Can a machine-learning model improve the prediction of nodal stage after a positive sentinel lymph node biopsy in breast cancer?

Background: The current standard for evaluating axillary nodal burden in clinically node negative breast cancer is sentinel lymph node biopsy (SLNB). However, the accuracy of SLNB to detect nodal stage N2-3 remains debatable. Nomograms can help the decision-making process between axillary treatment options. The aim of this study was to create a new model to predict the nodal stage N2-3 after a positive SLNB using machine learning methods that are rarely seen in nomogram development.Material and methods: Primary breast cancer patients who underwent SLNB and axillary lymph node dissection (ALND) between 2012 and 2017 formed cohorts for nomogram development (training cohort, N = 460) and for nomogram validation (validation cohort, N = 70). A machine learning method known as the gradient boosted trees model (XGBoost) was used to determine the variables associated with nodal stage N2-3 and to create a predictive model. Multivariate logistic regression analysis was used for comparison.Results: The best combination of variables associated with nodal stage N2-3 in XGBoost modeling included tumor size, histological type, multifocality, lymphovascular invasion, percentage of ER positive cells, number of positive sentinel lymph nodes (SLN) and number of positive SLNs multiplied by tumor size. Indicating discrimination, AUC values for the training cohort and the validation cohort were 0.80 (95%CI 0.71-0.89) and 0.80 (95%CI 0.65-0.92) in the XGBoost model and 0.85 (95%CI 0.77-0.93) and 0.75 (95%CI 0.58-0.89) in the logistic regression model, respectively.Conclusions: This machine learning model was able to maintain its discrimination in the validation cohort better than the logistic regression model. This indicates advantages in employing modern artificial intelligence techniques into nomogram development. The nomogram could be used to help identify nodal stage N2-3 in early breast cancer and to select appropriate treatments for patients.

Physicians' self-assessment of cancer pain treatment skills--more training required.

PURPOSE: Adequate pain control is essential in cancer treatment. We surveyed Finnish physicians' perception on their skills and training needs on palliative pain management. METHODS: A structured questionnaire with multiple choices and open ended questions was used for collecting data in 2006-2008. Of 720 physicians participating, 59 were working in oncology and 661 physicians in internal medicine, geriatrics, and primary health care. RESULTS: The principles of the WHO guidelines of cancer pain management were not well known. Forty-six percent of oncologists and 32% of other physicians (P < 0.0001) knew the analgesic ladder consisting of three steps. Forty-seven percent of oncologists and 61% of other physicians considered pain treatment of cancer patients being well managed in Finland. Only 24% of oncologists and 5% of other physicians considered the education in palliative care being currently at a satisfactory level. Oncologists reported a need of training in interaction and communication skills, ethical questions, and palliative home care. The other physicians expressed the strongest need for training in pain management and palliative care. CONCLUSIONS: To have more confidence in treating cancer, pain physicians would benefit in training and education in palliative care. It should be systematically included both in general and specialist training and continuous medical education.

Clinicopathological significance of cyclooxygenase-2 and cell cycle-regulatory proteins expression in patients with esophageal squamous cell carcinoma.

The aim of this study was to examine the expression of the molecular markers cyclooxygenase-2 (COX-2), Ki-67, cyclin A, and p27 in patients with esophageal squamous cell carcinoma (ESCC), to ascertain the relationship of these makers with the clinicopathological significance of the patients, and to assess the additional prognostic value of the expression profile of these proteins for ESCC patients. The expression levels of COX-2, Ki-67, cyclin A, and p27 proteins of a series of primarily resected ESCC samples were determined by immunohistochemistry method. Clinicopathological and molecular factors affecting survival were analyzed by multivariate analysis. A total of 78 specimens were included in this study. Expression of COX-2 was observed in 43 (55.1%) cases, and high levels of expression of Ki-67, p27, and cyclin A were observed in 57 (73.0%), 33 (42.3%), 43 (55.1%) cases, respectively. The results of univariate survival analysis indicated that more advanced tumor stage, lymph node involvement, systemic dissemination, the levels of expression of COX-2, Ki-67, cyclin A, and p27 were associated with survival (all P-value < 0.05). Multifactorial survival analysis revealed that only lymph node involvement, over-expression of cyclin A, and low p27 expression were associated with the survival of the patients (hazard ratios = 2.83, 4.7, 2.9, respectively; P= 0.025, 0.042, 0.005, respectively). Among the molecular markers assessed, the expression of cell proliferation markers cyclin A and p27 are independent prognostic factors in patients with ESCC, whereas neither COX-2 nor Ki-67 is of independent prognostic value.

