[Whole genome sequencing to find the primary tumour in cancer of unknown primary origin]. / Onbekende primaire tumor opsporen met 'whole genome sequencing'.

Cancer of unknown primary origin (CUP) remains a serious problem. The incidence in the Netherlands is stable, 1-2 percent of all new cancer cases. In general, patients undergo a long diagnostic trajectory and only a minority receive a tumour directed treatment. More than half of the patients die within two months after the diagnosis. A complete analysis of the DNA of a tumour specimen by means of whole genome sequencing may be helpful in finding the primary tumour. Dutch medical oncologists and pathologists set up a protocol for CUP patients, in which WGS may be implemented in the diagnostic procedure.

Complete genomic characterization in patients with cancer of unknown primary origin in routine diagnostics.

BACKGROUND: In ∼3%-5% of patients with metastatic disease, tumor origin remains unknown despite modern imaging techniques and extensive pathology work-up. With long diagnostic delays and limited and ineffective therapy options, the clinical outcome of patients with cancer of unknown primary (CUP) remains poor. Large-scale genome sequencing studies have revealed that tumor types can be predicted based on distinct patterns of somatic variants and other genomic characteristics. Moreover, actionable genomic events are present in almost half of CUP patients. This study investigated the clinical value of whole genome sequencing (WGS) in terms of primary tumor identification and detection of actionable events, in the routine diagnostic work-up of CUP patients. PATIENTS AND METHODS: A WGS-based tumor type 'cancer of unknown primary prediction algorithm' (CUPPA) was developed based on previously described principles and validated on a large pan-cancer WGS database of metastatic cancer patients (>4000 samples) and 254 independent patients, respectively. We assessed the clinical value of this prediction algorithm as part of routine WGS-based diagnostic work-up for 72 CUP patients. RESULTS: CUPPA correctly predicted the primary tumor type in 78% of samples in the independent validation cohort (194/254 patients). High-confidence predictions (>95% precision) were obtained for 162/254 patients (64%). When integrated in the diagnostic work-up of CUP patients, CUPPA could identify a primary tumor type for 49/72 patients (68%). Most common diagnoses included non-small-cell lung (n = 7), gastroesophageal (n = 4), pancreatic (n = 4), and colorectal cancer (n = 3). Actionable events with matched therapy options in clinical trials were identified in 47% of patients. CONCLUSIONS: Genome-based tumor type prediction can predict cancer diagnoses with high accuracy when integrated in the routine diagnostic work-up of patients with metastatic cancer. With identification of the primary tumor type in the majority of patients and detection of actionable events, WGS is a valuable diagnostic tool for patients with CUP.

Factors influencing the quality and functioning of oncological multidisciplinary team meetings: results of a systematic review.

BACKGROUND: Discussing patients with cancer in a multidisciplinary team meeting (MDTM) is customary in cancer care worldwide and requires a significant investment in terms of funding and time. Efficient collaboration and communication between healthcare providers in all the specialisms involved is therefore crucial. However, evidence-based criteria that can guarantee high-quality functioning on the part of MDTMs are lacking. In this systematic review, we examine the factors influencing the MDTMs' efficiency, functioning and quality, and offer recommendations for improvement. METHODS: Relevant studies were identified by searching Medline, EMBASE, and PsycINFO databases (01-01-1990 to 09-11-2021), using different descriptions of 'MDTM' and 'neoplasm' as search terms. Inclusion criteria were: quality of MDTM, functioning of MDTM, framework and execution of MDTM, decision-making process, education, patient advocacy, patient involvement and evaluation tools. Full text assessment was performed by two individual authors and checked by a third author. RESULTS: Seventy-four articles met the inclusion criteria and five themes were identified: 1) MDTM characteristics and logistics, 2) team culture, 3) decision making, 4) education, and 5) evaluation and data collection. The quality of MDTMs improves when the meeting is scheduled, structured, prepared and attended by all core members, guided by a qualified chairperson and supported by an administrator. An appropriate amount of time per case needs to be established and streamlining of cases (i.e. discussing a predefined selection of cases rather than discussing every case) might be a way to achieve this. Patient centeredness contributes to correct diagnosis and decision making. While physicians are cautious about patients participating in their own MDTM, the majority of patients report feeling better informed without experiencing increased anxiety. Attendance at MDTMs results in closer working relationships between physicians and provides some medico-legal protection. To ensure well-functioning MDTMs in the future, junior physicians should play a prominent role in the decision-making process. Several evaluation tools have been developed to assess the functioning of MDTMs. CONCLUSIONS: MDTMs would benefit from a more structured meeting, attendance of core members and especially the attending physician, streamlining of cases and structured evaluation. Patient centeredness, personal competences of MDTM participants and education are not given sufficient attention.

Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.

BACKGROUND: Guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of nonmetastatic muscle-invasive bladder cancer (MIBC). NAC is, however, underutilized in practice because of its associated limited overall survival (OS) benefit and significant treatment-related toxicity. We hypothesized that the absence of circulating tumour cells (CTCs) identifies MIBC patients with such a favourable prognosis that NAC may be withheld. PATIENTS AND METHODS: The CirGuidance study was an open-label, multicentre trial that included patients with clinical stage T2-T4aN0-N1M0 MIBC, scheduled for radical cystectomy. CTC-negative patients (no CTCs detectable using the CELLSEARCH system) underwent radical surgery without NAC; CTC-positive patients (≥1 detectable CTCs) were advised to receive NAC, followed by radical surgery. The primary endpoint was the 2-year OS in the CTC-negative group with a prespecified criterion for trial success of ≥75% (95% confidence interval (CI) ±5%). RESULTS: A total of 273 patients were enrolled. Median age was 69 years; median follow-up was 36 months. The primary endpoint of 2-year OS in the CTC-negative group was 69.5% (N = 203; 95% CI 62.6%-75.5%). Two-year OS was 58.2% in the CTC-positive group (N = 70; 95% CI 45.5%-68.9%). CTC-positive patients had a higher rate of cancer-related mortality [hazard ratio (HR) 1.61, 95% CI 1.05-2.45, P = 0.03] and disease relapse (HR 1.87, 95% CI 1.28-2.73, P = 0.001) than CTC-negative patients. Explorative analyses suggested that CTC-positive patients who had received NAC (n = 22) survived longer than CTC-positive patients who had not (n = 48). CONCLUSION: The absence of CTCs in MIBC patients was associated with improved cancer-related mortality and a lower risk of disease relapse after cystectomy; however, their absence alone does not justify to withhold NAC. Exploratory analyses suggested that CTC-positive MIBC patients might derive more benefit from NAC. TRIAL REGISTRATION: Netherlands Trial Register NL3954; https://www.trialregister.nl/trial/3954.

Three bedside techniques to quantify dynamic pulmonary hyperinflation in mechanically ventilated patients with chronic obstructive pulmonary disease.

