SIRIUS, Ultra-Scintillating Upconversion Breast Implant for Remote Orthotopic Photodynamic Therapy.

Present day strategies for delivery of wireless photodynamic therapy (PDT) to deep-seated targets are limited by the inadequacy of irradiance and insufficient therapeutic depth. Here we report the design and preclinical validation of a flexible wireless upconversion nanoparticle (UCNP) implant (SIRIUS) that is capable of large field, high intensity illumination for PDT of deep-seated tumors. The implant achieves this by incorporating submicrometer core-shell-shell NaYF4 UCNPs into its design, which significantly enhances upconversion efficiency and mitigates light loss from surface quenching. We demonstrate the efficacy of SIRIUS UCNP implant mediated PDT in preclinical breast cancer disease models. In our in vitro experiments, SIRIUS directed 5-Aminolevulinic Acid (5-ALA) based wireless PDT leads to significant reactive oxygen species (ROS) generation and tumor apoptosis in hormonal receptor+/HER2+ (MCF7) and triple-negative (MDA-MB-231) breast cancer cell lines. In our in vivo rodent model, SIRIUS-driven PDT is shown to be significant in regressing tumors when applied to orthotopically inoculated breast tumors. Following successful preclinical validation, we also describe a clinical prototype of UCNP breast implant with potential dual cosmetic and onco-therapeutic functions. SIRIUS is an upconversion breast implant for wireless PDT that fulfils all the design prerequisites necessary for seamless clinical translation.

Photoacoustic Tomography Appearance of Fat Necrosis: A First-in-Human Demonstration of Biochemical Signatures along with Histological Correlation.

A 50-year-old woman with no past medical history presented with a left anterior chest wall mass that was clinically soft, mobile, and non-tender. A targeted ultrasound (US) showed findings suggestive of a lipoma. However, focal "mass-like" nodules seen within the inferior portion suggested malignant transformation of a lipomatous lesion called for cross sectional imaging, such as MRI or invasive biopsy or excision for histological confirmation. A T1-weighted image demonstrated a large lipoma that has a central fat-containing region surrounded by an irregular hypointense rim in the inferior portion, confirming the benignity of the lipoma. An ultrasound-guided photoacoustic imaging (PA) of the excised specimen to derive the biochemical distribution demonstrated the "mass-like" hypoechoic regions on US as fat-containing, suggestive of benignity of lesion, rather than fat-replacing suggestive of malignancy. The case showed the potential of PA as an adjunct to US in improving the diagnostic confidence in lesion characterization.

Impact of contrast-enhanced mammography in surgical management of breast cancers for women with dense breasts: a dual-center, multi-disciplinary study in Asia.

OBJECTIVE: To evaluate the impact of pre-operative contrast-enhanced mammography (CEM) in breast cancer patients with dense breasts. METHODS: We conducted a retrospective review of 232 histologically proven breast cancers in 200 women (mean age: 53.4 years ± 10.2) who underwent pre-surgical CEM imaging across two Asian institutions (Singapore and Taiwan). Majority (95.5%) of patients had dense breast tissue (BI-RADS category C or D). Surgical decision was recorded in a simulated blinded multi-disciplinary team setting on two separate scenarios: (i) pre-CEM setting with standard imaging, and clinical and histopathological results; and (ii) post-CEM setting with new imaging and corresponding histological findings from CEM. Alterations in surgical plan (if any) because of CEM imaging were recorded. Predictors CEM of patients who benefitted from surgical plan alterations were evaluated using logistic regression. RESULTS: CEM resulted in altered surgical plans in 36 (18%) of 200 patients in this study. CEM discovered clinically significant larger tumor size or extent in 24 (12%) patients and additional tumors in 12 (6%) patients. CEM also detected additional benign/false-positive lesions in 13 (6.5%) of the 200 patients. Significant predictors of patients who benefitted from surgical alterations found on multivariate analysis were pre-CEM surgical decision for upfront breast conservation (OR, 7.7; 95% CI, 1.9-32.1; p = 0.005), architectural distortion on mammograms (OR, 7.6; 95% CI, 1.3-42.9; p = .022), and tumor size of ≥ 1.5 cm (OR, 1.5; 95% CI, 1.0-2.2; p = .034). CONCLUSION: CEM is an effective imaging technique for pre-surgical planning for Asian breast cancer patients with dense breasts. KEY POINTS: • CEM significantly altered surgical plans in 18% (nearly 1 in 5) of this Asian study cohort with dense breasts. • Significant patient and imaging predictors for surgical plan alteration include (i) patients considered for upfront breast-conserving surgery; (ii) architectural distortion lesions; and (iii) tumor size of ≥ 1.5 cm. • Additional false-positive/benign lesions detected through CEM were uncommon, affecting only 6.5% of the study cohort.

