Towards the use of diffuse reflectance spectroscopy for real-time in vivo detection of breast cancer during surgery

Background

Breast cancer surgeons struggle with differentiating healthy tissue from cancer at the resection margin during surgery. We report on the feasibility of using diffuse reflectance spectroscopy (DRS) for real-time in vivo tissue characterization.

Methods

Evaluating feasibility of the technology requires a setting in which measurements, imaging and pathology have the best possible correlation. For this purpose an optical biopsy needle was used that had integrated optical fibers at the tip of the needle. This approach enabled the best possible correlation between optical measurement volume and tissue histology. With this optical biopsy needle we acquired real-time DRS data of normal tissue and tumor tissue in 27 patients that underwent an ultrasound guided breast biopsy procedure. Five additional patients were measured in continuous mode in which we obtained DRS measurements along the entire biopsy needle trajectory. We developed and compared three different support vector machine based classification models to classify the DRS measurements.

Results

With DRS malignant tissue could be discriminated from healthy tissue. The classification model that was based on eight selected wavelengths had the highest accuracy and Matthews Correlation Coefficient (MCC) of 0.93 and 0.87, respectively. In three patients that were measured in continuous mode and had malignant tissue in their biopsy specimen, a clear transition was seen in the classified DRS measurements going from healthy tissue to tumor tissue. This transition was not seen in the other two continuously measured patients that had benign tissue in their biopsy specimen.

Conclusions

It was concluded that DRS is feasible for integration in a surgical tool that could assist the breast surgeon in detecting positive resection margins during breast surgery.Trail registration NIH US National Library of Medicine–clinicaltrails.gov, NCT01730365. Registered: 10/04/2012 https://clinicaltrials.gov/ct2/show/study/NCT01730365

     

The diabetes online community: the importance of forum use in parents of children with type 1 diabetes

Online forums for chronic health conditions emerged as early as 30 yr ago and interest in their study has blossomed. Type 1 diabetes (T1D) forums have grown exponentially since 2005. Therefore, a comprehensive evaluation of these forums is needed. This study assesses the demographics and motivations of parents who use type 1 diabetes forums and the potential impact that forum membership (FM) has on parenting stress and hypoglycemic fear. One hundred and two parents were recruited through online T1D forums and asked to complete qualitative and quantitative measures of their experience with the T1D forums. Results of this study suggest that parents who use T1D forums mirror those who participate in clinic‐based research protocols and are primarily motivated to participate in forums to increase their diabetes knowledge and gain social support. Indeed, parents who use T1D forums report high levels of trust, social support, and perceived knowledge gained. However, FM was positively related to increased self‐reported parenting stress frequency and hypoglycemic fear behaviors. Taken together, the relationships formed within these communities may have a significant impact on the experience of these caregivers. The need for future research and potential implications for physicians, including parent debriefing, are discussed.     

Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro

BACKGROUND AND AIMS: The gastroprokinetic activities of ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), prompted us to compare the effect of ghrelin with that of synthetic peptide (growth hormone releasing peptide 6 (GHRP-6)) and non-peptide (capromorelin) GHS-R agonists both in vivo and in vitro. METHODS: In vivo, the dose dependent effects (1-150 nmol/kg) of ghrelin, GHRP-6, and capromorelin on gastric emptying were measured by the 14C octanoic breath test which was adapted for use in mice. The effect of atropine, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME), or D-Lys3-GHRP-6 (GHS-R antagonist) on the gastroprokinetic effect of capromorelin was also investigated. In vitro, the effect of the GHS-R agonists (1 microM) on electrical field stimulation (EFS) induced responses was studied in fundic strips in the absence and presence of L-NAME. RESULTS: Ghrelin, GHRP-6, and capromorelin accelerated gastric emptying in an equipotent manner, with bell-shaped dose-response relationships. In the presence of atropine or l-NAME, which delayed gastric emptying, capromorelin failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying but did not effectively block the action of the GHS-R agonists, but this may be related to interactions with other receptors. EFS of fundic strips caused frequency dependent relaxations that were not modified by the GHS-R agonists. L-NAME turned EFS induced relaxations into cholinergic contractions that were enhanced by ghrelin, GHRP-6, and capromorelin. CONCLUSION: The 14C octanoic breath test is a valuable technique to evaluate drug induced effects on gastric emptying in mice. Peptide and non-peptide GHS-R agonists accelerate gastric emptying of solids in an equipotent manner through activation of GHS receptors, possibly located on local cholinergic enteric nerves.     

Adaptive differentiation of murine lymphocytes. IV. (Responder × Nonresponder) F(1) T cells can be taught to preferentially help nonresponder,rather than responder, B cells

