Severity and 1-month outcome of SARS-CoV-2 infection in patients with solid cancers: a Danish nationwide cohort study.

BACKGROUND: Cancer patients are vulnerable to infections, are older and often have comorbidities in comparison to the general population, which increases the risk for severe outcomes related to COVID-19 diagnosis. METHODS: This study is a prospective, nationwide study in patients with solid cancer and SARS-CoV-2 infection included between 10 March to 15 June 2020. Patient's baseline characteristics were collected. The study's primary outcome was overall survival within 30 days of verified SARS-CoV-2 infection. Secondary outcomes were hospital admission, admission to an ICU, and need for supplemental oxygen. RESULTS: A total of 112 patients with a cancer diagnosis and verified SARS-CoV-2 infection were identified. After one month of follow up, hospitalization was required for 54% (n = 61) and 21% of the patients had died and 14 of the 23 deceased cancer patients were ≥70 years. Most patients were classified with mild COVID-19 symptoms (66%, n = 74); however, 48% (n = 23) of the ≥70-year-olds patients were classified with severe or critical COVID-19 symptoms. Among the total study population, 61% (n = 68) had comorbidities and comorbidity were more frequently observed among the deceased (91%, n = 21) and older cancer patients (≥70 years, 81%, n = 39). CONCLUSIONS: Acknowledging the low sample size in this study, our work shows that age and comorbidities, but not recent cytotoxic therapy, are associated with adverse outcomes of SARS-CoV-2 infection for patients with solid cancer. Particularly, patients with progressive disease seem to be at greater risk of a fatal outcome from COVID-19.HighlightsAge, performance status, and comorbidities are strong predictors of adverse outcome in cancer patients with SARS-CoV-2 infection.Patients with progressive cancer disease seem to be at greater risk of a fatal outcome from COVID-19.Recent cytotoxic therapy, however, did not seem to be associated with increased risk for adverse outcomes of SARS-CoV-2 infection for patients with solid cancer.

Patients' preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study.

BACKGROUND: Patients with HER2-positive early breast cancer (EBC) preferred subcutaneous (s.c.) trastuzumab, delivered via single-use injection device (SID), over the intravenous (i.v.) formulation (Cohort 1 of the PrefHer study: NCT01401166). Here, we report patient preference, healthcare professional satisfaction, and safety data pooled from Cohort 1 and also Cohort 2, where s.c. trastuzumab was delivered via hand-held syringe. PATIENTS AND METHODS: Patients were randomized to receive four adjuvant cycles of 600 mg fixed-dose s.c. trastuzumab followed by four cycles of standard i.v. trastuzumab, or vice versa. The primary endpoint was overall preference proportions for s.c. or i.v., assessed by patient interviews in the evaluable ITT population. RESULTS: A total of 245 patients were randomized to receive s.c. followed by i.v. and 243 received i.v. followed by s.c. (evaluable ITT populations: 235 and 232 patients, respectively). s.c. was preferred by 415/467 [88.9%; 95% confidence interval (CI) 85.7-91.6; P < 0.0001; two-sided test against null hypothesis of 65% s.c. preference]; 45/467 preferred i.v. (9.6%; 95% CI 7-13); 7/467 indicated no preference (1.5%; 95% CI 1-3). Clinician-reported adverse events occurred in 292/479 (61.0%) and 245/478 (51.3%) patients during the pooled s.c. and i.v. periods, respectively (P < 0.05; 2 × 2 χ(2)); 16 patients (3.3%) in each period experienced grade 3 events; none were grade 4/5. CONCLUSIONS: PrefHer revealed compelling and consistent patient preferences for s.c. over i.v. trastuzumab, regardless of SID or hand-held syringe delivery. s.c. was well tolerated and safety was consistent with previous reports, including the HannaH study (NCT00950300). No new safety signals were identified compared with the known i.v. profile in EBC. PrefHer and HannaH confirm that s.c. trastuzumab is a validated and preferred option over i.v. for improving patients' care in HER2-positive breast cancer. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01401166.