Biochemical "decoding" of breast ultrasound images with optoacoustic tomography fusion: First-in-human display of lipid and collagen signals on breast ultrasound.

To date, studies which utilized ultrasound (US) and optoacoustic tomography (OT) fusion (US-OT) in biochemical differentiation of malignant and benign breast conditions have relied on limited biochemical data such as oxyhaemoglobin (OH) and deoxyhaemoglobin (DH) only. There has been no data of the largest biochemical components of breast fibroglandular tissue: lipid and collagen. Here, the authors believe the ability to image collagen and lipids within the breast tissue could serve as an important milestone in breast US-OT imaging with many potential downstream clinical applications. Hence, we would like to present the first-in-human US-OT demonstration of lipid and collagen differentiation in an excised breast tissue from a 38-year-old female.

Association between Breast Cancer Polygenic Risk Score and Chemotherapy-Induced Febrile Neutropenia: Null Results.

BACKGROUND: The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients. METHODS: This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t-tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls. RESULTS: PRS distributions were not significantly different in any of the comparisons. Higher PRSoverall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79-1.06]; FNc: 0.87 [0.73-1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRSER-pos) and ER-negative weighted PRS (PRSER-neg). CONCLUSION: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.

Overlap of high-risk individuals predicted by family history, and genetic and non-genetic breast cancer risk prediction models: implications for risk stratification.

BACKGROUND: Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear. METHODS: In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%. RESULTS: Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history. CONCLUSIONS: Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk.

Factors Attracting or Deterring Female Medical Students in Asia From Pursuing a Surgical Career, and the Impact of Surgical Clerkship, Mentorship, and Role Models: A Multicultural Asian Perspective From a National Prospective Cohort Study.

BACKGROUND: Female surgeons are highly underrepresented in Asian countries, where prescriptive gender norms are widespread and more deeply embedded in societies. MATERIALS AND METHODS: A nationwide structured questionnaire was completed by 1741 Singaporean third- and fifth-year medical students after the completion of an 8-week general surgery rotation, during 2015-2017. Results were analyzed using mixed-effects hierarchical models which took into account clustering of survey responses under the teaching hospitals which students were posted to and medical students' year of study. RESULTS: Female medical students had a poorer perception of general surgery than male students (3.22 ± 0.91 versus 3.41 ± 0.89; P < 0.0001) before the clerkship. However, the clerkship improved female students' opinion to a greater extent than male students (+0.84 ± 1.06 versus +0.59 ± 1.03; P < 0.0001), resulting in female and male students having comparable attitudes toward surgery after the clerkship (4.06 ± 0.79 versus 4.00 ± 0.87; P = 0.2435). A total of 40.4% of female students responded that they were inspired to pursue a surgical career after the clerkship, and we identified 13 pedagogical traits of faculty and resident mentors which were associated with female students' career aspirations. Female students were more likely to consider intellectual challenges arising from cases (ratio: 1.045 [95% confidence interval 1.004-1.088, P = 0.0292]) and the presence of role models (ratio: 1.068 [95% confidence interval: 1.020-1.118, P = 0.0048]) as "pull" factors compared with their male contemporaries, but were deterred from a surgical career to a greater extent by eight "push" factors. CONCLUSIONS: A surgical clerkship itself could be regarded as an effective intervention for improving female medical students' enthusiasm for surgery, which may help to address the "pipeline problem" of few female students applying for surgical training after medical school. A greater emphasis on "pull factors" and pedagogical qualities of mentors could be used to improve the clerkship experience, to attract more female students to surgery.

