Research and applications: Machine learning for predicting the response of breast cancer to neoadjuvant chemotherapy

Objective

To employ machine learning methods to predict the eventual therapeutic response of breast cancer patients after a single cycle of neoadjuvant chemotherapy (NAC).

Materials and methods

Quantitative dynamic contrast-enhanced MRI and diffusion-weighted MRI data were acquired on 28 patients before and after one cycle of NAC. A total of 118 semiquantitative and quantitative parameters were derived from these data and combined with 11 clinical variables. We used Bayesian logistic regression in combination with feature selection using a machine learning framework for predictive model building.

Results

The best predictive models using feature selection obtained an area under the curve of 0.86 and an accuracy of 0.86, with a sensitivity of 0.88 and a specificity of 0.82.

Discussion

With the numerous options for NAC available, development of a method to predict response early in the course of therapy is needed. Unfortunately, by the time most patients are found not to be responding, their disease may no longer be surgically resectable, and this situation could be avoided by the development of techniques to assess response earlier in the treatment regimen. The method outlined here is one possible solution to this important clinical problem.

Conclusions

Predictive modeling approaches based on machine learning using readily available clinical and quantitative MRI data show promise in distinguishing breast cancer responders from non-responders after the first cycle of NAC.     

Referral patterns, clinical examination and the two-week-rule for breast cancer: a cohort study

Introduction

Current NHS guidelines require patients with suspected breast cancer to be seen urgently at a specialist breast clinic. The aim of this study was to assess referral patterns and clinical findings of patients referred to a specialist breast clinic.

Materials and Methods

A prospective database was maintained for consecutive patients referred. Symptoms and clinical findings in primary and secondary care were recorded. Correlation with final diagnoses was made. Tertiary referral patients were excluded.

Results

1098 patients attended a specialist breast clinic over six months. 588 (54%) were referred as urgent, 285 (26%) routinely and 225 (20%) were unspecified. 492 (45%) patients were referred with the incorrect referral priority. 42 patients were unexamined in primary care. Examination findings in primary and secondary care correlated in only 487 (46%) patients. Examination in primary care when compared with secondary care was highly sensitive for detecting breast lumps, but specificity was low. 86 patients (8%) were diagnosed with breast cancer, 72 (84%) were referred urgently, 6 (7%) routinely and 8 (9%) as unspecified priority. Regardless of the clinical expertise of the referrer, sensitivity and specificity of the two-week guidelines for cancer are low.

Conclusions

Examination findings in primary and secondary care correlate in only 46% of referrals. Additionally, 55% of referrals were of the correct priority. The two-week rule guidelines have poor sensitivity and specificity for cancer. The safest and fairest policy would be to abandon the concept of urgent referral criteria and see all patients in a timely fashion. Alternatively, simplifying the referral criteria would improve sensitivity and specificity for cancer without leading to increased waiting times.     

Environmental risk factors for oesophageal cancer in Malawi: A case-control study

Aim

There is a high burden of oesophageal cancer in Malawi with dismal outcomes. It is not known whether environmental factors are associated with oesophageal cancer. Without knowing this critical information, prevention interventions are not possible. The purpose of this analysis was to explore environmental factors associated with oesophageal cancer in the Malawian context.

Methods

A hospital-based case-control study of the association between environmental risk factors and oesophageal cancer was conducted at Kamuzu Central Hospital in Lilongwe, Malawi and Queen Elizabeth Central Hospital in Blantyre, Malawi. Ninety-six persons with squamous cell carcinoma and 180 controls were enrolled and analyzed. These two groups were compared for a range of environmental risk factors, using logistic regression models. Unadjusted and adjusted odds ratios and 95% confidence intervals (CI) were calculated.

Results

Firewood cooking, cigarette smoking, and use of white maize flour all had strong associations with squamous cell carcinoma of the oesophagus, with adjusted odds ratios of 12.6 (95% CI: 4.2–37.7), 5.4 (95% CI: 2.0–15.2) and 6.6 (95% CI: 2.3–19.3), respectively.