BACKGROUND: Dynamic pulmonary hyperinflation may develop in patients with chronic obstructive pulmonary disease (COPD) due to dynamic airway collapse and/or increased airway resistance, increasing the risk of volutrauma and hemodynamic compromise. The reference standard to quantify dynamic pulmonary hyperinflation is the measurement of the volume at end-inspiration (Vei). As this is cumbersome, the aim of this study was to evaluate if methods that are easier to perform at the bedside can accurately reflect Vei. METHODS: Vei was assessed in COPD patients under controlled protective mechanical ventilation (7 ± mL/kg) on zero end-expiratory pressure, using three techniques in a fixed order: (1) reference standard (Veireference): passive exhalation to atmosphere from end-inspiration in a calibrated glass burette; (2) ventilator maneuver (Veimaneuver): measuring the expired volume during a passive exhalation of 45s using the ventilator flow sensor; (3) formula (Veiformula): (Vt × Pplateau)/(Pplateau - PEEPi), with Vt tidal volume, Pplateau is plateau pressure after an end-inspiratory occlusion, and PEEPi is intrinsic positive end-expiratory pressure after an end-expiratory occlusion. A convenience sample of 17 patients was recruited. RESULTS: Veireference was 1030 ± 380 mL and had no significant correlation with Pplateau (r2 = 0.06; P = 0.3710) or PEEPi (r2 = 0.11; P = 0.2156), and was inversely related with Pdrive (calculated as Pplateau -PEEPi) (r2 = 0.49; P = 0.0024). A low bias but rather wide limits of agreement and fairly good correlations were found when comparing Veimaneuver and Veiformula to Veireference. Vei remained stable during the study period (low bias 15 mL with high agreement (95% limits of agreement from - 100 to 130 mL) and high correlation (r2 = 0.98; P < 0.0001) between both measurements of Veireference). CONCLUSIONS: In patients with COPD, airway pressures are not a valid representation of Vei. The three techniques to quantify Vei show low bias, but wide limits of agreement.

Shared decision-making in the ICU from the perspective of physicians, nurses and patients: a qualitative interview study.

OBJECTIVE: To identify views, experiences and needs for shared decision-making (SDM) in the intensive care unit (ICU) according to ICU physicians, ICU nurses and former ICU patients and their close family members. DESIGN: Qualitative study. SETTING: Two Dutch tertiary centres. PARTICIPANTS: 19 interviews were held with 29 participants: seven with ICU physicians from two tertiary centres, five with ICU nurses from one tertiary centre and nine with former ICU patients, of whom seven brought one or two of their close family members who had been involved in the ICU stay. RESULTS: Three themes, encompassing a total of 16 categories, were identified pertaining to struggles of ICU physicians, needs of former ICU patients and their family members and the preferred role of ICU nurses. The main struggles ICU physicians encountered with SDM include uncertainty about long-term health outcomes, time constraints, feeling pressure because of having final responsibility and a fear of losing control. Former patients and family members mainly expressed aspects they missed, such as not feeling included in ICU treatment decisions and a lack of information about long-term outcomes and recovery. ICU nurses reported mainly opportunities to strengthen their role in incorporating non-medical information in the ICU decision-making process and as liaison between physicians and patients and family. CONCLUSIONS: Interviewed stakeholders reported struggles, needs and an elucidation of their current and preferred role in the SDM process in the ICU. This study signals an essential need for more long-term outcome information, a more informal inclusion of patients and their family members in decision-making processes and a more substantial role for ICU nurses to integrate patients' values and needs in the decision-making process.

Comparing practice and outcome of laparoscopic liver resection between high-volume expert centres and nationwide low-to-medium volume centres.

BACKGROUND: Based on excellent outcomes from high-volume centres, laparoscopic liver resection is increasingly being adopted into nationwide practice which typically includes low-medium volume centres. It is unknown how the use and outcome of laparoscopic liver resection compare between high-volume centres and low-medium volume centres. This study aimed to compare use and outcome of laparoscopic liver resection in three leading European high-volume centres and nationwide practice in the Netherlands. METHOD: An international, retrospective multicentre cohort study including data from three European high-volume centres (Oslo, Southampton and Milan) and all 20 centres in the Netherlands performing laparoscopic liver resection (low-medium volume practice) from January 2011 to December 2016. A high-volume centre is defined as a centre performing >50 laparoscopic liver resections per year. Patients were retrospectively stratified into low, moderate- and high-risk Southampton difficulty score groups. RESULTS: A total of 2425 patients were included (1540 high-volume; 885 low-medium volume). The median annual proportion of laparoscopic liver resection was 42.9 per cent in high-volume centres and 7.2 per cent in low-medium volume centres. Patients in the high-volume centres had a lower conversion rate (7.4 versus 13.1 per cent; P < 0.001) with less intraoperative incidents (9.3 versus 14.6 per cent; P = 0.002) as compared to low-medium volume centres. Whereas postoperative morbidity and mortality rates were similar in the two groups, a lower reintervention rate (5.1 versus 7.2 per cent; P = 0.034) and a shorter postoperative hospital stay (3 versus 5 days; P < 0.001) were observed in the high-volume centres as compared to the low-medium volume centres. In each Southampton difficulty score group, the conversion rate was lower and hospital stay shorter in high-volume centres. The rate of intraoperative incidents did not differ in the low-risk group, whilst in the moderate-risk and high-risk groups this rate was lower in high-volume centres (absolute difference 6.7 and 14.2 per cent; all P < 0.004). CONCLUSION: High-volume expert centres had a sixfold higher use of laparoscopic liver resection, less conversions, and shorter hospital stay, as compared to a nationwide low-medium volume practice. Stratification into Southampton difficulty score risk groups identified some differences but largely outcomes appeared better for high-volume centres in each risk group.