Push and pull factors, and the role of residents in nurturing medical students' interest in surgery as a career option in a multicultural Asian context: Results of a prospective national cohort study.

BACKGROUND: Studies in Caucasian populations suggest that interest among medical students in pursuing a surgical career is dwindling. We sought to investigate these trends and to evaluate the impact of resident teaching in a multiethnic Asian population. STUDY DESIGN: Between 2015 and 2017, 1780 Singaporean third- and fifth-year medical students completed a structured anonymized questionnaire following the completion of an 8-week general surgery rotation. Medical students' impressions of their faculty and resident mentors were analyzed using hierarchical multilevel mixed-effects models. RESULTS: Respondents' opinions of general surgery improved from 3.31 ± 0.91 points to 4.03 ± 0.83 points on a 5-point Likert scale (P < 0.0001). Medical students were more likely to regard their interaction with residents as a "pull" factor compared to their interaction with faculty members (74.7% vs 65.6%; P < 0.0001). Our analyses revealed 9 statistically-significant "pull" factors and 5 "push" factors which attract or deter Asian medical students from a career in surgery. Comparing the pedagogical qualities of resident and faculty mentors, we found that residents surpassed faculty mentors in 9 domains, had comparable appraisal scores on 3 domains, and fared worse than faculty on 8 domains. Importantly, residents fared better at promoting interest in a surgical career (P = 0.0006) and influencing the career aspirations of medical students (P < 0.0001) compared with faculty members. CONCLUSIONS: To our knowledge, this is the largest study from a Southeast Asian country providing representative sample numbers. With this knowledge of pull and push factors, the surgical clerkship can be improved by emphasizing pull factors and preparing students to cope with the push factors. Finally, our findings suggest that roping in residents as mentors to medical students may improve the pipeline of students interested in pursuing surgery after medical school.

Ultrasound Guided Optoacoustic Tomography in Assessment of Tumor Margins for Lumpectomies.

PURPOSE: To determine the accuracy of a handheld ultrasound-guided optoacoustic tomography (US-OT) probe developed for human deep-tissue imaging in ex vivo assessment of tumor margins postlumpectomy. METHODS: A custom-built two-dimensional (2D) US-OT-handheld probe was used to scan 15 lumpectomy breast specimens. Optoacoustic signals acquired at multiple wavelengths between 700 and 1100 nm were reconstructed using model linear algorithm, followed by spectral unmixing for lipid and deoxyhemoglobin (Hb). Distribution maps of lipid and Hb on the anterior, posterior, superior, inferior, medial, and lateral margins of the specimens were inspected for margin involvement, and results were correlated with histopathologic findings. The agreement in tumor margin assessment between US-OT and histopathology was determined using the Bland-Altman plot. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of margin assessment using US-OT were calculated. RESULTS: Ninety margins (6 × 15 specimens) were assessed. The US-OT probe resolved blood vessels and lipid up to a depth of 6 mm. Negative and positive margins were discriminated by marked differences in the distribution patterns of lipid and Hb. US-OT assessments were concordant with histopathologic findings in 87 of 89 margins assessed (one margin was uninterpretable and excluded), with diagnostic accuracy of 97.9% (kappa = 0.79). The sensitivity, specificity, PPV, and NPV were 100% (4/4), 97.6% (83/85), 66.7% (4/6), and 100% (83/83), respectively. CONCLUSION: US-OT was capable of providing distribution maps of lipid and Hb in lumpectomy specimens that predicted tumor margins with high sensitivity and specificity, making it a potential tool for intraoperative tumor margin assessment.

Computed tomography of the thorax for gastric cancer staging: Is it necessary?

