Transcriptome profiles of stem-like cells from primary breast cancers allow identification of ITGA7 as a predictive marker of chemotherapy response.

BACKGROUND: Breast cancer stem cells (BCSCs) are drivers of therapy-resistance, therefore are responsible for poor survival. Molecular signatures of BCSCs from primary cancers remain undefined. Here, we identify the consistent transcriptome of primary BCSCs shared across breast cancer subtypes, and we examine the clinical relevance of ITGA7, one of the genes differentially expressed in BCSCs. METHODS: Primary BCSCs were assessed using immunohistochemistry and fluorescently labelled using Aldefluor (n = 17). Transcriptomes of fluorescently sorted BCSCs and matched non-stem cancer cells were determined using RNA-seq (n = 6). ITGA7 expression was examined in breast cancers using immunohistochemistry (n = 305), and its functional role was tested using siRNA in breast cancer cells. RESULTS: Proportions of BCSCs varied from 0 to 9.4%. 38 genes were significantly differentially expressed in BCSCs; genes were enriched for functions in vessel morphogenesis, motility, and metabolism. ITGA7 was found to be significantly downregulated in BCSCs, and low expression significantly correlated with reduced survival in patients treated with chemotherapy, and with chemoresistance in breast cancer cells in vitro. CONCLUSIONS: This study is the first to define the molecular profile of BCSCs from a range of primary breast cancers. ITGA7 acts as a predictive marker for chemotherapy response, in accordance with its downregulation in BCSCs.

Correction to: Does C-reactive protein day 1 post-surgery have a predictive role for post-operative complications: a single-centre perspective following published meta-analysis.

The first sentence of the article should read as follows.

Current margin practice and effect on re-excision rates following the publication of the SSO-ASTRO consensus and ABS consensus guidelines: a national prospective study of 2858 women undergoing breast-conserving therapy in the UK and Ireland.

INTRODUCTION: There is variation in margin policy for breast conserving therapy (BCT) in the UK and Ireland. In response to the Society of Surgical Oncology and American Society for Radiation Oncology (SSO-ASTRO) margin consensus ('no ink on tumour' for invasive and 2 mm for ductal carcinoma in situ [DCIS]) and the Association of Breast Surgery (ABS) consensus (1 mm for invasive and DCIS), we report on current margin practice and unit infrastructure in the UK and Ireland and describe how these factors impact on re-excision rates. METHODS: A trainee collaborative-led multicentre prospective study was conducted in the UK and Ireland between 1st February and 31st May 2016. Data were collected on consecutive BCT patients and on local infrastructure and policies. RESULTS: A total of 79 sites participated in the data collection (75% screening units; average 372 cancers annually, range 70-900). For DCIS, 53.2% of units accept 1 mm and 38% accept 2-mm margins. For invasive disease 77.2% accept 1 mm and 13.9% accept 'no ink on tumour'. A total of 2858 patients underwent BCT with a mean re-excision rate of 17.2% across units (range 0-41%). The re-excision rate would be reduced to 15% if all units applied SSO-ASTRO guidelines and to 14.8% if all units followed ABS guidelines. Of those who required re-operation, 65% had disease present at margin. CONCLUSION: There continues to be large variation in margin policy and re-excision rates across units. Altering margin policies to follow either SSO-ASTRO or ABS guidelines would result in a modest reduction in the national re-excision rate. Most re-excisions are for involved margins rather than close margins.

Predictive Value of C-Reactive Protein for Complications Post-Laparoscopic Roux-En-Y Gastric Bypass.

BACKGROUND: Laparoscopic roux-en-Y gastric bypass (LRYGB) has gained increasing popularity as the primary procedure of choice for the management of patients with morbid obesity. Despite the advances, a few patients will still develop complications and predicting these early complications in morbidly obese patients can prove to be difficult. Radiological investigations have limited diagnostic value and have associated side effects and cost. We propose that C-reactive protein (CRP) is a useful predictor for early postoperative complications. This study aims to determine the ability of CRP taken on postoperative day 1 (POD 1) and 2 to predict occurrence of complications within 30 days of surgery. METHODS: This retrospective observational study selected 183 consecutive patients from the York bariatric database between 01 December 2010 and 23 March 2015. EXCLUSIONS: Patients undergoing dual procedures, conversion to open, and if no postoperative CRP measurement was performed. RESULTS: In total, 138 patients satisfied the inclusion criteria during the study period (median age 44 years [20-68], BMI 50.6 kg/m2 [38.3-62.5]). Fifteen (10.8 %) patients had minor complications (CD of 2) and 8 (5.6 %) had major complications (CD 3 or above). A CRP of greater than 127 mg/L on POD 2 was found to predict complications with 93 % sensitivity and 64 % specificity with diagnostic accuracy 0.82 (95 % confidence interval 0.731-0.908). CONCLUSIONS: In our patients, CRP on POD 2 has been shown to be a good predictor of both minor and major complications and can therefore be used to guide clinicians in making decision as to which patients may need further investigation or who can be safely discharged.

