Chemotherapy-induced gut microbiome disruption, inflammation, and cognitive decline in female patients with breast cancer.

Chemotherapy is notorious for causing behavioral side effects (e.g., cognitive decline). Notably, the gut microbiome has recently been reported to communicate with the brain to affect behavior, including cognition. Thus, the aim of this clinical longitudinal observational study was to determine whether chemotherapy-induced disruption of the gut microbial community structure relates to cognitive decline and circulating inflammatory signals. Fecal samples, blood, and cognitive measures were collected from 77 patients with breast cancer before, during, and after chemotherapy. Chemotherapy altered the gut microbiome community structure and increased circulating TNF-α. Both the chemotherapy-induced changes in microbial relative abundance and decreased microbial diversity were related to elevated circulating pro-inflammatory cytokines TNF-α and IL-6. Participants reported subjective cognitive decline during chemotherapy, which was not related to changes in the gut microbiome or inflammatory markers. In contrast, a decrease in overall objective cognition was related to a decrease in microbial diversity, independent of circulating cytokines. Stratification of subjects, via a reliable change index based on 4 objective cognitive tests, identified objective cognitive decline in 35% of the subjects. Based on a differential microbial abundance analysis, those characterized by cognitive decline had unique taxonomic shifts (Faecalibacterium, Bacteroides, Fusicatenibacter, Erysipelotrichaceae UCG-003, and Subdoligranulum) over chemotherapy treatment compared to those without cognitive decline. Taken together, gut microbiome change was associated with cognitive decline during chemotherapy, independent of chemotherapy-induced inflammation. These results suggest that microbiome-related strategies may be useful for predicting and preventing behavioral side effects of chemotherapy.

Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Acidification and alkalinization pretreatments of biowastes and their effect on P solubility and dynamics when placed in soil.

BACKGROUND: Sustainability concerns as well as recent increases in fertilizer prices exacerbates the need to optimise the use of biowastes as fertilizers. For this reason, we investigated how different pretreatments affect the P dynamics when biofertilizers are placed in the soil. METHODS: Sewage sludge (SS), sewage sludge ash (SS-ash), meat and bone meal (MBM), and the solid fraction of biogas digestate (BGF) were pretreated with H2SO4, NaOH, and Ca(OH)2 and incubated for 2 and 12 days, respectively, in a one-dimensional reaction system for detailed studies of the interactions in the biomaterial-soil interface and the soil adjacent to the placement zone. RESULTS: Our results showed that acidification and treatment with NaOH increased the P solubility of the biomaterials. The P loss from the biomaterial layer to the soil was correlated with water-extractable P in the biomaterials (0.659) and water-extractable P in the soil (0.809). Acidification significantly increased the total amount of P depleted from the biomaterial to the soil whereas NaOH pre-treatment did not. However, for NaOH-treated SS and SS-ash, the apparent recoveries were significantly higher compared to the acidification due to a decrease in soil P sorption capacity as the soil pH increased due to residual alkalinity in the biomaterials. CONCLUSIONS: Acidification showed promising results by increasing the P solubility of all the biomaterials, and the alkalinization of SS and SS-ash with NaOH by increasing the apparent recovery in the soil. However, further studies are needed to assess the effects of these treatments on plant growth and P uptake.

Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study.

