Understanding clinical practice and survival outcomes in patients with unresectable stage III non-small-cell lung cancer in a single centre in Quebec.

Methods: A retrospective cohort study considered patients 18 or more years of age diagnosed between January 2007 and May 2018 with unresectable stage iii non-small-cell lung cancer (nsclc) who received combined chemoradiation (crt). Survival was analyzed using the Kaplan-Meier method to determine median overall (os) and progression-free survival (pfs) and the associated 95% confidence intervals (cis). Cox regression analysis was performed to identify factors prognostic for survival, including age, sex, smoking status, Eastern Cooperative Oncology Group performance status (ecog ps), histology, treatment type, tumour size, and nodal status. Results: Of 226 patients diagnosed with unresectable stage iii disease, 134 (59%) received combined crt. Mean age was 63 years; most patients were white, were current smokers, had an ecog ps of 0 or 1, and had nonsquamous histology. Median pfs was 7.03 months (95% ci: 5.6 months to 8.5 months), and os for the cohort was 18.7 months (95% ci: 12.4 months to 24.8 months). Of those patients, 78% would have been eligible for durvalumab consolidation therapy. Univariate analysis demonstrated a significant os benefit (p = 0.010) for concurrent crt (ccrt) compared with sequential crt (scrt). Disease-specific survival remained significantly better in the ccrt group (p = 0.004). No difference in pfs was found between the ccrt and scrt groups. In addition, tumour size and nodal involvement were significant discriminating factors for survival (p < 0.05). In this patient cohort, 64% of patients progressed and received subsequent therapy. Based on multivariate analysis, tumour size and nodal station were the only factors predictive of survival in patients with unresectable stage iii nsclc treated with crt. Conclusions: Combined crt has been the standard treatment for unresectable stage iii nsclc. In our study, a trend of better survival was seen for ccrt compared with scrt. Factors predictive of survival in patients with stage iii disease treated with crt were tumour size and nodal station. Most patients with stage iii disease would potentially be eligible for durvalumab maintenance therapy based on the eligibility criteria from the pacific trial. The use and effectiveness of novel treatments will have to be further studied in our real-world patient population and similar populations elsewhere.

The metastatic site does not influence PD-L1 expression in advanced non-small cell lung carcinoma.

INTRODUCTION: PD-L1 expression by immunohistochemistry (IHC) testing with Tumor Proportion Score (TPS) ≥50% and ≥1% is required to be eligible for first- and second-line Pembrolizumab treatment for metastatic non-small cell lung cancer (NSCLC) respectively. Stage IV NSCLC often presents with metastasis to multiple distant sites which are easily accessible for biopsy. Knowing whether PD-L1 IHC TPS can be indifferently measured from different metastatic site is therefore an important clinical question. In this study, we evaluated PD-L1 expression in NSCLC from varied distant metastatic sites. METHODS: A total of 580 NSCLC specimens of distant metastases were retrieved for study, including 35 paired samples from two different metastatic sites. The metastatic sites included brain, bone, remote lymph nodes, serous membranes (pleura, pericardium and peritoneum), extra-thoracic solid organs and skin/soft tissues. The samples were cytology cell blocks, small biopsies or surgical resections. IHC was performed using Dako PD-L1 IHC 22C3 pharmDx. A total of 100 viable tumor cells was required for adequacy. TPS ≥ 50% and 1-49% were defined as high and low PD-L1 expression respectively. RESULTS: PD-L1 TPS scores were not significantly different across a range of distant metastatic sites nor between metastases in paired samples. CONCLUSION: Our results suggest that the PD-L1 TPS scoring is similar across different metastatic sites and any site biopsied will yield necessary information for guiding clinical management.

Cytology cell blocks are suitable for immunohistochemical testing for PD-L1 in lung cancer.