Conclusions

Several modifiable risk factors were found to be strongly associated with squamous cell carcinoma. Research is needed to confirm these associations and then determine how to intervene on these modifiable risk factors in the Malawian context.     

The prevalence of BRCA1/2 mutations of triple-negative breast cancer patients in Xinjiang multiple ethnic region of China

Background

The screening of BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer, early-onset breast cancer and bilateral breast cancer patients. There is still some controversy about whether this screening should be done in triple-negative breast cancers. Therefore, we evaluated the BRCA mutation prevalence in patients with triple-negative breast cancer in a multi-ethnic region of China.

Methods

A total 96 women who were diagnosed with triple-negative breast cancer in the Xinjiang region of China were enrolled in this study. BRCA1 and BRCA2 screening was performed by polymerase chain reaction-denaturing high-performance liquid chromatography (PCR-DHPLC) sequencing analysis. All mutations were confirmed with direct sequencing.

Results

The prevalence of a BRCA1/2 germline mutation was about 25% (24/96) in the Xinjiang region of China. Among 35 selected cases with a family history and/or bilateral breast cancers, the BRCA1/2 mutation prevalence was 25.7% (9/35). Of the remaining 61 patients with unselected triple-negative breast cancer, the BRCA1/2 mutation prevalence was 24.6% (15/61), and all 15 individuals with these mutations were premenopausal patients.

Conclusions

These results suggest that premenopausal women with triple-negative breast cancer may be candidates for genetic testing for BRCA1/2 in the Xinjiang region of China, even in the absence of a family history or bilateral breast cancer.     

Evaluation of surgical outcomes following oncoplastic breast surgery in early breast cancer and comparison with conventional breast conservation surgery

Background

The aim of this study was to determine whether oncoplastic breast surgery (OBS) ensures better tumour resection than conventional breast conservation surgery (BCS).

Methods

A prospective comparative study, conducted over a 3-year period, enrolled patients with early breast cancer who underwent OBS. The total volume of glandular resection, tumour volume resection and width of the margins obtained were noted. The incidence of complications, requirement of revision surgery and locoregional recurrence during follow-up period were also noted. The data were compared with matched controls who had undergone convention BCS in the past.

Results

Thirty-three patients underwent oncoplastic surgery and the data was compared with 46 patients of conventional breast conservation. The mean volume of specimen was higher in the oncoplastic group (173.5 cm³ vs 101.4 cm³, p = 0.03) though the tumour volume excised was similar (43.2 cm³ vs 36.4 cm³, p = 0.14). The mean margin widths were larger in the oncoplastic group (14 mm vs 6 mm, p = 0.01). There were more instances of close and positive margins seen in conventional BCS groups. The incidence of complication rate was similar. Median follow-up 18 months for oncoplasty group showed no cases of locoregional recurrence while in median follow-up of 38 months for conventional BCS group, six cases of locoregional relapse were noted.

Conclusions

Oncoplastic surgery results in excision of larger volume of breast tissue and correspondingly obtain wider surgical margins as compared to conventional BCS. Longer follow-up is required to determine if wider resection translates into better locoregional control.     

Research and applications: Semantic analysis of SNOMED CT for a post-coordinated database of histopathology findings

Objective

This research investigated the use of SNOMED CT to represent diagnostic tissue morphologies and notable tissue architectures typically found within a pathologist''s microscopic examination report to identify gaps in expressivity of SNOMED CT for use in anatomic pathology.

Methods

24 breast biopsy cases were reviewed by two board certified surgical pathologists who independently described the diagnostically important tissue architectures and diagnostic morphologies observed by microscopic examination. In addition, diagnostic comments and details were extracted from the original diagnostic pathology report. 95 unique clinical statements were extracted from 13 malignant and 11 benign breast needle biopsy cases.