BACKGROUND: Genomic analysis of circulating tumor DNA (ctDNA) is increasingly incorporated into the clinical management of patients with advanced cancer. Beyond tumor profiling, ctDNA analysis also can enable calculation of circulating tumor fraction (TF), which has previously been found to be prognostic. While most prognostic models in metastatic cancer are tumor type specific and require significant patient-level data, quantification of TF in ctDNA has the potential to serve as a pragmatic, tumor-agnostic prognostic tool. PATIENTS AND METHODS: This study utilized a cohort of patients in a nationwide de-identified clinico-genomic database with metastatic castration-resistant prostate cancer (mCRPC), metastatic breast cancer (mBC), advanced non-small-cell lung cancer (aNSCLC), or metastatic colorectal cancer (mCRC) undergoing liquid biopsy testing as part of routine care. TF was calculated based on single-nucleotide polymorphism aneuploidy across the genome. Clinical, disease, laboratory, and treatment data were captured from the electronic health record. Overall survival (OS) was evaluated by TF level while controlling for relevant covariables. RESULTS: A total of 1725 patients were included: 198 mCRPC, 402 mBC, 902 aNSCLC, and 223 mCRC. TF ≥10% was highly correlated with OS in univariable analyses for all cancer types: mCRPC [hazard ratio (HR) 3.3, 95% confidence interval (CI) 2.04-5.34, P < 0.001], mBC (HR 2.4, 95% CI 1.71-3.37, P < 0.001), aNSCLC (HR 1.68, 95% CI 1.34-2.1, P < 0.001), and mCRC (HR 2.11, 95% CI 1.39-3.2, P < 0.001). Multivariable assessments of TF had similar point estimates and CIs, suggesting a consistent and independent association with survival. Exploratory analysis showed that TF remained consistently prognostic across a wide range of cutpoints. CONCLUSIONS: Plasma ctDNA TF is a pragmatic, independent prognostic biomarker across four advanced cancers with potential to guide clinical conversations around expected treatment outcomes. With further prospective validation, ctDNA TF could be incorporated into care paradigms to enable precision escalation and de-escalation of cancer therapy based on patient-level tumor biology.

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. METHODS: We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. RESULTS: Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. CONCLUSIONS: HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

Effect of Perioperative ß-Blockers on Pulmonary Complications among Patients with Chronic Obstructive Pulmonary Disease Undergoing Lung Resection Surgery.

The aim of this study is to determine if COPD patients undergoing lung resection with perioperative ß-blocker use are more likely to suffer postoperative COPD exacerbations than those that did not receive perioperative ß-blockers. Methods. A historical cohort study of COPD patients, undergoing lung resection surgery at Memorial Sloan-Kettering Cancer Center between 2002 and 2006. Primary outcomes were the rate of postoperative COPD exacerbations, defined as any initiation or increase of glucocorticoids for documented bronchospasm. Results. 520 patients with COPD were identified who underwent lung resection. Of these, 205 (39%) received perioperative ß-blockers and 315 (61%) did not. COPD was mild among 361 patients (69% of all patients), moderate in 117 patients (23%), and severe in 42 patients (8%). COPD exacerbations occurred among 11 (5.4%) patients who received perioperative ß-blockers and among 20 (6.3%) patients who did not. Secondary outcomes, which included respiratory failure, 30-day mortality, and the presence or absence of any cardiovascular complication, ICU transfer, cardiovascular complication, or readmission within 30 days, did not differ in prevalence between the two groups. Conclusions. This study implies that perioperative ß-blockers use among COPD patients undergoing lung resection surgery does not impact the rate of exacerbations.

A vibrational spectroscopy study on anserine and its aqueous solutions.

In this study based on vibrational spectroscopic measurements and Density Functional Theory (DFT), we aimed for a reliable interpretation of the IR and Raman spectra recorded for anserine in the solid phase and water (H2O) and heavy water (D2O) solutions. Initial DFT calculations at the B3LYP/6-31G(d) searched possible conformers of the anserine zwitterion using a systematic conformational search. The corresponding equilibrium geometrical parameters and vibrational spectral data were determined for each of the stable conformers (in water) by the geometry optimization and hessian calculations performed at the same level of theory using the polarized continuum model (PCM). The same calculations were repeated to determine the most energetically preferred dimer structure for the molecule and the associated geometry, force field and vibrational spectral data. The harmonic force constants obtained from these calculations were scaled by the Scaled Quantum Mechanical Force Field (SQM) method and then used in the calculation of the refined wavenumbers, potential energy distributions, IR and Raman intensities. These refined theoretical data, which confirm the zwitterion structure for anserine in the solid phase or aqueous solvents, revealed the remarkable effects of intermolecular hydrogen bonding on the structural properties and observed IR and Raman spectra of this molecule.