Characteristics of clinically node negative breast cancer patients needing preoperative MRI.

BACKGROUND: International guidelines do not recommend magnetic resonance imaging (MRI) for all breast cancer patients at primary diagnostics. This study aimed to understand which patient or tumor characteristics are associated with the use of MRI. The role of MRI among other preoperative imaging methods in clinically node negative breast cancer was studied. MATERIAL AND METHODS: Patient and tumor characteristics were analyzed in association with the use of MRI by multivariable logistic regression analysis in 461 patients. Primary tumor size was compared between MRI, mammography (MGR), ultrasound (US) and histopathology by Spearman correlation. The delays in surgery and diagnosis were analyzed among patients with or without MRI, and axillary reoperations were evaluated. RESULTS: Age (p < 0.0001), primary operation method (p < 0.0001), tumor histology (p < 0.0001) and HER2 status (p = 0.0064) were associated with the use of MRI. Spearman correlations between tumor size in histopathology and the difference in tumor size between histopathology and imaging methods were 0.52 in MGR, 0.66 in US and 0.36 in MRI (p < 0.0001 for all). A seven-day delay in surgical treatment was observed among patients with MRI compared to patients without MRI (p < 0.0001). Axillary reoperation rates were similar in patients with or without MRI (p = 0.57). CONCLUSION: Patient selection through prearranged characterization is important in deciding on optimal candidates for preoperative MRI among breast cancer patients. MRI causes moderate delays in primary breast cancer surgery. Preoperative MRI is useful in the evaluation of tumor size but might be insufficient in detecting lymph node metastases.

Effects of sea buckthorn berries on infections and inflammation: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To study the effect of sea buckthorn berries on the number and duration of common cold (CC) infections. As secondary objectives the effects on digestive and urinary tract infections (DTI, UTI), and serum C-reactive protein (CRP) concentrations were also investigated. SUBJECTS: A total of 254 healthy volunteers were randomly assigned to receive sea buckthorn or placebo product during the study, which 233 of them completed. RESULTS: There were no significant differences in the number or duration of CC or DTI between groups (CC: relative risks (sea buckthorn vs placebo) for the number and duration were 1.15 (95% CI 0.90-1.48) and 1.05 (95% CI 0.87-1.27), respectively). In the sea buckthorn group, as compared to the placebo, the serum CRP concentrations decreased significantly (difference in median change -0.059 mg/l, P=0.039). The number of UTI was too small to draw solid conclusions, but the results indicate the subject merits further investigation. CONCLUSION: Sea buckthorn berries did not prevent CC or DTI. However, a reductive effect on CRP, a marker of inflammation, and a risk factor for cardiovascular diseases, was detected.

The effect of beta-glucan on the glycemic and insulin index.

OBJECTIVE: To determine the effects of oat products with increasing beta-glucan content on the glycemic (GI) and insulin indexes (II) of oat products, and to establish the effect of physical properties of beta-glucan on these physiological responses. DESIGN: Test group (n=10) randomly attended to three glucose tolerance tests and glycemic response tests for four oat bran products. SETTINGS: Functional Foods Forum and the Department of Food Chemistry, University of Turku, and the Department of Food Technology, University of Helsinki. SUBJECTS: One male and nine female volunteers were recruited from university students and staff, and all completed the study. INTERVENTIONS: GI and II of different products were calculated for each subject using the average of parallel glucose tolerance tests and the subsequent glycemic/insulinemic responses for each product. Average indexes for products were calculated according to the individual data. RESULTS: The glycemic responses to oat products with increasing amounts of beta-glucan had lower peak values than the reference glucose load. The amount of extractable beta-glucan had a high correlation between the glycemic and insulinemic response. CONCLUSION: In addition to the total amount of beta-glucan in oat products, the amount of extractable beta-glucan in oat products explains the magnitude of the decrease in glycemic responses to carbohydrate products.

Palliative chemotherapy with trofosfamide in advanced prostate cancer.

BACKGROUND: A phase II study with trofosfamide in hormone-refractory prostate cancer was conducted to test the palliative efficacy. PATIENTS AND METHODS: Twenty patients suffering from advanced prostate cancer were treated with per os trofosfamide after progression on androgen ablation and/or estramustine. The mean age was 72 years. The patients were treated with 150 mg/day as continuous treatment. The treatment was continued until progressive disease or severe toxicity. RESULTS: A decline in the prostate specific antigen (PSA) level was observed in 5 patients (27%) with a 0-25% decline in 2 patients and a >50% decline in 3 patients (16%, 95% confidence interval 3.4-39.6). There were no clinical or radiological complete (CR) or partial (PR) responses in 19 evaluable patients. Some toxicity was observed: 15 patients developed anaemia and grade 2-4 adverse effects were observed in 16 patients. One patient died of cardiac event. CONCLUSION: Trofosfamide has some activity in hormone-refractory advanced prostate cancer. When used in fragile or heavily pre-treated patients, careful monitoring for haematological and cardiac effects is recommended.

