Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE.

BACKGROUND: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. PATIENTS AND METHODS: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. CONCLUSIONS: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration.

Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post-NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. The information required to define pCR (ypT0/is ypN0 or ypT0 yp N0), residual ypT and ypN stage using the current AJCC/UICC system, and the Residual Cancer Burden system were recommended for quantification of residual disease in clinical trials.

Effects of Temperature, Humidity and Air Flow on Fungal Growth Rate on Loaded Ventilation Filters.

This study compares the fungal growth ratio on loaded ventilation filters under various temperature, relative humidity (RH), and air flow conditions in a controlled laboratory setting. A new full-size commercial building ventilation filter was loaded with malt extract nutrients and conidia of Cladosporium sphaerospermum in an ASHRAE Standard 52.2 filter test facility. Small sections cut from this filter were incubated under the following conditions: constant room temperature and a high RH of 97%; sinusoidal temperature (with an amplitude of 10°C, an average of 23°C, and a period of 24 hr) and a mean RH of 97%; room temperature and step changes between 97% and 75% RH, 97% and 43% RH, and 97% and 11% RH every 12 hr. The biomass on the filter sections was measured using both an elution-culture method and by ergosterol assay immediately after loading and every 2 days up to 10 days after loading. Fungal growth was detected earlier using ergosterol content than with the elution-culture method. A student's t-test indicated that Cladosporium sphaerospermum grew better at the constant room temperature condition than at the sinusoidal temperature condition. By part-time exposure to dry environments, the fungal growth was reduced (75% and 43% RH) or even inhibited (11% RH). Additional loaded filters were installed in the wind tunnel at room temperature and an RH greater than 95% under one of two air flow test conditions: continuous air flow or air flow only 9 hr/day with a flow rate of 0.7 m(3)/s (filter media velocity 0.15 m/s). Swab tests and a tease mount method were used to detect fungal growth on the filters at day 0, 5, and 10. Fungal growth was detected for both test conditions, which indicates that when temperature and relative humidity are optimum, controlling the air flow alone cannot prevent fungal growth. In real applications where nutrients are less sufficient than in this laboratory study, fungal growth rate may be reduced under the same operating conditions.

Investigations of protons passing through the CR-39/PM-355 type of solid state nuclear track detectors.

Solid State Nuclear Track Detectors of the CR-39∕PM-355 type were irradiated with protons with energies in the range from 0.2 to 8.5 MeV. Their intensities and energies were controlled by a Si surface barrier detector located in an accelerator scattering chamber. The ranges of protons with energies of 6-7 MeV were comparable to the thickness of the PM-355 track detectors. Latent tracks in the polymeric detectors were chemically etched under standard conditions to develop the tracks. Standard optical microscope and scanning electron microscopy techniques were used for surface morphology characterization.

Quality indicators in breast cancer care.

To define a set of quality indicators that should be routinely measured and evaluated to confirm that the clinical outcome reaches the requested standards, Eusoma has organised a workshop during which twenty four experts from different disciplines have reviewed the international literature and selected the main process and outcome indicators available for quality assurance of breast cancer care. A review of the literature for evidence-based recommendations have been performed by the steering committee. The experts have identified the quality indicators also taking into account the usability and feasibility. For each of them it has been reported: definition, minimum and target standard, motivation for selection and level of evidence (graded according to AHRO). In overall 17 main quality indicators have been identified, respectively, 7 on diagnosis, 4 on surgery and loco-regional treatment, 2 on systemic treatment and 4 on staging, counselling, follow-up and rehabilitation. Breast Units in Europe are invited to comply with these indicators and monitor them during their periodic audit meetings.

A preference-based index for the SF-12.

BACKGROUND: The SF-12 is a widely used generic measure of subjective health. As the scoring algorithms of the SF-12 do not include preference values, different approaches to assign a preference-based index are available that should be tested regarding their feasibility and validity. OBJECTIVES: To develop a concept for a preference-based index for the SF-12 on the basis of multi-attribute decision analysis and to perform initial tests of its feasibility and validity in an empirical study. METHODS: A multi-attribute preference function for the SF-12 was developed, estimated and tested for validity. Two mail surveys (n = 100, 200) and an interview (n = 72) were conducted with women who had an operation for breast cancer. Visual analogue scale (VAS) and standard gamble (SG) measures elicited preference-based valuations. RESULTS: Eight attributes were identified in the SF-12. Validity tests showed an average difference of 8 VAS score points between directly measured and predicted values for given health states. CONCLUSION: The initial results show that this approach might allow the direct assignment of a preference-based valuation to the SF-12. The quality of the psychometric features of the multi-attribute value function is encouraging. Future studies should test this concept more extensively, especially by determining parameters for a representative sample of the general population and by comparing performance with other approaches to value the SF-12.