Long-term impact of prior rituximab therapy and early lymphocyte recovery on auto-SCT outcome for diffuse large B-cell lymphoma.

Early lymphocyte recovery following auto-SCT for non-Hodgkin's lymphoma (NHL) has been reported to be associated with improved outcome. The significance of early lymphocyte recovery following a stem cell transplant in NHL subtype diffuse large B-cell lymphoma (DLBCL) in the rituximab era remains unclear. Patients who underwent an auto-SCT at our institution for DLBCL during the time period 1998-2008 (n=115) were included in the study. Patient characteristics were well-balanced in both rituximab naïve and rituximab-exposed groups. Prior rituximab therapy did not affect lymphocyte recovery on day 14 or day 28. Lymphocyte recovery on day 14 and day 28 and prior rituximab had no impact on survival after auto-SCT for DLBCL, despite early benefit. Other factors such as age, stage at presentation, number of salvage regimens, mobilization procedure, conditioning regimen, pre-transplant radiation therapy and pre-transplant disease status had no impact on survival. Our data showed that the survival benefit with early lymphocyte recovery and prior rituximab seen in previous reports may be lost with longer follow-up. Prior rituximab therapy does not appear to influence the lymphocyte count at days 14 and 28 following auto-SCT. Our findings suggest that future trials should consider manipulating the immune system as a post transplant intervention to improve long-term outcome.

Mechanical examinations on dental implants with porous titanium coating.

Due to its good biocompatibility, porous titanium is an interesting material for biomedical applications. Bone tissue can grow inside the porous structure and maintain a long and stable connection between the implant and the human bone. To investigate its long term stability, the mechanical behavior of porous titanium was tested under static and dynamic conditions and was compared to human bone tissue. A promising application of this material is the coating of dental implants. A manufacturing technique was developed and implants were produced. These implants were fatigue tested according to modified ISO 14801 and the micro structural change was examined. The fatigue test was statically modeled using finite element analysis (FEA). The results show that the implants resist a continuous load which is comparable to the loading conditions in the human jaw. The experiments show that the porous titanium has bone-like mechanical properties. Additionally the porous titanium shows an anisotropic behavior of its mechanical properties depending on the alignment of the pores. Finally, other potential applications of porous titanium are outlined.

Significance of non-calcified pulmonary nodules in patients with extrapulmonary cancers.

BACKGROUND: This study sought to determine the rate and patterns of malignancy in patients with extrapulmonary cancers and non-calcified pulmonary nodules, and to develop a statistical model to guide clinicians regarding choice of patients for diagnostic biopsy. METHOD: The medical records of 151 patients evaluated at the Memorial Sloan-Kettering Cancer Center between January 1999 and December 2001 for non-calcified pulmonary nodules were reviewed. Nodules were considered malignant based on the results of a diagnostic biopsy, and were considered benign if their appearance remained stable 2 years after the initial study, if they resolved, or if a biopsy showed a non-malignant condition. RESULTS: Sixty four of 151 patients (42%) were diagnosed with malignant nodules; 32 had newly diagnosed lung cancers, 28 had metastatic spread of their primary cancers, and four had lesions that were either new cancers or of undetermined aetiology. On univariate analysis the likelihood of malignancy increased with nodule size, tobacco exposure, and the finding of a solitary nodule. On multivariable analysis only nodule size and tobacco exposure were predictive of malignancy. The model had good predictive accuracy (area under the curve 0.751) but had insufficient discrimination for use as a clinical tool to determine which patients should undergo diagnostic biopsy. CONCLUSION: Nearly half the non-calcified pulmonary nodules identified in this series were malignant. Lung cancer was more common than metastatic disease. These findings support the need for close interval follow up and a low threshold for diagnostic biopsy in patients with extrapulmonary cancers and non-calcified pulmonary nodules. In smokers, such lesions should raise concern for lung cancer.

Effect of polymorphisms on the replicative capacity of protease inhibitor-resistant HIV-1 variants under drug pressure.