Results

75% of the inventoried diagnostic terms and statements could be represented by valid SNOMED CT expressions. The expressions included one pre-coordinated expression and 73 post-coordinated expressions. No valid SNOMED CT expressions could be identified or developed to unambiguously assert the meaning of 21 statements (ie, 25% of inventoried clinical statements). Evaluation of the findings indicated that SNOMED CT lacked sufficient definitional expressions or the SNOMED CT concept model prohibited use of certain defined concepts needed to describe the numerous, diagnostically important tissue architectures and morphologic changes found within a surgical pathology microscopic examination.

Conclusions

Because information gathered during microscopic histopathology examination provides the basis of pathology diagnoses, additional concept definitions for tissue morphometries and modifications to the SNOMED CT concept model are needed and suggested to represent detailed histopathologic findings in computable fashion for purposes of patient information exchange and research.

Trial registration number

UNMC Institutional Review Board ID# 342-11-EP.     

Neoadjuvant chemotherapy in Albinos with locally advanced skin cancer at a Blantyre Hospital: - Case Series

Albinism in Africa remains a public health concern with increasing numbers of advanced skin cancer in this population at presentation. There are challenges with availability of Radiotherapy (RT) units in Africa which is an important modality for controlling loco-regional disease alone or in combination with surgery. Proposed chemotherapy regimens have not been well validated through Randomized Controlled Trials thus posing difficulties for standard of care for units that do not have access to functional RT facilities. Malawi is one such country without radiotherapy.

Case summary

Seven patients with locally advanced skin cancer were seen in the adult oncology unit at Queen Elizabeth Central Hospital in Blantyre (QECH), Malawi between 2010 and 2013. QECH is one of the teaching hospitals in the country. All were subjected to neo-adjuvant chemotherapy. The primary treatment aim was cyto-reduction followed by surgery whilst the secondary outcome was general symptom control. Three patients achieved complete responses of which two underwent resection and a pectoralis major myocutaneous flap. One had a near complete response and three showed partial responses.

Conclusion

Neo-adjuvant chemotherapy may be a possible.     

Systematic review: epidemiology of oesophageal cancer in Sub-Saharan Africa

Background

Currently, oesophageal cancer is not a public health priority disease in Sub-Saharan Africa.

Aim

Analysis of published scientific studies regarding oesophageal cancer in Sub-Saharan Africa was done to ascertain the incidence, prevalence and geographical distribution of the disease in the region.

Methods

A pub med literature search was conducted for articles ranging from 1950 to 2009 database involving the following key words: oesophageal carcinoma, incidence, prevalence and sub-Saharan Africa.

Results

54 articles were retrieved, of which 16 were analyzed. Differences in the study methodologies used made the comparison amongst studies difficult. Overall, however, studies show that oesophageal cancer is on the increase in the region with its epicenter in the eastern and southern Africa. Incidence of the disease is higher in males than females and is prominent among 45–64 years age group in both sexes. Squamous cell carcinoma is a cell type more common than adenocarcinoma.

Conclusion

Oesophageal cancer is on the increase in the Sub-Saharan African Region with uneven geographical distribution. Therefore, countries in the region are encouraged together with global health organizations to include oesophageal cancer amongst diseases of public health importance for effective prevention, early diagnosis and effective treatment.     

High serum HTATIP2/TIP30 level in serous ovarian cancer as prognostic or diagnostic marker

Background

Human HIV-1 TAT interactive protein 2 (HTATIP2/TIP30) is an evolutionarily conserved gene that is expressed ubiquitously in human tissues and some tumor tissues. This protein has been found to be associated with some gynecological cancers; as such, this study aimed to investigate blood HTATIP2/TIP30 levels in patients with ovarian cancer.

Methods

Twenty-three women with ovarian cancer and 18 patients with various non-cancerous gynecological complaints (for example, dysfunctional uterine bleeding, fibroids, and urinary incontinence) were included in the study. The pathological diagnosis of ovarian cancer was adenocarcinoma. HTATIP2/TIP30 concentration in the patients’ blood samples was determined using ELISA kits.

Results

The HTATIP2/TIP30 level was significantly higher in the cancer group than in the control group (1.84 ± 0.82 versus 0.57 ± 0.13 ng/ml, mean ± SD).