Background: PD-L1 immunohistochemistry (IHC) testing is usually carried out on tissue blocks from core needle biopsy or surgical resections. In this study, we assessed the feasibility of using cytology cell blocks for PD-L1 IHC assay. Methods: A total of 1419 consecutive cases of non-small-cell lung cancer (NSCLC), including 371 cytology cell blocks, 809 small biopsies, and 239 surgical specimens, were included in the study. The cytology cell blocks were prepared with formalin only, methanol/alcohol only or both. PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1%-49% and ≥50% tumor cells. A total of 100 viable tumor cells were required for adequacy. Results: Of the cytology cell blocks, 92% of the specimens had an adequate number of tumor cells, not significantly different from small biopsies. The rate of TPS ≥50% differed between sample types and was observed in 42% of cytology cell blocks versus 36% of small biopsies (P = 0.04), and 29% of surgical resections (P = 0.001). The fixative methods did not affect the immunostaining, with overall PD-L1 high expression (TPS ≥50%) rates of 42% in formalin-fixed specimens versus 40% in specimens with combined fixation by methanol/alcohol and formalin (NS). The PD-L1 high expression rate was not associated with EGFR, ALK or KRAS molecular alterations. Higher stage (IV) was associated with higher PD-L1 TPS (P= 0.001). Conclusion: Our results show that when the TPS ≥50% is used as the end point, PD-L1 IHC performs well with cytology cell blocks. Cell blocks should be considered as a valuable resource for PD-L1 testing in advanced NSCLC. The clinical significance of higher PD-L1 IHC scores in cytology specimens needs to be evaluated prospectively.

Does the presence of emphysema increase the risk of radiation pneumonitis in lung cancer patients?

Introduction: Radiotherapy (rt) plays an important role in the treatment of lung cancer. One of the most common comorbidities in patients with lung cancer is pulmonary emphysema. The literature offers conflicting data about whether emphysema increases the occurrence and severity of radiation pneumonitis (rp). As a result, whether high doses of rt (with curative intent) should be avoided in patients with emphysema is still unclear. Objective: We measured the documented incidence of rp in patients with and without emphysema who received curative radiation treatment. Methods: This retrospective cohort study considered patients in the lung cancer clinical database of the Peter Brojde Lung Cancer Centre. Data from the database has been used previously for research studies, including a recent publication about emphysema grading, based on the percentage of lung occupied by emphysema on computed tomography (ct) imaging. Results: Using previously published methods, chest ct imaging for 498 patients with lung cancer was scored for the presence of emphysema. The analysis considered 114 patients who received at least 30 Gy radiation. Of those 114 patients, 64 (56%) had emphysema, with approximately 23% having severe or very severe disease. The incidence of rp was 34.4% in patients with emphysema (n = 22) and 32.0% in patients with no emphysema (n = 16, p = 0.48). No difference in the incidence of rp was evident between patients with various grades of emphysema (p = 0.96). Similarly, no difference in the incidence of rp was evident between the two treatment protocols-that is, definitive rt 17 (37%) and combined chemotherapy-rt 21 (31%, p = 0.5). Conclusions: In our cohort, the presence of emphysema on chest ct imaging was not associated with an increased risk of rp. That finding suggests that patients with lung cancer and emphysema should be offered rt when clinically indicated. However, further prospective studies will be needed for confirmation.

Lung cancer care trajectory at a Canadian centre: an evaluation of how wait times affect clinical outcomes.