A point-of-care thoracic ultrasound protocol for hospital medical emergency teams (METUS) improves diagnostic accuracy.

BACKGROUND: Point-of-care ultrasound (POCUS) has proven itself in many clinical situations. Few data on the use of POCUS during Medical Emergency Team (MET) calls exist. In this study, we hypothesized that the use of POCUS would increase the number of correct diagnosis made by the MET and increase MET's certainty. METHODS: Single-center prospective observational study on adult patients in need for MET assistance. Patients were included in blocks (weeks). During even weeks, the MET physician performed a clinical assessment and registered an initial diagnosis. Subsequently, the POCUS protocol was performed and a second diagnosis was registered (US+). During uneven weeks, no POCUS was performed (US-). A blinded expert reviewed the charts for a final diagnosis. The number of correct diagnoses was compared to the final diagnosis between both groups. Physician's certainty, mortality and possible differences in first treatment were also evaluated. RESULTS: We included 100 patients: 52 in the US + and 48 in the US- group. There were significantly more correct diagnoses in the US+ group compared to the US- group: 78 vs 51% (P  = 0.006). Certainty improved significantly with POCUS (P  <  0.001). No differences in 28-day mortality and first treatment were found. CONCLUSIONS: The use of thoracic POCUS during MET calls leads to better diagnosis and increases certainty. TRIAL REGISTRATION: ClinicalTrials.gov. Registered 12 July 2017, NCT03214809 https://www.clinicaltrials.gov/ct2/show/NCT03214809?term=metus&cntry=NL&draw=2&rank=1.

Increased sodium intake and decreased sodium excretion in ICU-acquired hypernatremia: A prospective cohort study.

PURPOSE: To provide more in-depth insight in the development of early ICU-acquired hypernatremia in critically ill patients based on detailed, longitudinal and quantitative data. MATERIALS AND METHODS: A comparative analysis was performed using prospectively collected data of ICU patients. All patients requiring ICU admission for more than 48 h between April and December 2018 were included. For this study, urine samples were collected daily and analyzed for electrolytes and osmolality. Additionally, plasma osmolality analyses were performed. Further data collection consisted of routine laboratory results, detailed fluid balances and medication use. RESULTS: A total of 183 patient were included for analysis, of whom 38% developed ICU-acquired hypernatremia. Whereas the hypernatremic group was similar to the non-hypernatremic group at baseline and during the first days, hypernatremic patients had a significantly higher sodium intake on day 2 to 5, a lower urine sodium concentration on day 3 and 4 and a worse kidney function (plasma creatinine 251 versus 71.9 µmol/L on day 5). Additionally, hypernatremic patients had higher APACHE IV scores (67 versus 49, p < 0.05) and higher ICU (23 versus 12%, p = 0.07) and 90-day mortality (33 versus 14%, p < 0.01). CONCLUSIONS: Longitudinal analysis shows that the development of early ICU-acquired hypernatremia is preceded by increased sodium intake, decreased renal function and decreased sodium excretion.

