumor formation. For example, daily injection of 1mg/kg urethane for 180 d failed to induce tumor growth in p53^+/– mice;⁸ to achieve tumor formation in these mice, the urethane dosage must be increased to 10 to 100 mg/kg daily for at least 180 d.⁸Another use of urethane is as an anesthetic. Electrophysiologists use urethane-containing anesthesia during the recording of electrical activity from the brain or retina of rodents, including that during vision testing through electroretinography (ERG) and a light-evoked encephalographic evaluation known as the visual evoked potential (VEP). Inducing anesthesia by combining urethane (560 to 1000 mg/kg) with ketamine (25 to 40 mg/kg) and xylazine (5.6 to 10 mg/kg) is ideal in this context because it avoids the confounding influences of higher doses of anesthetics on electrical responses, yet maintains a sufficient depth of anesthesia to obtain readable electrical signals.^5-7,18,25,27 However, in light of concerns regarding urethane-induced tumor formation, these recordings typically are only performed once in each rodent subject, just prior to euthanasia. This practice greatly limits the amount of information that can be obtained from a single animal. Longitudinal ERG and VEP from the same animal are needed to understand the progression of disease and therapeutic efficacy of various treatments.Longitudinal assessments of vision in models of glaucoma, trauma to the eye or brain, or inherited retinal degenerations provide information on disease course and therapeutic windows (for review, see reference 29). In addition, these types of assessments would strengthen therapy studies by determining the duration of therapeutic efficacy.²⁹ Importantly, most studies of visual system degeneration use C57BL/6-based models, in which vision loss is induced either through mechanical or genetic manipulation. Although different mice can be assessed at each time point, this strategy decreases the power of statistical analysis and increases the total number of mice needed for each study. The hypothesis of the current study is that repeated injection of an anesthetic mixture containing 560 mg/kg urethane, 28 mg/kg ketamine, and 5.6 mg/kg xylazine does not decrease overall physical health according to 2 scoring systems or induce tumors in C57BL/6 mice.     

Subgingival plaque control by a simplified oral hygiene regime plus local chlorhexidine or metronidazole

This study determined the effects of a simplified oral hygiene regime plus local applications of metronidazole or chlorhexidine on the subgingival microflora. Twenty-one patients, with periodontal pockets 4 mm or deeper, underwent one session of scaling, root planing, and oral hygiene instruction (Bass method but without emphasis on interdental cleaning). Eight patients performed once daily subgingival irrigation with 0.2% chlorhexidine gluconate solution for 28 days. Thirteen patients had either 0.5% metronidazole in dialysis tubings or 40% metronidazole in acrylic resin strips inserted subgingivally once weekly, also for four weeks.
For each subject, subgingival plaque was obtained from two chemically treated (test) and one non-chemically treated (control) pockets at days 0 (prior to scaling and root planing), 7, 14, 21, 28, 56, and 84. The subgingival microflora was assessed using darkfield microscopy. Bacteria were characterized as cocci, motile organisms, spirochaetes, and others (straight and curved rods, filaments and fusiforms).
Both chlorhexidine and metronidazole groups showed beneficial change still apparent at the end of the study (3 months). Great increases in proportions of cocci and reductions in spirochaetes and all other forms of bacteria were observed. Metronidazole reduced spirochaetes more but, unlike chlorhexidine, had a variable effect on motiles. Root planing alone had less effect. Generally, metronidazole and chlorhexidine appeared equally beneficial. It was concluded that in spirochaete-dominated plaque, metronidazole may be preferred agent. Where motiles predominate, chlorhexidine may be the topical agent of choice.     

Can Composite Nutritional Supplement Based on the Current Guidelines Prevent Vitamin and Mineral Deficiency After Weight Loss Surgery?

Background

Nutritional deficiencies occur after weight loss surgery. Despite knowledge of nutritional risk, there is little uniformity of postoperative vitamin and mineral supplementation. The objective of this study was to evaluate a composite supplement based on the clinical practice guidelines proposed in 2008 regarding vitamin and mineral supplementation after Roux-en-Y gastric bypass. The composite included iron (Fe) and calcium as well.

Methods

A retrospective chart review of 309 patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB) was evaluated for the development of deficiencies in iron and vitamins A, B₁, B₁₂, and D. Patients were instructed to take a custom vitamin and mineral supplement that was based on society-approved guidelines. The clinical practice guidelines were modified to include 1600 international units (IU) of vitamin D₃ instead of the recommended 800 IU.

Results

The compliant patients’ deficiency rates were significantly lower than those of the noncompliant patients for iron (p?=?0.001), vitamin A (p?=?0.01), vitamin B₁₂ (p?≈?0.02), and vitamin D (p?<?0.0001). Women’s menstrual status did not significantly influence the development of iron deficiency.

Conclusions

Use of a composite based on guidelines proposed by the AACE, TOS, and the ASMBS appears to be effective for preventing iron and vitamins A, B₁, B₁₂, and D deficiencies in the LRYGB patients during the first postoperative year. Separation of calcium and Fe does not need to be mandatory. Even with simplification, compliance is far from universal.

     

Absence of significant interactive effects of high-dose D-cycloserine and ethanol in healthy human subjects: preliminary insights into ethanol actions at the glycine B site of NMDA glutamate receptors

Background: Ethanol reduces N‐methyl‐d ‐aspartate (NMDA) glutamate receptor function via multiple cellular targets. It is not yet clear whether direct ethanol antagonism of the glycine_B co‐agonist site of NMDA receptors is relevant to this effect. The purpose of this study was to evaluate whether ethanol effects at the glycine_B co‐agonist site was clinically relevant by evaluating some aspects of the psychopharmacologic interactions between the glycine_B partial agonist, d ‐cycloserine (DCS), and ethanol in healthy human subjects. Methods: All subjects completed 4 test days under double‐blind conditions in which DCS or placebo was administered orally prior to ethanol or an ethanol‐tainted placebo drink. Two groups of healthy subjects were studied. A first group of subjects (n = 25) were pretreated orally with DCS 500 mg or placebo 4 hours prior to ethanol (0.8 g/kg, p.o. or placebo) administration. A second group of subjects (n = 20) were pretreated with DCS 1000 mg or placebo prior to ethanol administration. Outcomes included subjective and cognitive responses to the experimental interventions. Results: Predictable ethanol responses were observed in both groups of subjects, although the response to ethanol and the breath alcohol levels, but not plasma alcohol levels, were slightly but significantly lower in the group that received the higher DCS dose. DCS produced mild sedative effects that were greater for the lower than the higher dose. It also produced a mild impairment of verbal fluency without impairing attention. No statistically significant interactions between ethanol and DCS emerged in analyses. However, the combination of ethanol and DCS produced significantly greater impairment than both ethanol or DCS administered alone on a test of verbal fluency and aspects of memory function. Implications: DCS and ethanol both produced sedative and cognitive effects, consistent with their ability to reduce NMDA receptor function. However, the absence of interactive effects observed in this study raises questions about the clinical significance of the glycine_B site as a target for ethanol in the brain at levels of ethanol intoxication associated with social drinking. However, it should be noted that this conclusion is limited to the dependent measures evaluated and the doses of ethanol and DCS studied.