BACKGROUND: Lung cancer continues to be one of the most common cancers in Canada, with approximately 28,400 new cases diagnosed each year. Although timely care can contribute substantially to quality of life for patients, it remains unclear whether it also improves patient outcomes. In this work, we used a set of quality indicators that aim to describe the quality of care in lung cancer patients. We assessed adherence with existing guidelines for timeliness of lung cancer care and concordance with existing standards of treatment, and we examined the association between timeliness of care and lung cancer survival. METHODS: Patients with lung cancer diagnosed between 2010 and 2015 were identified from the Pulmonary Division Lung Cancer Registry at our centre. RESULTS: We demonstrated that the interdisciplinary pulmonary oncology service successfully treated most of its patients within the recommended wait times. However, there is still work to be done to decrease variation in wait time. Our results demonstrate a significant association between wait time and survival, supporting the need for clinicians to optimize the patient care trajectory. INTERPRETATION: It would be helpful for Canadian clinicians treating patients with lung cancer to have wait time guidelines for all treatment modalities, together with standard definitions for all time intervals. Any reductions in wait times should be balanced against the need for thorough investigation before initiating treatment. We believe that our unique model of care leads to an acceleration of diagnostic steps. Avoiding any delay associated with referral to a medical oncologist for treatment could be an acceptable strategy with respect to reducing wait time.

Extensive study on physicochemical properties of polychlorinated biphenyls in a commercial ion trap mass spectrometer, relevance in analytical and environmental chemistry.

Polychlorinated biphenyls (PCBs) exist as 209 congeners, consisting of biphenyl molecules, where the number and substitution positions of halogen atoms are known to affect industrial uses, environmental transport mechanisms, distribution, fate, and toxicity. The complexity of the problem requires accurate physicochemical studies of an increasing number of congeners in order to understand the environmental and biological processes at play. This work presents a systematic study on the thermodynamic and kinetic properties of PCBs by quadrupole ion trap mass spectrometry. A clear relationship between structure and behavior of PCBs in mass spectrometry experiments has been observed. Overall data demonstrate that di-ortho congeners show lower thermodynamic stability and higher fragmentation rate than non/mono-ortho. Congeners follow different fragmentation mechanisms according to the number of chlorine atoms in ortho position of the biphenyl system. Experimental kinetic curves of mono/non-ortho and di-ortho congeners show a strong similarity with classical first-order kinetics curves; in particular, di-ortho congeners follow a first-order consecutive reaction, while mono/non-ortho follow a first-order parallel reaction. For each studied congener, the kinetic constant of reaction (fragmentation) has been determined. Data support environmental levels and biochemical transformations described in literature. The general picture of the PCB behavior inside a quadrupole ion trap provides the basis for the development of reliable and cost-effective analytical methods to the determination of ultra-low level trace of PCB congeners.

The potential role for acupuncture in treating symptoms in patients with lung cancer: an observational longitudinal study.

BACKGROUND: Most lung cancer patients experience multiple symptoms related either to the disease or its treatment. The commonly reported symptoms are pain, depression, anxiety, nausea, and poor well-being. The aim of the present study was to evaluate the effect of acupuncture as a potential treatment modality in symptomatic lung cancer patients. METHODS: This prospective observational study enrolled 33 lung cancer patients from the Peter Brojde Lung Cancer Centre between August 2010 and May 2012. All patients received 45-minute sessions of acupuncture, 1-2 times weekly for a minimum of 4 sessions. Symptom severity was assessed using the Edmonton Symptom Assessment System (esas) before and after completion of acupuncture. RESULTS: The study cohort included 30 patients with non-small- cell lung cancer and 3 with small-cell lung cancer. Mean age was 62 years (range: 36-88 years); 17 of the patients were women. Most of the patients had advanced-stage cancer (73%) and good performance status (Eastern Cooperative Oncology Group 0-1: 88%). Of these patients, 67% received anticancer treatment (chemotherapy or radiotherapy, or both) with acupuncture. Of the remaining 10 patients, 8 received acupuncture after a complete surgical resection of their tumour, and because of their advanced age, 2 received acupuncture and best supportive care. The median number of acupuncture sessions was 7 (interquartile range: 4-13 sessions). Statistically significant improvements in pain, appetite, nausea, nervousness, and well-being were observed. A clinically important improvement (2 points on the esas) was reported by 61% of patients for pain and by 33% for well-being. A significant positive correlation between improved well-being and the number of acupuncture sessions was observed. This correlation remained significant even after controlling for treatment and narcotic use. Receiver operating characteristic analysis demonstrated that a minimum of 6 acupuncture sessions are required for a 70% chance of a clinically important improvement in well-being. CONCLUSIONS: The present study is the first to demonstrate that acupuncture may be an effective approach for improving symptoms-in particular, pain and well-being-in lung cancer patients. Acupuncture is a safe and minimally invasive procedure, and it is potentially useful even in patients undergoing anticancer treatment.