Survival outcomes of patients with advanced melanoma from 2013 to 2017: Results of a nationwide population-based registry.

BACKGROUND: The treatment landscape has completely changed for advanced melanoma. We report survival outcomes and the differential impact of prognostic factors over time in daily clinical practice. METHODS: From a Dutch nationwide population-based registry, patients with advanced melanoma diagnosed from 2013 to 2017 were analysed (n = 3616). Because the proportional hazards assumption was violated, a multivariable Cox model restricted to the first 6 months and a multivariable landmark Cox model from 6 to 48 months were used to assess overall survival (OS) of cases without missing values. The 2017 cohort was excluded from this analysis because of the short follow-up time. RESULTS: Median OS of the 2013 and 2016 cohort was 11.7 months (95% confidence interval [CI]: 10.4-13.5) and 17.7 months (95% CI: 14.9-19.8), respectively. Compared with the 2013 cohort, the 2016 cohort had superior survival in the Cox model from 0 to 6 months (hazard ratio [HR] = 0.55 [95% CI: 0.43-0.72]) and in the Cox model from 6 to 48 months (HR = 0.68 [95% CI: 0.57-0.83]). Elevated lactate dehydrogenase levels, distant metastases in ≥3 organ sites, brain and liver metastasis and Eastern Cooperative Oncology Group performance score of ≥1 had stronger association with inferior survival from 0 to 6 months than from 6 to 48 months. BRAF-mutated melanoma had superior survival in the first 6 months (HR = 0.50 [95% CI: 0.42-0.59]). CONCLUSION(S): Prognosis for advanced melanoma in the Netherlands has improved from 2013 to 2016. Prognostic importance of most evaluated factors was higher in the first 6 months after diagnosis. BRAF-mutated melanoma was only associated with superior survival in the first 6 months.

Better survival after surgery of the primary tumor in stage IV inflammatory breast cancer.

INTRODUCTION: Information regarding the effects of resection of the primary tumor in stage IV inflammatory breast cancer (IBC) is scarce. We analyzed the impact of resection of the primary tumor on overall survival (OS) in a large stage IV IBC population. MATERIALS AND METHODS: Patients diagnosed with stage IV IBC between 2005 and 2016 were selected from the Netherlands Cancer Registry, excluding patients without any treatment. To correct for immortal time bias, we performed a landmark analysis including patients alive at least six months after diagnosis. With propensity score matching, patients undergoing surgery of the primary tumor were matched to patients not receiving surgery. Multivariable Cox proportional hazard analyses were performed to determine the association between treatment strategy and OS in the non-matched and matched cohort. RESULTS: Of the 580 included patients after landmark analysis, 441 patients (76%) received only non-surgical treatments and 139 (24%) underwent surgery (96% mastectomy). Median follow-up was 28.8 and 20.0 months in the surgery and no surgery group, respectively. Surgery in the non-matched cohort was independently associated with better survival (HR0.56[95%CI:0.42-0.75]). In the matched cohort (n = 202), surgically treated patients had improved survival over nonsurgically treated patients (p < 0.005). Multivariable analysis of the matched cohort revealed that surgery was still associated with better survival (HR0.62[95%CI:0.44-0.87]). CONCLUSION: Although residual confounding and confounding by severity cannot be ruled out, this study suggests that surgery of the primary tumor is associated with improved OS and should be considered as part of the treatment strategy in stage IV IBC.

Recruitment pattern of the diaphragm and extradiaphragmatic inspiratory muscles in response to different levels of pressure support.