Conclusions

We demonstrated the potential role of HTATIP2/TIP30 in ovarian cancer for the first time, thereby enlightening future studies targeting HTATIP2/TIP30 in ovarian cancer treatment, diagnosis, and prevention.     

Infection of Schistosomiasis japanicum is likely to enhance proliferation and migration of human breast cancer cells: mechanism of action of differential expression of MMP2 and MMP9

Objective

To study whether the infection of Schistosomiasis japanicum (S. japanicum) is related to enhanced proliferation and migration of cancer cells, and the molecular mechanism pertains to cancer cell metastasis in human host.

Methods

The gene of S. japanicum glutathione transferase (sjGST) cloned from S. japanicum was expressed, purified and applied in a series of assays to explore the effect of sjGST on proliferation and migration of MDA-MB-435S, and the expression of MMP2 and MMP9. Immunofluorescence assay for the binding of sjGST to MDA-MB-435S was also carried out.

Results

Results showed that sjGST enhanced proliferation and migration in human breast cancer cell MDA-MB-435S signifycantly at 50-200 nM, but did not enhance them in human lung cancer cell A549. Immunofluorescence assay for the binding of sjGST to MDA-MB-435S and A549 showed that GST was readily bound to the breast cancer cells, but showed almost no binding to human lung cancer cells. The assays for gelatinase activity showed that both MMP2 and MMP9 activities were increased significantly in the presence of sjGST (50-200 nM) in MDA-MB-435S, but they were not significant in A549.

Conclusions

Our current results show strongly that S. japanicum GST binds to MDA-MB-435S probably via its receptor, and enhances proliferation and migration of the cancer cells by up-regulatory expression of MMP2 and MMP9.     

Distinct outcomes in patients with different molecular subtypes of inflammatory breast cancer

Objectives:

To determine the outcome of patients with luminal A, luminal B, human epidermal growth factor receptor-2 (HER-2) positive, and triple negative molecular subtypes of inflammatory breast cancer (IBC) using a retrospective analysis.

Methods:

This study was conducted between February 2004 and February 2010 in 3 different hospitals in China. The clinical outcomes, pathological features, and treatment strategies were analyzed in 67 cases of IBC without distant metastases. A chi-square test and one-way ANOVA were used to assess outcomes between different subtypes. Overall survival (OS) was analyzed using the Kaplan-Meier method and multivariate analysis was conducted using the Cox regression model.

Results:

The 2-year OS rate was 55% for the entire cohort. Median OS time among patients with luminal A was 35 months, luminal B was 30 months, HER-2 positive was 24 months, and triple negative subtypes was 20 months, and they were significantly different from each other (p=0.001). Using multivariate analysis, luminal A had 76% (p=0.037), luminal B had 54% (p=0.048), and HER-2 positive subtypes had 47% (p=0.032) decreased risk of death compared with the triple negative subtype. Furthermore, elevated Ki-67 labeling was associated with increased risk of death, while the surgical treatment significantly improved patient survival.

Conclusion:

Breast cancer subtypes are associated with distinct outcomes in IBC patients. Patients that presented with triple negative IBC had poorer outcome than luminal A, luminal B, and HER-2 subtypes. These results indicate that IBC is a heterogeneous disease similar to the conventional breast cancer.Inflammatory breast cancer (IBC) is the most aggressive and fatal form of locally advanced breast cancer, and accounts for approximately 1-6% of all breast tumors.1 Like conventional breast cancer, IBC is a heterogeneous disease that has been stratified into different subtypes, mainly based on gene expression array data.2 These distinguishing subtypes of IBC show different clinical features and are associated with survival. However, array-based classification is limited in the clinic due to technical and budget constraints. For prognostic purposes, clinicians need more economical and practical methods, other than DNA array analysis to define subtypes of breast cancer. In 2011,3 the St. Gallen International Breast Cancer Conference Expert Panel adopted a new approach in defining alternative subtypes of breast cancer. These guidelines were based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2), and the Ki67 labeling index (LI), a cell proliferation marker.3 According to the new classification system, the 4 clinical subtypes are defined as follows: luminal A (ER and/or PR positive, HER-2 negative, Ki-67 LI ≤14%); luminal B (ER and/or PR positive, HER-2 negative, Ki-67 LI >14%; or ER and/or PR positive, HER-2 positive); HER-2 positive (ER and PR negative, HER-2 positive); and triple negative (ER, PR, HER-2 negative). The prognostic value of this newly defined subtyping has only been measured in patients with early stages of breast cancer. However, this subtyping approach has not been investigated in patients with IBC. Therefore, in the present study, these new clinical subtypes, clinicopathological characteristics, and prognoses in IBC patients were analyzed retrospectively.     