Risk of docetaxel-induced peripheral neuropathy among 1,725 Danish patients with early stage breast cancer.

Docetaxel-induced peripheral neuropathy (PN) can lead to sub-optimal treatment in women with early breast cancer. Here, we compare the frequency of dose reduction as a result of PN in two different adjuvant regimens. From the Danish Breast Cancer Cooperative Group READ trial we included 1,725 patients with early stage breast cancer who randomly were assigned to three cycles of epirubicin and cyclophosphamide followed by three cycles docetaxel (D100) or six cycles of cyclophosphamide and docetaxel (D75). Eligible patients completed chemotherapy, received docetaxel, and provided information on patient-reported outcome (secondary outcome of trial) including PN. Associations between PN and risk factors were analyzed by multivariate logistic regression. Overall 597 patients (34 %) reported PN, grades 2-4, during treatment, 194 (11 %) after the first cycle [early onset peripheral neuropathy (EPN)] and 403 (23 %) after subsequent cycles [later-onset peripheral neuropathy (LPN)]. The odds ratio (OR) of EPN was significantly increased for the D100 regimen (OR 3.10; 95 % CI 2.18-4.42) while this regimen was associated with reduced OR of LPN (OR 0.69; 95 % CI 0.54-0.88). Patients with PN received significantly lower cumulative doses of docetaxel than patients with no PN. Explorative analysis showed that OR of PN was significantly reduced if patients wore frozen gloves and socks during treatment (OR 0.56; 95 % CI 0.38-0.81) in the EPN group. Patients developing PN after the first cycle are less likely to receive docetaxel at the planned dose intensity and usage of frozen gloves and socks may modify the risk.

Determining in situ protein conformation and orientation from the amide-I sum-frequency generation spectrum: theory and experiment.

Vibrational sum-frequency generation (VSFG) spectra of the amide-I band of proteins can give detailed insight into biomolecular processes near membranes. However, interpreting these spectra in terms of the conformation and orientation of a protein can be difficult, especially in the case of complex proteins. Here we present a formalism to calculate the amide-I infrared (IR), Raman, and VSFG spectra based on the protein conformation and orientation distribution. Based on the protein conformation, we set up the amide-I exciton Hamiltonian for the backbone amide modes that generate the linear and nonlinear spectroscopic responses. In this Hamiltonian, we distinguish between nearest-neighbor and non-nearest-neighbor vibrational couplings. To determine nearest-neighbor couplings we use an ab initio 6-31G+(d) B3LYP-calculated map of the coupling as a function of the dihedral angles. The other couplings are estimated using the transition-dipole coupling model. The local-mode frequencies of hydrogen-bonded peptide bonds and of peptide bonds to proline residues are red-shifted. To obtain realistic hydrogen-bond shifts we perform a molecular dynamics simulation in which the protein is solvated by water. As a first application, we measure and calculate the amide-I IR, Raman, and VSFG spectra of cholera toxin B subunit docked to a model cell membrane. To deduce the orientation of the protein with respect to the membrane from the VSFG spectra, we compare the experimental and calculated spectral shapes of single-polarization results, rather than comparing the relative amplitudes of VSFG spectra recorded for different polarization conditions for infrared, visible, and sum-frequency light. We find that the intrinsic uncertainty in the interfacial refractive index--essential to determine the overall amplitude of the VSFG spectra--prohibits a meaningful comparison of the intensities of the different polarization combinations. In contrast, the spectral shape of most of the VSFG spectra is independent of the details of the interfacial refractive index and provides a reliable way of determining molecular interfacial orientation. Specifically, we find that the symmetry axis of the cholera toxin B subunit is oriented at an angle of 6° ± 17° relative to the surface normal of the lipid monolayer, in agreement with 5-fold binding between the toxin's five subunits and the receptor lipids in the membrane.

PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab.