Responses to the synthetic terpolymer L-glutamic acid, L-lysine, L-tyrosine (GLT) in the mouse are controlled by H-2-1inked Ir-GLTgenes. (Responder × nonresponder) F(1) hybrid mice, themselves phenotypic responders, can be primed with GLT to develop specific helper cells capable of interacting with 2,4-dinitrophenyl hapten (DNP)-primed F(1) B cells in response to DNP-GLT. Unlike the indiscriminant ability of F(1) helper T cells for conventional antigens (i.e. not Ir gene-controlled), which can help B cells of either parental type (as well as F(1)) equally well, GLT-primed F(1) T cells can only provide help under normal circumstances for B lymphocytes of responder parent origin; they are unable to communicate effectively with nonresponder parental B cells (1, and the present studies). The present studies reveal, however, that the induction of a parental cell-induced allogeneic effect during priming of F(1) mice to GLT actually dictates the direction of cooperating preference that will be displayed by such F(1) helper cells for B cells of one parental type or the other. Thus, F(1) T cells, primed to GLT under the influence of an allogeneic effect induced by parental BALB/c cells, develop into effective helpers for nonresponder A/J B cells, but fail to develop effective helpers for responder BALB/c B cells, and vice-versa. In contrast, F(1) T cells, primed to GLT under the influence of an allogeneic effect induced by either parental type, display significantly enhanced levels of helper activity for B cells derived from F(1) donors. These results are interpreted to reflect the existence of two interdependent events provoked by the allogeneic effect: one event augments the differentiation of GLT-specific helper T cells belonging to the subset corresponding to the opposite parental type; this would explain the development of increased helper activity provided to partner B cells of opposite parental type (as well as of F(1) origin). The second event, we postulate, involves the production of responses against the receptors which normally self-recognize native cell interaction determinants; this form of anti-idiotype response is restricted against self- recognizing receptors of the same parental type used for induction of the allogeneic effect, hence explaining diminished helper activity of such F(1) cells for partner B lymphocytes of corresponding parental type.     

Effect of weight loss,with or without exercise,on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial

Introduction

Physical inactivity and overweight are risk factors for postmenopausal breast cancer. The effect of physical activity may be partially mediated by concordant weight loss. We studied the effect on serum sex hormones, which are known to be associated with postmenopausal breast cancer risk, that is attributable to exercise by comparing randomly obtained equivalent weight loss by following a hypocaloric diet only or mainly by exercise.

Methods

Overweight, insufficiently active women were randomised to a diet (N = 97), mainly exercise (N = 98) or control group (N = 48). The goal of both interventions was to achieve 5–6 kg of weight loss by following a calorie-restricted diet or an intensive exercise programme combined with only a small caloric restriction. Primary outcomes after 16 weeks were serum sex hormones and sex hormone-binding globulin (SHBG). Body fat and lean mass were measured by dual-energy X-ray absorptiometry.

Results

Both the diet (−4.9 kg) and mainly exercise (−5.5 kg) groups achieved the target weight loss. Loss of body fat was significantly greater with exercise versus diet (difference −1.4 kg, P < 0.001). In the mainly exercise arm, the reduction in free testosterone was statistically significantly greater than that of the diet arm (treatment effect ratio [TER] 0.92, P = 0.043), and the results were suggestive of a difference for androstenedione (TER 0.90, P = 0.064) and SHBG (TER 1.05, P = 0.070). Compared with the control arm, beneficial effects were seen with both interventions, diet and mainly exercise, respectively, on oestradiol (TER 0.86, P = 0.025; TER 0.83, P = 0.007), free oestradiol (TER 0.80, P = 0.002; TER 0.77, P < 0.001), SHBG (TER 1.14; TER 1.21, both P < 0.001) and free testosterone (TER 0.91, P = 0.069; TER = 0.84, P = 0.001). After adjustment for changes in body fat, intervention effects attenuated or disappeared.

Conclusions

Weight loss with both interventions resulted in favourable effects on serum sex hormones, which have been shown to be associated with a decrease in postmenopausal breast cancer risk. Weight loss induced mainly by exercise additionally resulted in maintenance of lean mass, greater fitness, greater fat loss and a larger effect on (some) sex hormones. The greater fat loss likely explains the observed larger effects on sex hormones.

Trial registration

ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01511276","term_id":"NCT01511276"}}NCT01511276. Registered on 12 January 2012.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-015-0633-9) contains supplementary material, which is available to authorized users.     

Association of breast cancer risk loci with breast cancer survival

The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of evidence suggest that alleles influencing breast cancer risk might also be associated with breast cancer survival. We examined the associations between 35 breast cancer susceptibility loci and the disease over‐all survival (OS) in 10,255 breast cancer patients from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) of which 1,379 died, including 754 of breast cancer. We also conducted a meta‐analysis of almost 35,000 patients and 5,000 deaths, combining results from BPC3 and the Breast Cancer Association Consortium (BCAC) and performed in silico analyses of SNPs with significant associations. In BPC3, the C allele of LSP1‐rs3817198 was significantly associated with improved OS (HR_per‐allele=0.70; 95% CI: 0.58–0.85; p_trend = 2.84 × 10^?4; HR_{heterozygotes} = 0.71; 95% CI: 0.55–0.92; HR_homozygotes = 0.48; 95% CI: 0.31–0.76; p_2DF = 1.45 × 10^?3). In silico, the C allele of LSP1‐rs3817198 was predicted to increase expression of the tumor suppressor cyclin‐dependent kinase inhibitor 1C (CDKN1C). In the meta‐analysis, TNRC9‐rs3803662 was significantly associated with increased death hazard (HR_META =1.09; 95% CI: 1.04–1.15; p_trend = 6.6 × 10^?4; HR_{heterozygotes} = 0.96 95% CI: 0.90–1.03; HR_homozygotes = 1.21; 95% CI: 1.09–1.35; p_2DF=1.25 × 10^?4). In conclusion, we show that there is little overlap between the breast cancer risk single nucleotide polymorphisms (SNPs) identified so far and the SNPs associated with breast cancer prognosis, with the possible exceptions of LSP1‐rs3817198 and TNRC9‐rs3803662.