Imaging overview of metaplastic carcinomas of the breast: a large study of 71 cases.

OBJECTIVE:: To review the clinical presentation, baseline imaging features, surgical management and final surgical pathology of metaplastic carcinoma of the breast. METHODS:: A total of 71 cases were identified over a 10-year period from two major UK breast cancer institutions. Imaging at diagnosis including mammography, ultrasound, MRI and CT scans and histological diagnosis were reviewed. Follow-up data including local and systemic recurrence were retrieved. RESULTS:: Of the 71 cases, 60 (84.5%) cases presented with a palpable lump. 60 (84.5%) cases showed a mass on mammography, of whom 47 (78.3%) cases were ill defined and 17.0% cases showed calcifications associated with a mass lesion. All 71 cases were seen as a mass on ultrasound. The imaging score was R3 or R4 in 26 cases and R5 in 47 cases. 16 patients underwent MRI with most (93.8%) showing a solid mass with central necrosis. No metastatic disease was seen in the 13 patients who underwent staging CT. Despite having a larger size, 50% of the cases successfully underwent breast conservative surgery. Positive axillary lymph nodes were seen in 11 (15.5%) cases. CONCLUSION:: In this series, metaplastic cancers were palpable in 85% cases, tended to be large at the time of presentation and imaging showed characteristics of malignancy. Only 11 (15.5%) cases had nodal involvement. ADVANCES IN KNOWLEDGE:: Metaplastic carcinomas are often palpable and of large size at the time of presentation. Metaplastic carcinomas raise the concern for malignancy on mammography and ultrasound, warranting further biopsy. Metaplastic carcinomas tend to be grade 3 and triple receptor negative.

Faecal calprotectin in patients with suspected colorectal cancer: a diagnostic accuracy study.

BACKGROUND: NICE guidance exists for the use of faecal calprotectin (FC) when irritable bowel syndrome or inflammatory bowel disease are suspected. Often, however, colorectal cancer is considered within the differential. Should FC have a high diagnostic accuracy for colorectal cancer, it may be applicable as a primary care screening test for all patients with lower gastrointestinal symptoms. AIM: To determine the negative and positive predictive value (NPV/PPV) of FC in patients referred from primary care with suspected colorectal cancer. DESIGN AND SETTING: A diagnostic accuracy study conducted at a single secondary care site METHOD: Consenting patients referred with suspected colorectal cancer within the '2-week wait' pathway provided a stool sample for FC prior to investigation. FC levels were reconciled with end diagnoses: cancer, adenomatous polyps ≥10 mm, and all enteric organic disease. RESULTS: A total of 654 patients completed the evaluation; median age 69 years, female 56%. The NPV for colorectal cancer was 98.6% and 97.2% when including polyps ≥10 mm. The PPV for all organic enteric disease was 32.7%. The diagnostic yield for cancer based on clinical suspicion was 6.3%. By altering the FC cut-off to fix the NPV at 97.0%, the PPV for cancer increased from 8.7% to 13.3%. CONCLUSION: FC has a high NPV for colorectal cancer and significant polyps in patients with suspected cancer. In total, 27.8% of patients had a normal FC and could safely have been spared a '2-week wait' referral. The addition of FC testing into the current symptom-based assessment has the potential to increase colorectal cancer detection rate yet be clinically and cost effective.

Postoperative pulmonary complications following major elective abdominal surgery: a cohort study.

BACKGROUND: Postoperative pulmonary complications (PPC) are an under-reported but major cause of perioperative morbidity and mortality. The aim of this prospective, contemporary, multicentre cohort study of unselected patients undergoing major elective abdominal surgery was to determine the incidence and effects of PPC. METHODS: Data on all major elective abdominal operations performed over a 2-week period in December 2014 were collected in six hospitals. The primary outcome measure of PPC at 7 days was used. Univariate and multivariate analyses were performed to investigate how different factors were associated with PPC and the effects of such complications. RESULTS: Two hundred sixty-eight major elective abdominal operations were performed, and the internal validation showed that the data set was 99 % accurate. Thirty-two (11.9 %) PPC were reported at 7 days. PPC was more common in patients with a history of chronic obstructive pulmonary disease compared to those with no history (26.7 vs. 10.2 %, p < 0.001). PPC was not associated with other patient factors (e.g. age, gender, body mass index or other comorbidities), type/method of operation or postoperative analgesia. The risk of PPC appeared to increase with every additional minute of operating time independent of other factors (odds ratio 1.01 (95 % confidence intervals 1.00-1.02), p = 0.007). PPC significantly increase the length of hospital stay (10 vs. 3 days). Attendance to the emergency department within 30 days (27.3 vs. 10.6 %), 30-day readmission (21.7 vs. 9.9 %) and 30-day mortality (12.5 vs. 0.0 %) was higher in those with PPC. CONCLUSIONS: PPC are common and have profound effects on outcomes. Strategies need to be considered to reduce PPC.