The role of drug pressure on the replicative capacity of protease inhibitor-resistant HIV-1 variants and the contribution of a common amino-acid polymorphism in the protease gene (L63P) to this process were investigated. Using HIV-1 variants resistant to the protease inhibitors saquinavir (G48V/L90M) or indinavir (A71V/V82T/I84V), viral replication was studied in the presence or absence of inhibitor and a mutation at position 63. The initial changes diminished enzyme function of the protease and reduced replicative capacity for both virus mutants. Addition of the respective inhibitor blocked the wild-type, but was also able to delay the replication kinetics of either mutant, revealing the limits of resistance. Importantly, the polymorphic change L63P, although not conferring inhibitor resistance by itself, provided a significant replication benefit to both mutant viruses, particularly under drug pressure, and may reveal a far-reaching compensating power of polymorphic changes. This may drive evolution and the directed selection of protease inhibitor-resistant HIV-1 variants, a finding with significant clinical and diagnostic implications.

[Rapid analysis of biocompatibility with graded test samples exemplified by Ni-NiTi-Ti]. / Schnelle Analyse der Biokompatibilität mittels gradierter Probekörper am Beispiel von Ni-NiTi-Ti.

The biocompatibility of nickel-titanium alloys was investigated by single-culture experiments on functionally graded samples with a stepwise change in composition from nickel to titanium, including NiTi shape memory alloy of a 50:50 mixture. This approach permitted a considerable decrease of experimental resources by simultaneously studying a full variation of composition. The results indicate a good biocompatibility for a nickel content up to about 50%. The cells used in the biocompatibility studies comprised human osteoblast-like osteosarcoma cells (SAOS-2, MG-63), primary human osteoblasts (HOB), and murine fibroblasts (3T3).

Mutational status of overexpressed p16 in head and neck cancer: evidence for germline mutation of p16/p14ARF.

Inactivation of the p16 tumor suppressor gene is a common phenomenon in squamous cell carcinoma of the head and neck (SCCHN). Less commonly described is the observation of p16 overexpression in SCCHN. Since overexpression of p16 is a potent predictor of outcome in other cancers, we were interested in determining the level of expression of p16 in our SCCHN specimens as a prerequisite to later prognostic studies. We were also interested in determining the mutational status of p16 in these tumors, in order to determine whether the combination of overexpression and gene alteration may predict a different clinical outcome from overexpression alone. A total of 84 specimens of SCCHN were selected for study. These specimens were obtained from all major sites within the oral cavity, oropharynx, pharynx and larynx. The level of expression of p16 in SCCHN specimens was measured by semi-quantitative RT-PCR. In 35 cases, RNA was also isolated from matched normal tissue obtained from a negative tumor margin. In the other 49 cases, the expression level was compared with the level of expression measured in pooled normal RNA obtained from 10 specimens of normal epithelial tissue. Overexpression of p16 was documented when the level of expression in the tumor specimen was 2-fold or greater above the level of expression found in normal tissue. A total of 46 specimens demonstrated overexpression of p16 (55%). All specimens demonstrating overexpression were then subject to sequence analysis. Thirty specimens (65%) showed p16-specific gene alterations, ranging from intragenic deletions to single point mutations, and 15 of these cases concomitantly affect p14ARF. A single specimen demonstrated a silent point mutation within the p16 reading frame. This mutation produces a stop codon at residue 85 in the context of the p14ARF reading frame, predicting premature termination of p14ARF within a previously determined nucleolar localization signal. This observation suggests that in some cases at least, p14ARF may be a selective target for alteration, independently of p16. Analysis of a normal tissue specimen obtained from a negative tumor margin, and a blood sample obtained approximately five years after surgery indicate that this p14ARF-specific alteration may represent a germline mutation.

Bronchiolitis obliterans organizing pneumonia in cancer: a case series.