Survival markers related to bone metastases in prostate cancer.

Prognostic value of a bone resorption marker, tartrate-resistant acid phosphatase isoform 5b (TRACP 5b), and two matrix metalloproteinases (MMP-2 and MMP-9) was compared with the standard clinical analyses of total alkaline phosphatase (tALP) and prostate-specific antigen (PSA), in prostate cancer (PC) patients with (BM+) or without (BM-) bone metastases. Diagnostic accuracy evaluation showed the highest area under the curve for tALP (AUC=0.98), followed by PSA (AUC=0.87), TRACP 5b (AUC=0.82), MMP-9 (AUC=0.62) and MMP-2 (AUC=0.53). Significantly shorter survival was observed for patients with tALP (p<0.001), TRACP 5b (p=0.002) and PSA (p<0.001) levels, above the determined cut-off values compared with lower marker levels. In multivariate Cox regression analysis, only tALP and PSA, in addition to Gleason score were independent prognostic factors for survival. Of the three novel markers tested, only TRACP 5b proved to be predictive of survival in PC with bone metastases. MMP-2 and -9 are thus not recommended for further studies in this context.

Serum TRACP 5b and ICTP as markers of bone metastases in breast cancer.

BACKGROUND: The purpose of this cross-sectional study was to evaluate the value of serum tartrate-resistant acid phosphatase 5b (TRACP 5b) and carboxyterminal telopeptide of type I collagen (ICTP) separately and in combination as markers of bone metastases compared to total alkaline phosphatase (tALP) in breast cancer. MATERIALS AND METHODS: Two groups of patients were studied, one with verfied bone metastases (N=46) and one without bone metastases (N=141). Bone marker levels were correlated with the presence or absence of bone metastases. RESULTS: Serum TRACP 5b concentrations exhibited the largest area under the receiver-operating characteristics (ROC) curve (AUC=0.845), followed by ICTP (0.818) and tALP (0.814) when all patients were included in the analysis. With the combination of TRACP 5b and ICTP, the AUC increased to 0.881. In multivariate regression analysis, all three markers were significant predictors of bone metastases. CONCLUSION: Serum TRACP 5b, ICTP and tALP exhibited equal performances in the detection of bone metastases. The combination of TRACP with ICTP did not significantly improve the detection of bone metastases over tALP.

Docetaxel: standard recommended dose of 100 mg/m(2) is effective but not feasible for some metastatic breast cancer patients heavily pretreated with chemotherapy-A phase II single-center study.

PURPOSE: Patients with metastatic breast cancer, especially those with progression after several prior chemotherapy treatments, need efficient chemotherapy. This study investigates the efficacy and toxicity of docetaxel in metastatic breast cancer patients with previous chemotherapy for metastatic disease. PATIENTS AND METHODS: Thirty-one women (median age, 52 years; range, 40 to 65 years) treated for metastatic breast cancer with docetaxel were included. Eleven patients had one metastatic site, 10 patients had two, and 10 patients had three or more. The planned dose of docetaxel per course was the standard treatment of 100 mg/m(2) (or 75 mg/m(2) if liver enzyme levels were abnormal) every 3 weeks, given for six or eight cycles. RESULTS: The overall response rate was 48% (three complete responses [CR] and 11 partial responses [PR] ), and the median duration of response was 7 months (range, 2 to 16 months). Twenty patients (65%) experienced fatigue, and 27 patients (87%) had alopecia. Fifteen cases (48%) of grade 4 leukopenia were observed. Edema with a weight gain of 2 to 15 kg was seen in 12 patients (39%), and mucositis occurred in 20 patients (65%). Twenty-three patients (74%) interrupted treatment before reaching the planned number of courses, nine patients owing to progression of cancer and 14 owing to toxicity. Dose reduction was required in 18 (61%) of the patients. Only two patients were able to receive the planned eight courses without dose reduction. CONCLUSION: Docetaxel is highly active in metastatic breast cancer, even as a third-line treatment, and can be considered as an efficient standard option in second-line treatment. The standard recommended dose level of 100 mg/m(2) is not feasible in heavily pretreated patients; therefore, for such patients, an initial dose level not exceeding 75 mg/m(2) is recommended.

Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer.

PURPOSE: The combination of interferon alfa-2a (IFNalpha2a) plus vinblastine (VLB) induces objective tumor responses in patients with advanced renal cell cancer. However, no prospective randomized trial has shown that this treatment prolongs overall survival. We compared overall survival after treatment with IFNalpha2a plus VLB versus VLB alone in patients with advanced renal cell cancer. PATIENTS AND METHODS: We prospectively randomized 160 patients with locally advanced or metastatic renal cell cancer to receive either VLB alone or IFNalpha2a plus VLB for 12 months or until progression of disease. In both groups, VLB was administered intravenously at 0.1 mg/kg every 3 weeks, and in the combination group IFNalpha2a was administered subcutaneously at 3 million units three times a week for 1 week, and 18 million units three times a week thereafter for the second and subsequent weeks. For patients unable totolerate IFNalpha2a at 18 million units per injection, the dose was reduced to 9 million units. RESULTS: Median survival was 67.6 weeks for the 79 patients receiving IFNalpha2a plus VLB and 37.8 weeks for the 81 patients treated with VLB (P =.0049). Overall response rates were 16. 5% for patients treated with IFNalpha2a plus VLB and 2.5% for patients treated with VLB alone (P =.0025). Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters, but no toxic deaths were reported. CONCLUSION: The combination of IFNalpha2a plus VLB is superior to VLB alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. This is the first study to demonstrate that survival can be prolonged by using IFNalpha2a for these patients.

Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.

A versatile transformation system for the cellulolytic filamentous fungus Trichoderma reesei.

An efficient transformation system for the cellulolytic filamentous fungus Trichoderma reesei has been developed. Transformation was obtained with plasmid carrying the dominant selectable marker amdS or the argB gene of Aspergillus nidulans, which was found to complement the respective argB mutation of T. reesei. The transformation frequency can be up to 600 transformants per microgram of transforming DNA. The efficiency of co-transformation with unselected DNA was high (approx. 80%). The transforming DNA was found to be integrated at several different locations, often in multiple tandem copies in the T. reesei genome. In addition, the Escherichia coli beta-galactosidase was expressed in T. reesei in enzymatically active form from the A. nidulans gpd promoter.

Xylitol vs glucose: effect on the rate of gastric emptying and motilin, insulin, and gastric inhibitory polypeptide release.

The effect of xylitol and glucose on the rate of gastric emptying and intestinal transit and on motilin, gastric inhibitory polypeptide (GIP), and insulin release were studied in human volunteers. A single oral dose of 200 mL water containing 30 g glucose or 30 g xylitol, mixed with a 99mtechnetium-tin (99mTc-Sn) colloid, was used. Similar dosing without the label was used in motilin, GIP, and insulin studies. Xylitol decreased the rate of gastric emptying but concomitantly accelerated intestinal transit compared with glucose. The half-times for gastric emptying were 77.5 +/- 4.6 and 39.8 +/- 3.4 min after ingestion of xylitol and glucose solutions, respectively. Glucose suppressed motilin and stimulated GIP secretion; xylitol stimulated motilin secretion but had no effect on GIP, which is currently the main candidate for the role of enterogastrone. The accelerated intestinal transit and increase in plasma motilin observed after xylitol ingestion were thought to be causally related to the diarrhea and gastrointestinal discomfort produced by it.

Second cancers in patients with brain tumours--impact of treatment.

The records of the Finnish Cancer Registry from 1953 to 1994 were used to assess the risk of subsequent primary cancer among 14,493 brain tumour patients. They had been treated with surgery only (n = 9804), radiotherapy (n = 4099), chemotherapy and radiotherapy (n = 493) or chemotherapy alone (n = 97). By the end of 1994, 403 subsequent primary cancers were registered in these patients, whilst the expected number based on national incidence was 332. The standardised incidence ratio (SIR) was 1.2 (95% confidence interval (CI) 1.1-1.3). A significant excess risk of tumours in the central nervous system (CNS) including meningeomas (SIR 2.6, 95% CI 1.7-3.8), non-Hodgkin's lymphoma (SIR 2.6, 95% CI 1.6-4.1) and skin melanoma (SIR 1.9, 95% CI 1.0-3.1) was observed. CNS tumours were observed in excess among patients treated with surgery alone (SIR 2.0, 95% CI 1.2-3.2) and with radiotherapy (SIR 5.1, 95% CI 2.5-9.4). In conclusion, brain tumours are associated with an increased risk of both CNS second tumours and non-CNS second cancers, especially non-Hodgkin's lymphoma and melanoma. A moderately increased risk of second tumours in the CNS was observed among brain tumour patients treated with surgery only and a larger excess among those treated with radiotherapy.