BACKGROUND: This study was conducted to determine the frequency of PIK3CA mutations and human epidermal growth factor receptor-2 (HER2) phosphorylation status (pHER2-Tyr1221/1222) and if PIK3CA, phosphatase and tensin homolog (PTEN), or pHER2 has an impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS: Two hundred and forty HER2-positive early-stage breast cancer patients receiving adjuvant treatment (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2) before administration of 1 year trastuzumab were assessable. PTEN and pHER2 expression were assessed by immunohistochemistry. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing. RESULTS: Five-year overall survival (OS) and invasive disease-free survival were 87.8% and 81.0%, respectively. Twenty-six percent of patients had a PIK3CA mutation, 24% were PTEN low, 45% pHER2 high, and 47% patients had increased PI3K pathway activation (PTEN low and/or PIK3CA mutation). No significant correlations were observed between the clinicopathological variables and PIK3CA, PTEN, and pHER2 status. In both univariate and multivariate analyses, patients with PIK3CA mutations or high PI3K pathway activity had a significant worse OS [multivariate: hazard ratio (HR) 2.14, 95% confidence interval (CI) 1.01-4.51, P=0.046; and HR 2.35, 95% CI 1.10-5.04, P=0.03]. CONCLUSION: Patients with PIK3CA mutations or increased PI3K pathway activity had a significantly poorer survival despite adequate treatment with adjuvant chemotherapy and trastuzumab.

[One-sided acquired pulmonary lobar emphysema -- successful treatment with selective intubation and one-sided high-frequency ventilation]. / Erworbenes einseitiges Lobaremphysem von Frühgeborenen -- eine erfolgreiche Behandlung mit selektiver Intubation und einseitiger Hochfrequenzventilation.

Mechanical ventilation of preterm and newborn infants is associated with the risk of inducing a pulmonary baro- or volutrauma which may lead to one-sided acquired pulmonary lobar emphysema (APLE). We report a case of a preterm infant with severe APLE compromising hemodynamics due to mediastinal-shift, which was successfully treated with selective one-sided intubation and high-frequency ventilation. We assume that a brief malposition of the endotracheal tube initiated the emphysema of the left pulmonary lobe. We deduce recommendations for avoiding APLE from literature and our experience.

Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG).

The purpose of this study was to examine the effect on survival of delaying the start of adjuvant chemotherapy for early breast cancer for up to 3 months after surgery. In the nation-wide clinical trials of the Danish Breast Cancer Cooperative Group, 7501 breast cancer patients received chemotherapy within 3 months of surgery between 1977 and 1999: 352 with classical cyclofosfamide, metotrexate and 5-fluorouracil (CMF); 6065 with CMF i.v. and 1084 with cyclofosfamide, epirubicin and 5-fluorouracil. For the analysis, the time between surgery and the start of chemotherapy was divided into four strata (1-3, 4, 5 and 6-13 weeks). The results show that within the three groups of chemotherapy, there was an even distribution of known prognostic factors across the four strata of initiation of chemotherapy. There was no pattern indicating a benefit from early start of chemotherapy. No significant interactions were found for subgroups of patients with a poorer prognosis (many involved lymph nodes, high-grade malignancies or hormone receptor negative disease). In conclusion, we have found no evidence for a survival benefit due to early initiation of adjuvant chemotherapy within the first 2-3 months after surgery.

The prognostic relevance of estimates of proliferative activity in early breast cancer.

AIMS: Immunohistochemical estimates of cell proliferation evaluated with MIB-1 antibody have been suggested as prognostic indicators in different types of carcinoma. This study investigates whether MIB-1 scores add additional prognostic impact when evaluated together with classical clinicopathological parameters at diagnosis in early breast cancer patients. MATERIALS AND METHODS: Tumour specimens from 365 consecutively treated breast cancer patients were immunostained for MIB-1 and evaluated under the microscope using systematic random sampling accomplished by the CAST-grid system. RESULTS: The systematic random sampling technique resulted in MIB-1 estimates with very high interobserver and intraobserver reproducibilities (P < 0.0001). Median MIB-1 was 16% (range 0-83%). Patients were stratified by MIB-1 in tertiles, and increasing MIB-1 was significantly associated with poor overall and disease-specific survival in node-positive patients, but not in node-negative patients. High MIB-1 was significantly related to large tumour size, and strongly associated with high grade, high mitotic score, negative oestrogen receptor status and young age. In multivariate analysis, both with and without malignancy grade and number of mitoses included in the analysis, MIB-1 estimates showed no independent prognostic impact. CONCLUSIONS: High MIB-1 estimates did not add independent prognostic information at diagnosis when evaluated together with classical prognostic markers of early breast cancer.

Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients.

PURPOSE: Few studies have examined the possible importance of biologic prognostic factors in breast cancer connected with differentiation and growth in predicting response to a specific adjuvant treatment. HER2, epidermal growth factor receptor (EGFR), and p53 have all been suggested as possible markers of tamoxifen resistance. The aim of this study was to investigate interactions between adjuvant treatment with tamoxifen and the content of EGFR, HER2, and p53 in steroid receptor-positive patients. PATIENTS AND METHODS: A total of 1,716 high-risk postmenopausal breast cancer patients were randomly assigned to treatment with tamoxifen (868 women) or to observation (848 women) in a prospective trial (Danish Breast Cancer Cooperative Group's 77c protocol). The content of the steroid receptors and expression of p53, EGFR, and HER2 were determined by immunohistochemical analysis of paraffin-embedded tissue. The length of follow-up was 10 years. The end point for this analysis was disease-free survival. RESULTS: Multivariate analysis demonstrated no increased risk of recurrence after treatment with tamoxifen for HER2-, EGFR-, and p53-positive, high-risk, steroid receptor-positive patients. Patients with steroid receptor-positive tumors and positive immunohistochemical staining for HER2, EGFR or p53 benefited from treatment with tamoxifen for 1 year, although the latter variable contained independent prognostic information by itself. CONCLUSION: With the statistical power of the present randomized study, we did not find support for the hypothesis that HER2/EGFR or p53 status predicts benefit from tamoxifen treatment in estrogen receptor-positive patients with early-stage breast cancer. Thus, neither HER2, EGFR, nor p53 overexpression/accumulation should be used as a contraindication for giving tamoxifen.

Immunohistochemical assessment of oestrogen and progesterone receptors: correlations with the DCC method and clinical outcome in primary breast cancer patients.

Two different methods to determine steroid receptors were analysed with respect to their ability to estimate prognosis in primary breast cancer patients. The immunohistochemical assay (IHA) was compared with the dextran-coated charcoal (DCC) method of receptor determination. A random sample of 281 patients with invasive ductal carcinoma was drawn from 841 consecutive patients with primary breast carcinoma treated at Odense University Hospital between 1 January 1980 and 31 December 1990. Receptor determination by the DCC method had been carried out previously in 164 patients for the oestrogen receptor and in 132 patients for the progesterone receptor. The former group was reassessed by IHA with the antibody ER1D5, and the latter with the antibody PgR-ICA. The median follow-up time was 8.3 years (range 2.9-12.9 years). A cutoff of zero was used for the DCC method. Immunohistochemical results were quantified by counting in systematically random sampled fields of vision and values above zero were considered to be positive. Overall agreement of positive and negative cases was 86% for the oestrogen receptor and 83% for the progesterone receptor. Although the study included a limited number of patients, receptor positive cases fared better than negative cases in all situations. Investigation of the prognostic power revealed that classification based on IHA allowed better discrimination of patients than classification based on the DCC method. The reason for this difference might be because distinction between benign and malignant tissue is possible using the IHAmethod. Thus, IHAresults appear to be more clinically relevant.

Correlation between molecular genetic analyses and immunohistochemical evaluation of the epidermal growth factor receptor and p185HER2.