Bronchiolitis obliterans with organizing pneumonia (BOOP) is an infrequently encountered clinical condition that can mimic a number of other pathologic lung processes. The presentation of this treatable condition in cancer patients has not been described in any large series. We conducted a retrospective study of patients with BOOP at Memorial Sloan-Kettering Cancer Center, NewYork, NY, U.S.A. from January 1992 to December 1999. The type and treatment of primary cancer, clinical and radiographic features of initial BOOP presentation, and outcome following therapy were recorded. Forty-three patients with an underlying diagnosis of cancer were found on lung biopsy to have BOOP as an isolated entity. BOOP was encountered in patients with a variety of clinical presentations, and many types of malignancies. The symptom patterns were non-specific, as were the physiological abnormalities. The only clear relationship between the underlying malignancyand the diagnosis of BOOP at presentation was in the chest radiographic findings. Patients with solid organ tumors were more likely to have nodular or mass like radiographic abnormalities (81%) than to have diffuse infiltrates (19%). We observed the opposite pattern in patients with hematologic malignancies (22% vs.67%). The vast majority of patients recovered from this condition. In conclusion, For cancer patients, BOOP represents a treatable cause of lung disease with protean manifestations. BOOP can mimic pulmonary malignancy and pulmonary infection. In cancer patients, the evaluation of new pulmonary symptoms accompanied by radiographic changes should include a consideration of this diagnosis.

A newly recognized syndrome--radiation-related bronchiolitis obliterans and organizing pneumonia. A case report and literature review.

Bronchiolitis obliterans and organizing pneumonia (BOOP) is a syndrome that has been associated with a variety of underlying disorders, including infection, collagen vascular diseases and toxic fume inhalation. Rarely, however, BOOP has been associated with radiation- or chemotherapy-induced pulmonary toxicity. Over the past 3 years, several case series have reported BOOP in the unique setting of radiation in breast cancer patients. This study describes our experience with this newly recognized syndrome and a review of the English-language literature on this syndrome.

Fiberoptic bronchoscopy in allogeneic bone marrow transplantation: findings in the era of serum cytomegalovirus antigen surveillance.

STUDY OBJECTIVES: Pulmonary complications occur in half of allogeneic bone marrow transplantation (BMT) patients. The incidence of these complications has been reduced by prophylaxis against Pneumocystis carinii pneumonia, preemptive therapy in patients at high risk for cytomegalovirus (CMV) reactivation, and, more recently, screening for serum CMV antigen. Since fiberoptic bronchoscopy (FOB) has historically been the primary diagnostic test to evaluate BMT patients with pulmonary disease, a review was performed to determine the impact, if any, that current prophylaxis and screening policies may have had on FOB utility. DESIGN: The records of 174 adult patients undergoing BMT between January 1997 and December 1999 were reviewed to determine the diagnostic yield of FOB and the frequency by which FOB altered management. RESULTS: Sixty-one patients underwent 76 bronchoscopies. FOB was diagnostic in 32 patients (42.1% of cases) and directly changed management in 24 patients (31.6% of cases). Half of these changes included the withdrawal of an antimicrobial agent. The most common findings were infection (32 cases) and diffuse alveolar hemorrhage (6 cases). CMV was the most prevalent infection identified, but FOB resulted in the addition of antiviral therapy to only two patients. P carinii pneumonia was not diagnosed in any patient studied. CONCLUSIONS: These data suggest a changing spectrum of pulmonary disease in BMT patients. FOB has limited impact on the diagnoses of CMV disease or P carinii pneumonia with current prophylaxis and screening strategies. It may be useful in identifying other infectious etiologies and in eliminating unnecessary antimicrobials.

Unusual freshwater near-drowning syndrome in a hospitalized postlobectomy patient.

Near-drowning syndrome depends on the duration of submersion, the amount of fluid aspirated, and the severity of hypoxia. We report a case in which a patient developed ARDS shortly after undergoing a left upper lobectomy and a chest wall resection for a lung carcinoma. On further investigation, the ARDS was caused by near-drowning in a basin of freshwater: the patient's face was submerged by the patient's companion as part of a cultural tradition of trying to clean his lung. We believe that this case presents the etiology of freshwater near-drowning syndrome due to an ethnogenic practice not previously reported.