BACKGROUND: Inappropriate ventilator assist plays an important role in the development of diaphragm dysfunction. Ventilator under-assist may lead to muscle injury, while over-assist may result in muscle atrophy. This provides a good rationale to monitor respiratory drive in ventilated patients. Respiratory drive can be monitored by a nasogastric catheter, either with esophageal balloon to determine muscular pressure (gold standard) or with electrodes to measure electrical activity of the diaphragm. A disadvantage is that both techniques are invasive. Therefore, it is interesting to investigate the role of surrogate markers for respiratory dive, such as extradiaphragmatic inspiratory muscle activity. The aim of the current study was to investigate the effect of different inspiratory support levels on the recruitment pattern of extradiaphragmatic inspiratory muscles with respect to the diaphragm and to evaluate agreement between activity of extradiaphragmatic inspiratory muscles and the diaphragm. METHODS: Activity from the alae nasi, genioglossus, scalene, sternocleidomastoid and parasternal intercostals was recorded using surface electrodes. Electrical activity of the diaphragm was measured using a multi-electrode nasogastric catheter. Pressure support (PS) levels were reduced from 15 to 3 cmH2O every 5 min with steps of 3 cmH2O. The magnitude and timing of respiratory muscle activity were assessed. RESULTS: We included 17 ventilated patients. Diaphragm and extradiaphragmatic inspiratory muscle activity increased in response to lower PS levels (36 ± 6% increase for the diaphragm, 30 ± 6% parasternal intercostals, 41 ± 6% scalene, 40 ± 8% sternocleidomastoid, 43 ± 6% alae nasi and 30 ± 6% genioglossus). Changes in diaphragm activity correlated best with changes in alae nasi activity (r2 = 0.49; P < 0.001), while there was no correlation between diaphragm and sternocleidomastoid activity. The agreement between diaphragm and extradiaphragmatic inspiratory muscle activity was low due to a high individual variability. Onset of alae nasi activity preceded the onset of all other muscles. CONCLUSIONS: Extradiaphragmatic inspiratory muscle activity increases in response to lower inspiratory support levels. However, there is a poor correlation and agreement with the change in diaphragm activity, limiting the use of surface electromyography (EMG) recordings of extradiaphragmatic inspiratory muscles as a surrogate for electrical activity of the diaphragm.

The use of an external ultrasound fixator (Probefix) on intensive care patients: a feasibility study.

BACKGROUND: In critical care medicine, the use of transthoracic echo (TTE) is expanding. TTE can be used to measure dynamic parameters such as cardiac output (CO). An important asset of TTE is that it is a non-invasive technique. The Probefix is an external ultrasound holder strapped to the patient which makes it possible to measure CO using TTE in a fixed position possibly making the CO measurements more accurate compared to separate TTE CO measurements. The feasibility of the use of the Probefix to measure CO before and after a passive leg raising test (PLR) was studied. Intensive care patients were included after detection of hypovolemia using Flotrac. Endpoints were the possibility to use Probefix. Also CO measurements with and without the use of Probefix, before and after a PLR were compared to the CO measurements using Flotrac. Side effects in terms of skin alterations after the use of Probefix and patient's comments on (dis)comfort were evaluated. RESULTS: Ten patients were included; in eight patients, sufficient recordings with the use of Probefix could be obtained. Using Bland-Altman plots, no difference was found in accuracy of measurements of CO with or without the use of Probefix before and after a PLR compared to Flotrac generated CO. There were only mild and temporary skin effects of the use of Probefix. CONCLUSIONS: In this small feasibility study, the Probefix could be used in eight out of ten intensive care patients. The use of Probefix did not result in more or less accurate CO measurements compared to manually recorded TTE CO measurements. We suggest that larger studies on the use of Probefix in intensive care patients are needed.

Metastatic behavior and overall survival according to breast cancer subtypes in stage IV inflammatory breast cancer.