Sentinel-node biopsy for axillary staging in breast cancer: results from a large prospective German multi-institutional trial.

PURPOSE: To analyse the reliability of sentinel-node biopsy (SNB) in a multicentre setting and define conditions for the routine use of the procedure. MATERIAL AND METHODS: SNB with consecutive axillary clearing was performed in 1124 breast cancer patients. The detection rate of a sentinel lymph node and its dependence on the choice of lymphography technique, patient selection, and technical procedure were analysed. The diagnostic performance of the sentinel-node method was compared to clinical, ultrasound-guided and histological staging. In order to study training effects all learning periods were included. RESULTS: Twenty-two institutions with a total of 89 surgeons participated in the trial. The detection rate (overall: 85.2%) was found to be related to the applied lymphography technique, the experience of the institution and various technical factors of the procedure itself. The false-negative rate (FNR, overall: 8.2%) was independent of patient selection and technical features. The FNR did not depend on experience in the application of the method, but seemed related to surgical accuracy to detect sentinel nodes. Compared to conventional staging procedures (palpation, ultrasound) SNB yielded highly reproducible results for the prediction of the axillary status even in a multicentre setting involving surgeons with different training status. CONCLUSION: SNB is suited as standard of care procedure. Measures of quality control appear more important than learning periods to minimize the FNR.

Shoulder-arm morbidity following axillary dissection and sentinel node only biopsy for breast cancer.

AIMS: The purpose of this study was to examine the outcome of shoulder-arm morbidity in patients with breast cancer after various axillary staging procedures. We used a new specific summation score to compare conventional axillary node dissection (AD) and sentinel node only biopsy for postoperative shoulder-arm morbidity. METHODS: Eighty-five patients undergoing conventional AD and 66 patients undergoing sentinel node biopsy were evaluated both subjectively (questionnaire) and objectively (clinical examination) for reduced muscle strength, limited range of motion, lymphedema and pain, dysesthesias and loss of sensitivity. The symptoms elicited were rated by their severity with a single summation score describing all symptoms reported. RESULTS: Subjective evaluation of patients undergoing breast conserving surgery showed a highly significant difference in favor of SNB only (P< or =0.002). On clinical examination the outcome of patients with SNB only was also significantly or highly significantly better (difference in arm volume:P =0.007; difference in arm muscle strength: P=0.016; loss of sensitivity: P<0.001). Of a total score of 100 (=no symptoms), the mean for AD patients was 80.2 vs 92.8 for SNB patients (P=0.001). In patients undergoing total mastectomy the difference was only significant for pain sensations and total scores. CONCLUSIONS: SNB appears to reduce morbidity. Summation scores are a suitable and practicable tool for describing the symptoms associated with axillary surgery.

Pre-operative staging of invasive breast cancer with MR mammography and/or PET: boon or bunk?

This study compared pre-operative staging with MR mammography (MRM) and positron emission tomography (PET) in patients with clinically suspected breast cancer according to the Breast Imaging Reporting and Data System, category 5. A total of 43 patients with breast cancer were examined. MRM included both T(2) weighted turbo spin echo sequences and T(1) weighted gradient echo sequences (three-dimensional fast low angle shot) before and after application of gadolinium-DPTA. All patients then underwent examination with a modern full-ring PET scanner following injection of fluorodeoxyglucose. We evaluated the efficacy of these methods in the diagnosis of primary tumour, contralateral carcinomas, bifocal, trifocal or multifocal disease, as well as non-invasive cancer portions and tumour size. Determination of patients' N-status was only attempted using PET. All findings were validated by histological examination. MRM was slightly superior to PET in several areas, such as in the respective methods' sensitivity and specificity. Sensitivities for MRM and PET were: 100% vs 93.0% in diagnosis of the primary tumour; 100% vs 100% in diagnosis of contralateral carcinomas; and 95.2% vs 92.5% in diagnosis of bifocal, trifocal or multifocal disease. Specificities for MRM and PET were: 100% vs 97.5% in diagnosis of contralateral carcinomas; and 96.8% vs 90.3% in diagnosis of bifocal, trifocal or multifocal disease. Non-invasive cancer portions and tumour sizes were equally well determined with both methods. The sensitivity of PET for detection of lymph node involvement was 80% and specificity 95%. MRM and PET were superior to conventional methods in nearly all areas studied; the findings of one or both of the methods impacted positively on patients' surgical treatment in 12.5-15% of cases. Pre-operative MRM and/or PET can have a positive influence on surgical treatment planning. Therefore, it appears useful to perform pre-operative staging with MRM or PET in these patients.

Endoscopic axillary surgery in breast cancer.