Several methods have been developed for the measurement of gene amplification and expression. This study compared different molecular genetic analyses (Southern blot analysis (SBA) and polymerase chain reaction (PCR)) with immunohistochemical (IHC) evaluation of the corresponding protein content. PCR may be used as a semi-quantitative analysis of gene amplification and allows DNA extraction from paraffin-embedded blocks. SBA is more accurate than PCR to measure the exact degree of amplification, but only DNA extracted from frozen or fresh tissue can be used. We examined 23 breast tumors and 16 lung tumors, where the genes HER-1 coding for the epidermal growth factor receptor (EGFR) and HER-2 coding for p185HER-2 were analysed. Furthermore, PCR performed on DNA from frozen tissue was compared to PCR on DNA extracted from paraffin-embedded blocks. The results showed correlation between the different analyses, especially when the gene copy number was highly amplified. Some breast tumors showed moderately increased gene copy number of HER-1 by SBA, but no increased protein content by IHC evaluation. This probably reflects that minor degrees of genetic aberrations are not sufficient to cause major biological disturbances, because regulatory cellular pathways are still operating.

Prognostic significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in primary breast cancer.

The uPA-mediated pathway of plasminogen activation is central to cancer metastasis. Whether uPA and PAI-1 are related to local recurrence, metastatic spread or both is not clear. We present a retrospective study of 429 primary breast cancer patients with a median follow-up of 5.1 years, in which the levels of uPA and PAI-1 in tumour extracts were analysed by means of an enzyme-linked immunosorbent assay. The median values of uPA and PAI-1, which were used as cut-off points, were 4.5 and 11.1 ng mg(-1) protein respectively. The levels of uPA and PAI-1 were correlated with tumour size, degree of anaplasia, steroid receptor status and number of positive nodes. Patients with high content of either uPA or PAI-1 had increased risk of relapse and death. We demonstrated an independent ability of PAI-1 to predict distant metastasis (relative risk 1.7, confidence limits 1.22 and 2.46) and that neither uPA nor PAI-1 provided any information regarding local recurrence.

Measurement in speed skating tournaments.

Twenty principal components analyses were performed on the results of 10 European and 10 World male speed skating championships. The first principal component obtained was defined as 'the ability to skate well at all tournament distances'. Therefore the rank order of the participants' skating ability could be estimated in an alternative way to allow validation of the scoring method currently in force. This validity coefficient turned out to be so high (r = 0.967) that it does not seem necessary to adopt a more sophisticated method, despite a few demonstrable shortcomings of the one in use. However, there remains a considerable proportion of variance (10-34%) that can not be explained by systematic aspects of skating ability.

Sub-structure of synthetic casein micelles.

Casein micelles of different composition were synthesized in various ways and their sub-structure was investigated with the electron microscope by means of thin sections. Earlier studies of Schmidt et al. (1974) using the freeze-fracturing technique had shown no differences in the sub-structure of natural micelles and artificial micelles containing Ca and casein only. Contrary to these results our present studies showed that for the production of synthetic casein micelles with the same sub-structure as the natural ones it is necessary to add at least 2 other ions to the casein solution besides Ca2+: these are phosphate and citrate. The citrate ions play an important role in forming the material of the dark framework of the micelles visible in electron micrographs of unstained thin sections. This supports the hypothesis of Pyne & McGann (1960) that casein micelles contain a citrate apatite.

Up-to-date access to cardiovascular problems.

The regulatory systems that control the pump function of the heart are the mechanisms that modulate the level of myocardial contractility and the lenght-tension relationship. The Frank-Starling relationship is important in balancing -- beat-to-beat -- the outputs of both ventricles. More drastic changes in circulatory dynamics, as during exercise and in old age, are accompanied by changes in myocardial contractility. The young heart normally becomes smaller during exercise, even though the cardiac output is markedly increased. The increased myocardial contractility and the normal distensibility make it possible that the length-tension curve moves to the left and upward. The old heart and the failing heart tend to a relative dilation, even though the cardiac output is markedly decreased. Because of the diminished myocardial contractility in combination with the decreased distensibility, the length-tension curve is moved to the right and downward.