BACKGROUND: The utility of computed tomography scans of the thorax, abdomen, and pelvis for gastric cancer staging has been recommended in many countries. However, the validity of the use of computed tomography thorax in gastric cancer staging has not been challenged. METHODS: A retrospective review was conducted on our gastric cancer registry from 1998 till 2012 in the National University Hospital, Singapore. We performed computed tomography thorax only in selected cases. We defined isolated lung metastasis as the presence of suspicious findings on computed tomography thorax in the absence of metastasis elsewhere. RESULTS: A total of 808 gastric cancer cases were reviewed. The mean age of the patients was 66 years (standard deviation 13.53), and 67% were male. In all, 238 patients (30%) had metastatic disease at presentation, and 1 (0.42%) had isolated lung metastasis. The most common site of metastasis was intra-abdominal (73.8%). Among the patients who underwent surgery, the overall distant recurrence rate was 30%, of which only 83 (30%) patients had lung metastasis and all had concurrent metastasis in an intra-abdominal site. CONCLUSION: The rarity of isolated lung metastasis in gastric cancer suggests the limited value of computed tomography thorax as a routine staging tool for gastric cancers.

Routine histological sampling of doughnuts post oncologic anterior resection is not necessary.

BACKGROUND: A stapled end-to-end colo-rectal anastomosis is increasingly adopted following a proctectomy for various colorectal conditions. The ensuing doughnuts of colonic tissue created from the stapling device have been routinely sent for histological analysis. However, its efficacy remains debatable. This study aims to determine if there is a role in sending colonic doughnuts for histological examination following a stapled end-to-end colo-rectal anastomosis following proctectomy for colorectal cancers. METHODS: A retrospective review of all histological reports of the doughnuts from patients who underwent a proctectomy followed by a stapled end-to-end colo-rectal anastomosis for colorectal cancer in the National University Hospital, Singapore, from 2004-2010 was performed. RESULTS: A total of 336 patients who underwent a stapled end-to-end anastomosis following proctectomy for colorectal cancer from 2004-2010 had available histological reports. The specimen margins and colonic doughnuts were all negative for malignancy. Clinical decisions were not altered based on doughnut histology results. A total cost of USD$61,017.60 was incurred for the histological processing of these doughnuts. CONCLUSION: There appears to be no additional oncological or cost benefits in sending doughnuts after a stapled end-to-end colo-rectal anastomosis following proctectomy for colorectal cancers except in selected clinico-pathological conditions whereby the risk of a positive margin is deemed higher.

Is continuation of antiplatelets until coronary artery bypass safe in Asians?

BACKGROUND: Controversies have arisen about the risks of discontinuing antiplatelets prior to coronary artery bypass grafting. METHODS: We retrospectively studied the effects of different strategies of antiplatelet discontinuation prior to coronary artery bypass on perioperative bleeding and major adverse cardiovascular events in Asian patients in a single center in Singapore. RESULTS: 402 patients were divided into 4 groups: group A had no antiplatelets before surgery; antiplatelets were stopped for 5-7 days in group B; 2-4 days in group C; and 0-1 day in group D. Compared to group B, group D had longer intensive care unit stays and more intraoperative transfusions of blood (p = 0.006) and blood products (p < 0.05). The 1-year major adverse cardiovascular event rate was higher in groups A and D (p = 0.027). Stopping antiplatelets within 24 h of surgery was one of multiple independent predictors of intraoperative transfusion but not the 1-year major adverse cardiovascular event rate. Patients on aspirin alone had less intraoperative transfusion of platelets and postoperative minor bleeding than those on combined therapy. CONCLUSION: Continuation of antiplatelets until 2 days before coronary artery bypass in Asian patients in our institution is unlikely to increase the risks of bleeding and perioperative transfusion. Taking antiplatelets within 24 h of surgery seems to be associated with a higher rate of 1-year major adverse cardiovascular events and bleeding, and an increased risk of blood product transfusion. Thirty-day and 1-year major adverse cardiovascular event rates were higher in patients without antiplatelet treatment.