BACKGROUND: The aim was to provide an assessment of the current status of endoscopic axillary surgery in patients with breast cancer. METHODS: Fifty-three patients underwent endoscopic lymphadenectomy. The surgical efficiency (operating time, number of resected nodes, intraoperative and postoperative complications), short-term morbidity (duration of drainage, total lymph flow, seroma rate) and long-term outcome (pain, numbness, mobility, strength, oedema) were assessed. The incidence and severity of different arm symptoms were compared with the results of 396 patients treated with a conventional axillary procedure. Finally, all available data relating to endoscopic axillary surgery were reviewed. RESULTS: The operating time ranged from 60 to 150 min. A mean 17 (range 10-28) lymph nodes was resected. The extent of postoperative lymphorrhoea (mean 372 ml) and the seroma rate (eight of 34 patients) were not significantly reduced in comparison with conventional surgery. The assessment of long-term morbidity revealed fewer disturbances of sensitivity and a decreased rate of severe symptom intensity for pain, oedema and complaints related to mobility. CONCLUSION: Despite excellent visualization of anatomical landmarks and improved long-term morbidity, endoscopic lymph node dissection cannot be regarded as a suitable technique for routine axillary management in breast cancer because of long operating times.

Long-term morbidity following axillary dissection in breast cancer patients--clinical assessment, significance for life quality and the impact of demographic, oncologic and therapeutic factors.

OBJECTIVE: This study describes in detail the surgery-related symptoms following axillary lymph node dissection in breast cancer patients and considers both their significance for long term quality of life and the impact of possible influencing factors. MATERIAL AND METHODS: Three hundred and ninety six patients were studied retrospectively using a self-report questionnaire and a clinical examination. The symptoms, numbness, pain, edema, arm strength and mobility were evaluated. The subjective assessment of the degree of symptom intensity was compared with objective measurements. The extent of surgery (number of resected nodes, level of dissection) as well as the influence of demographic, oncologic and adjuvant measures (age, time interval, number of involved nodes, chemotherapy) were evaluated. RESULTS: Shoulder-arm morbidity and fear of cancer recurrence were the most important long-term sources of distress following breast cancer surgery in our study population. Demographic, oncologic and therapeutic measures including the extent of surgery had no influence on long-term morbidity. The intensity of all evaluated symptoms was reported to be more severe in patients' subjective statements than in the results of clinical assessment. CONCLUSION: Shoulder-arm morbidity following axillary dissection is a frustrating polysymptomatic disease that seems to be relatively unaffected by therapeutic measures. The surgical trauma necessary for adequate tumor staging (removal of 10 lymph nodes) seems decisive for the postsurgery syndrome following axillary dissection. For node-positive patients complete axillary clearing may improve tumor control without worsening long-termmorbidity. New techniques, such as the sentinel-node-biopsy, that selects patients with negative axillary status while preserving the integrity of axillary structures, may improve the overall morbidity.

Studies of ventilation efficiency in a protective isolation room by the use of a scale model.

OBJECTIVE: To assess the ability of a protective isolation room ventilation system to reduce patient exposure to airborne infectious agents, using a small-scale model that permits cost-effective and unobtrusive study of relevant indices of performance. DESIGN: A one-half scale model of a protective isolation room at the University of Minnesota Hospital was constructed and equipped for tracer gas experiments to assess ventilation efficiency. MEASUREMENTS: Tracer gas (SF6) was injected into the model supply air. Tracer gas concentration was recorded over time and analyzed to determine local and room mean age of air. Age of air is a direct measurement of ventilation efficiency and can be used to predict patient exposure to contamination. RESULTS: Although for the room taken as a whole, ventilation efficiency was close to 50% (a value corresponding to perfect mixing), the experimental results for the local mean age of air indicate that some parts of the model were ventilated much better than others. CONCLUSION: Room air exchange rate is only one parameter useful in assessing ventilation in patient areas. Effective distribution of ventilation air also is critical to the control of airborne contamination. Areas of the room with poor ventilation would be expected to have higher concentrations of airborne infectious agents and other contaminants. Patient exposure can be minimized by placing the patient in well-ventilated areas of the room. Improved ventilation designs may reduce patient exposure further without increasing actual airflow rate.

[Importance and value of roentgen studies as outcome criteria in rheumatoid arthritis]. / Wertigkeit und Aussagefähigkeit von Röntgenuntersuchungen als Outcome-Kriterium bei rheumatoider Arthritis.

In order to evaluate the objectivity and validity of radiographic parameters in rheumatoid arthritis (RA) we studied 56 patients with definite RA. Inter-observer variation was assessed comparing the scorings (Larsen classification) of two independent experienced observers. Total radiographic scores were highly significantly correlated (r = 0.89). Yet, we could not find relevant associations between radiographic findings and clinical outcome parameters (pain, morning stiffness, dexterity, grip strength, and patient's overall assessment). Thus, hand radiographs in RA provide highly reproducible results. Its validity concerning patient outcome, however, has to be interpreted very carefully.