BACKGROUND: Distant metastatic disease is frequently observed in inflammatory breast cancer (IBC), with a poor prognosis as a consequence. The aim of this study was to analyze the association of hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) based breast cancer subtypes in stage IV inflammatory breast cancer (IBC) with preferential site of distant metastases and overall survival (OS). METHODS: For patients with stage IV IBC, diagnosed in the Netherlands between 2005 and 2016, tumors were classified into four breast cancer subtypes: HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. Patient, tumor, and treatment characteristics and sites of metastases were compared. OS of the subtypes was compared using Kaplan-Meier curves and the log-rank test. Association between subtype and OS was assessed in multivariable models using logistic regression. RESULTS: In total, 744 eligible patients were included: 340 (45.7%) tumors were HR+/HER2-, 148 (19.9%) HR-/HER2+, 131 (17.6%) HR+/HER2+, and 125 (16.8%) HR-/HER2-. Bone was the most common metastatic site in all subtypes. A significant predominance of bone metastases was found in HR+/HER2- IBC (71.5%), and liver and lung metastases in the HR-/HER2+ (41.2%) and HR-/HER2- (40.8%) subtypes, respectively. In multivariable analysis, the HR-/HER2- subtype was associated with significantly worse OS as compared to the other subtypes. CONCLUSION: Breast cancer subtypes in stage IV IBC are associated with distinct patterns of metastatic spread and display notable differences in OS. The use of breast cancer subtypes can guide a more patient-tailored staging directed to metastatic site and extend of disease.

Pathologic complete response and overall survival in breast cancer subtypes in stage III inflammatory breast cancer.

PURPOSE: To analyze the influence of hormone receptors (HR) and Human Epidermal growth factor Receptor-2 (HER2)-based molecular subtypes in stage III inflammatory breast cancer (IBC) on tumor characteristics, treatment, pathologic response to neoadjuvant chemotherapy (NACT), and overall survival (OS). METHODS: Patients with stage III IBC, diagnosed in the Netherlands between 2006 and 2015, were classified into four breast cancer subtypes: HR+/HER2- , HR+/HER2+ , HR-/HER2+ , and HR-/HER2- . Patient-, tumor- and treatment-related characteristics were compared. In case of NACT, pathologic complete response (pCR) was compared between subgroups. OS of the subtypes was compared using Kaplan-Meier curves and the log-rank test. RESULTS: 1061 patients with stage III IBC were grouped into subtypes: HR+/HER2- (N = 453, 42.7%), HR-/HER2- (N = 258, 24.3%), HR-/HER2+ (N = 180,17.0%), and HR+/HER2+ (N = 170,16.0%). In total, 679 patients (85.0%) received NACT. In HR-/HER2+ tumors, pCR rate was highest (43%, (p < 0.001). In case of pCR, an improved survival was observed for all subtypes, especially for HR+/HER2+ and HR-/HER2+ tumor subtypes. Trimodality therapy (NACT, surgery, radiotherapy) improved 5-year OS as opposed to patients not receiving this regimen: HR+/HER2- (74.9 vs. 46.1%), HR+/HER2+ (80.4 vs. 52.6%), HR-/HER2+ (76.4 vs. 29.7%), HR-/HER2- (47.6 vs. 27.8%). CONCLUSIONS: In stage III IBC, breast cancer subtypes based on the HR and HER2 receptor are important prognostic factors of response to NACT and OS. Patients with HR-/HER2- IBC were less likely to achieve pCR and had the worst OS, irrespective of receiving most optimal treatment regimen to date (trimodality therapy).

Suicide after inhaling a pyrethrins containing insecticide spray.

Pesticide self-poisoning is rare in developed countries. We report a suicide case after inhalation of a pyrethrins containing insecticide spray. The patient presented at the emergency department with respiratory failure. Despite mechanical ventilation, he developed severe pulmonary inflammation with a systemic inflammatory response syndrome and died 5 days later. Studies reporting on acute pyrethrins or pyrethroids insecticide poisoning in both occupational and non-occupational cases usually describe mild and self-limiting respiratory symptoms as the predominant symptom. Severe or fatal cases of pyrethrins or pyrethroids poisoning are very rare. Patients with asthma or allergies are apparently more at risk for severe symptoms. In these cases, early and aggressive treatment with bronchodilatators, steroids, antihistamines and epinephrine should be considered.