Limitations of mammography in the diagnosis of breast diseases compared with ultrasonography: a single-center retrospective analysis of 274 cases

Background

The aim of this study is to compare X-ray mammography (MG) and ultrasonography (US) in the diagnosis of breast diseases in Chinese women.

Methods

We retrospectively analyzed X-ray mammograms of 274 patients with US and surgical/pathological results of breast diseases diagnosed at The Second Affiliated Hospital of Anhui Medical University (Hefei, China) between March 2011 and November 2014. The MG and US data were compared to surgical records using the results from post-surgical pathological examinations as the gold standard.

Results

The overall sensitivity, specificity, accuracy, false-positive, false-negative, positive predictive value, and negative predictive value for the detection of breast cancer were 88.5%, 57.9%, 73.7%, 42.1%, 11.5%, 69.2%, and 82.5%, respectively, for MG and 95.9%, 66.7%, 81.8%, 33.3%, 4.1%, 75.5%, and 93.8%, respectively, for US. Of the 274 cases, lesion size by MG agreed with surgery in 133 (48.5%) patients compared with 216 (78.8%) by US (P < 0.01). Lesion location by MG agreed with surgery in 146 (53.3%) patients compared with 257 (93.8%) by US (P < 0.01). These values were then stratified according to age, menstrual status, breast density, and breast volume, and the agreement rates of MG with surgery were lower than that of US (all P < 0.01), except when the lesion size was >5 cm (P > 0.05).

Conclusions

US was better than MG in the preoperative evaluation of breast diseases of Chinese women. These results suggest that US could be more useful for detecting breast lesions in China, especially for younger women with dense breasts.     

The PSA tracker: A computerised health care system initiative in Northern Ireland

Intoduction

The follow-up of men with prostate cancer forms a large part of many urologists workload. However, a rising PSA usually announces disease progression long before any clinically apparent symptom. Thus, many men can be safely monitored with PSA measurement alone. To facilitate this process, PSA tracking software was introduced to remotely monitor PSA results, minimising the work required for follow-up.

Methods

Stable prostate cancer patients were into the PSA tracker. When each PSA test was performed, the result was reviewed. The program automatically generated patient reminder letters, summary reports for clinic use and all correspondence to patients and primary care physicians.

Results

Since 2006, 65 patients have been entered into the PSA tracker. Median age was 81 (57–94) years. 274 outpatient appointments have been saved, indicating a potential saving of £32,000. More importantly it increased the capacity of the department to assess new patients. For the individual patient, the system has saved them, a median of 3 appointments each.

Conclusion

Remote follow-up of prostate cancer is associated with significant savings for both healthcare organisations and individual patients. This example, further demonstrates the benefits of implanting healthcare software for patients and hospitals.     

Independent and joint effects of serum 25-hydroxivitamin D and calcium on breast cancer ratio in an Iran population: A cross-sectional study

Background:

It has been suggested that Vitamin D and calcium have protective effects against breast cancer. The results about breast cancer and serum Vitamin D and calcium levels are still controversial, indefinite, and insufficient to determine the amount of nutritional needs. Thus, we investigated the association between serum 25-hydroxyvitamin D(25-OH-D) and calcium on the ratio of breast cancer at diagnosis time.