PSMD9 expression predicts radiotherapy response in breast cancer.

BACKGROUND: More than 50% of cancer patients are recommended to receive radiotherapy. Recommendations are based mainly on clinical and pathological factors and not intrinsic tumour radio-sensitivity. Use of radiotherapy according to predictive markers would potentially reduce costly over-treatment, and improve the treatment risk-benefit ratio and cancer outcomes. Tumour expression of the 26S proteasome has been reported to predict radiotherapy response: low expression was associated with higher rates of local recurrence after radiotherapy, suggesting that low proteasome expression and activity was associated with radio-resistance. However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers. Our aim was to further analyse the relevance of 26S proteasome expression, focussing specifically on the PSMD9 subunit, in the largest clinical cohort to date, and to investigate the functional role of PSMD9 in radio-sensitivity in breast cancer cell lines. METHODS: We examined expression of PSMD9 using immunohistochemistry in a cohort of 157 breast cancer patients, including 32 cases (20.4%) that subsequently developed local recurrences. The value of expression as a prognostic or radiotherapy predictive marker was tested using Kaplan-Meier and Cox regression analyses. PSMD9 function was examined in breast cancer cell lines MCF7 and MDA-MB-231 using siRNA knock-downs and colony forming assays after irradiation. RESULTS: Low tumour PSMD9 expression was significantly associated with a reduced incidence of local recurrence in patients receiving adjuvant radiotherapy (univariate log rank p = 0.02; multivariate regression p = 0.009), but not in those treated without radiotherapy, suggesting that low PSMD9 expression was associated with relative tumour radio-sensitivity. In support of this, reduction of PSMD9 expression using siRNA in breast cancer cell lines in vitro sensitized cells to radiotherapy. CONCLUSIONS: We conclude that PSMD9 expression may predict radiotherapy benefit, with low expression indicative of relative radio-sensitivity, the opposite of previous reports relating to 26S proteasome expression. Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.

Intussusception in the elderly.

We present the case of an 82-year-old Caucasian lady with a 16-day history of colicky lower abdominal pain and reduced appetite. When presenting to hospital she was haemodynamically stable with no fever. Examination revealed a soft but tender abdomen with normal bowel sounds. No masses or hernias were present. Per-rectal examination revealed an empty rectum. Investigations showed raised inflammatory markers, white cell count 11.9 and C reactive protein 24, in addition to which she had dilated loops of small and large bowel on the abdominal radiograph. The patient underwent an emergency laparotomy where a mass in the descending colon was found to be intussuscepting into the proximal sigmoid colon for which a Hartmanns procedure was performed. Histopathology confirmed a Dukes B T3 N0 Mx adenocarcinoma.

Perioperative reductions in circulating lymphocyte levels predict wound complications after excisional breast cancer surgery.

OBJECTIVE: Postoperative wound complications after excisional surgery for primary breast cancer can result in patients requiring additional treatments and delay adjuvant therapy and are associated with worse prognoses.We investigated factors that might predispose patients to wound complications. BACKGROUND: A number of patient characteristics have been associated with wound complications, but there is currently no quantitative measure of the risk of their occurrence. Our hypothesis was that wound complications are related, in part, to the immune status of patients. METHODS: We recruited patients undergoing surgery for primary breast cancer and determined their circulating levels of various immune cells shortly before and after surgery as a measure of immune status. RESULTS: One hundred seventeen patients were recruited; 16 (13.7%) developed wound complications. The following patient and tumor characteristics were associated with higher wound complication rates: diabetes (P = 0.02); larger tumors (T2/3 vs T1; P = 0.02); metastatic axillary nodes (P = 0.006). With respect to immune status, no significant differences in preoperative levels of circulating immune cells were detected between patients who developed wound complications and those who did not. However, patients who developed complications showed greater reductions in lymphocyte levels 4 hours postoperatively than those who did not (P <0.001). Multivariate analyses demonstrated that falls in lymphocyte levels of greater than 20% or 50% 4 hours postoperatively acted as a significant and independent predictor of wound complications (P < 0.005 and P < 0.0001,respectively). CONCLUSIONS: Perioperative changes in lymphocyte levels could provide a practical predictive marker for wound complications on which selective antibiotic prophylaxis could be based.