Risk of a new primary cancer among patients with lung cancer of different histological types.

The risk of a new primary cancer (NPC) among 77548 Finnish lung cancer patients from 1953 to 1995 was analysed by the histological type of the lung cancer. The relative risks were expressed as standardised incidence ratios (SIR, ratio of the observed and expected numbers of cases). During the follow-up, 1148 NPCs were observed among men and 152 among women. After exclusion of lung cancers, the risk of NPC was elevated in both males (SIR 1.07; 95% confidence interval (CI) 1.00-1.14) and females (SIR 1.21; 95% CI 1.02-1.42). The excess was larger among lung cancer patients with small-cell carcinoma and adenocarcinoma than those with squamous-cell carcinoma. In all major histological groups of lung cancer, significant excess risks were found for cancers of the larynx (SIRs 2.94-4.25), and bladder (SIRs 2.16-2.86). Significantly elevated SIRs were also found for cancers of the stomach (SIR 1.42; 95% CI 1.12-1.76) and kidney (SIR 2.18; 95% CI 1.56-2.97) in squamous-cell carcinoma; for brain tumours (SIR 3.26; 95% CI 1.20-7.09) in small-cell carcinoma; and for cancers of the prostate (SIR 1.68; 95% CI 1.21-2.27) and thyroid (SIR 3.79; 95% CI 1.23-8.85), and brain tumours (SIR 2.34; 95% CI 1.07-4.43) in adenocarcinoma. The risk of contracting NPC at sites where the majority of tumours are adenocarcinomas was elevated among patients with adenocarcinoma of the lung, but not among squamous-cell or small-cell carcinoma patients. In adenocarcinoma, the excess risks of several smoking-related cancers tended to be somewhat lower than those in the other two histological categories. The relative risk of a NPC among patients diagnosed with lung cancer in 1985-1995 was higher than that of patients from earlier periods in all comparable follow-up categories (up to 10 years), possibly suggesting that the increased use of cytostatic drugs had increased the risk of NPC.

Multivariate analysis of prognostic factors in 106 patients with malignant glioma.

The aim of this study was to evaluate the outcome and prognostic factors influencing survival in 106 patients with supratentorial malignant gliomas treated with radiotherapy. The study group included 84 patients treated by surgery and post-operative radiotherapy and 22 patients treated by postbiopsy irradiation. Radiotherapy was delivered to the tumour area with a 2 cm margin, the aimed curative dose was 60 Gy in 6-7 weeks. The 60-month overall survival (Kaplan-Meier) was 20%. Following a univariate analysis, younger age (P < 0.001), longer duration of symptoms (P = 0.009), good performance status after radiotherapy (P < 0.001), other than grade 4 histology (P < 0.001) and higher radiation dose (P < 0.001) were associated with better overall survival rates. Multivariate analysis found that age, symptom duration, histology, extent of symptoms and radiation dose were independent prognostic factors influencing survival. In conclusion, conventional radiotherapy of supratentorial malignant gliomas results in survival that is comparable to results from clinical experiments with different fractionation schedules and radiation with chemotherapy or radiosensitisers. To improve the results, new approaches are needed, especially for patients with the poorest prognosis after standard treatment.

Paclitaxel changes sympathetic control of blood pressure.

Paclitaxel has become part of standard therapy in the treatment of ovarian and breast cancer. Concern has been raised about the effects of paclitaxel on cardiovascular function. Therefore, this study of the effects of paclitaxel on autonomic cardiovascular control was initiated. Eighteen women treated for ovarian or breast cancer were examined with autonomic cardiovascular function tests, once before the treatment and once after the second course of paclitaxel. Heart rate and blood pressure variability and changes in heart rate and blood pressure responses to the tests were measured. Baroreflex sensitivity was calculated from the Valsalva manoeuvre non-invasively. Paclitaxel did not change heart rate variability at rest compared with the pretreatment level. However, medium frequency variability of blood pressure was smaller after treatment with paclitaxel. Paclitaxel treatment did not impair the heart rate and blood pressure responses to the autonomic function tests. The results do imply that paclitaxel alters sympathetic control of blood pressure. Nevertheless, paclitaxel does not appear to precipitate autonomic cardiac neuropathy.