Materials and Methods:

We carried out a hospital-based cross-sectional study in a population of Iran. It comprised 57 breast cancer cases, who were newly diagnosed, and 85 controls in 2013. The serum 25-OH-D and calcium levels were measured.

Results:

There was not any significant association between 25-OH-D and breast cancer ratio. Odds ratio (OR) comparing the highest quartile to the lowest quartile was 1.03(95% confidence interval[CI] 0.33–3.22, P-trend 0.95). Having sufficient (>75 nmol/L) serum 25-OH-D levels compared to insufficient serum 25-OH-D levels was not associated with a significantly decreased ratio of breast cancer (OR 0.55, 95% CI 0.23–1.29, P = 0.17). Furthermore, an association between calcium and breast cancer did not get statistical significance (OR 0.51, 95% CI 0.17–1.49, P-trend 0.31). The joint effect was negative interaction.

Conclusion:

Vitamin D and calcium do not act on decreasing ratio of breast cancer. Decreasing ratio of breast cancer in relation to serum calcium and Vitamin D level at diagnosis time needs more assessments.     

Presence of key findings in the medical record prior to a documented high-risk diagnosis

Background

Failure or delay in diagnosis is a common preventable source of error. The authors sought to determine the frequency with which high-information clinical findings (HIFs) suggestive of a high-risk diagnosis (HRD) appear in the medical record before HRD documentation.

Methods

A knowledge base from a diagnostic decision support system was used to identify HIFs for selected HRDs: lumbar disc disease, myocardial infarction, appendicitis, and colon, breast, lung, ovarian and bladder carcinomas. Two physicians reviewed at least 20 patient records retrieved from a research patient data registry for each of these eight HRDs and for age- and gender-compatible controls. Records were searched for HIFs in visit notes that were created before the HRD was established in the electronic record and in general medical visit notes for controls.

Results

25% of records reviewed (61/243) contained HIFs in notes before the HRD was established. The mean duration between HIFs first occurring in the record and time of diagnosis ranged from 19 days for breast cancer to 2 years for bladder cancer. In three of the eight HRDs, HIFs were much less likely in control patients without the HRD.

Conclusions

In many records of patients with an HRD, HIFs were present before the HRD was established. Reasons for delay include non-compliance with recommended follow-up, unusual presentation of a disease, and system errors (eg, lack of laboratory follow-up). The presence of HIFs in clinical records suggests a potential role for the integration of diagnostic decision support into the clinical workflow to provide reminder alerts to improve the diagnostic focus.     

Research and applications: Identifying survival associated morphological features of triple negative breast cancer using multiple datasets

Background and objective

Biomarkers for subtyping triple negative breast cancer (TNBC) are needed given the absence of responsive therapy and relatively poor prediction of survival. Morphology of cancer tissues is widely used in clinical practice for stratifying cancer patients, while genomic data are highly effective to classify cancer patients into subgroups. Thus integration of both morphological and genomic data is a promising approach in discovering new biomarkers for cancer outcome prediction. Here we propose a workflow for analyzing histopathological images and integrate them with genomic data for discovering biomarkers for TNBC.

Materials and methods

We developed an image analysis workflow for extracting a large collection of morphological features and deployed the same on histological images from The Cancer Genome Atlas (TCGA) TNBC samples during the discovery phase (n=44). Strong correlations between salient morphological features and gene expression profiles from the same patients were identified. We then evaluated the same morphological features in predicting survival using a local TNBC cohort (n=143). We further tested the predictive power on patient prognosis of correlated gene clusters using two other public gene expression datasets.

Results and conclusion

Using TCGA data, we identified 48 pairs of significantly correlated morphological features and gene clusters; four morphological features were able to separate the local cohort with significantly different survival outcomes. Gene clusters correlated with these four morphological features further proved to be effective in predicting patient survival using multiple public gene expression datasets. These results suggest the efficacy of our workflow and demonstrate that integrative analysis holds promise for discovering biomarkers of complex diseases.