Systemic lupus erythematosus developing immediately after necrotizing fasciitis.

Necrotizing fasciitis (NF) is a medical-surgical emergency characterized by severe bacterial infection that affects the subcutaneous tissue and spreads to the underlying fascia; usually it is caused by penetrating trauma, sometimes by surgical therapy, very rarely by minor insults such as insect bites. Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease involving virtually all the key components of the immune system. Although cases of post-infection autoimmunity were already described, a literature search using Pub Med and Medline revealed that SLE was never reported to occur in patients affected, immediately before, with NF. We observed and herein report, however, a case of a woman showing an insect-bite-induced NF, which was immediately followed by the development of a SLE. In conclusion, this case of postinfection autoimmunity provides early evidence of a patient developing SLE immediately after NF, and suggests that caution in the follow-up of NF is necessary, because NF might favor the development of a severe autoimmunity.

The predictive value of pre-treatment inflammatory markers in advanced non-small-cell lung cancer.

BACKGROUND: Accurate prediction of outcome in advanced non-small-cell lung cancer (NSCLC) remains challenging. Even within the same stage and treatment group, survival and response to treatment vary. We set out to determine the predictive value of inflammatory markers C-reactive protein (CRP) and white blood cells (WBCS) in patients with advanced NSCLC. PATIENTS AND METHODS: Patients were assigned a prognostic index (PI): 0 for crp 10 mg/L or less and WBCS 11x109/L or less, 1 if one of the two markers was elevated, and 2 if both markers were elevated. We then used chest computed tomography (CT) imaging to evaluate response after 2 cycles of chemotherapy treatment. RESULTS: Of 134 patients, 46 had a PI of 0; 60, a PI of 1; and 28, a PI of 2. Disease progressed in 41 patients. Progression was significantly more frequent among patients with a PI of 2 (p = 0.008). Median survival was 20.0 months for the PI 0 group, 10.4 months for the PI 1 group, and 7.9 months for the PI 2 group (p < 0.001). The PI was the only significant prognostic factor for survival even after adjustment for performance status, smoking, and weight loss (hazard ratio: 1.57; 95% confidence interval: 1.2 to 2.14; p = 0.004). CONCLUSIONS: Inflammatory state correlates significantly with both chemotherapy response and survival in stage IV NSCLC. The PI may provide additional guidance for therapeutic decision-making.

Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence.

INTRODUCTION: cP450aromatase deficiency provides clues for the understanding of the role of aromatase in prepubertal and pubertal human health and disease. Placental aromatization of androgens protects the female fetus against the virilizing action of fetal androgens. After birth, the dual effect of aromatase deficiency, excessive androgens, and insufficient estrogens is responsible for a variable clinical picture. Nineteen cases of aromatase gene (CYP19) deficiency have been reported. PHENOTYPE: Phenotype is dependent on sex and age. In newborns, aromatase deficiency should be considered in the etiology of 46,XX DSD, after ruling out congenital adrenal hyperplasia. In prepubertal aromatase deficient girls, high levels of ovarian androgens and gonadotropins facilitate the formation of ovarian cysts. Bone mineralization can be affected and bone aging is delayed. In pubertal girls, there is poor sexual development and abnormal virilization. The phenotype may be variable according to enzyme activity level. Insulin sensitivity may be abnormal in both men and women. Finally, aromatase might also play a role in the regulation of testicular cell mass in the newborn testis. CONCLUSION: Adequate interpretation of clinical data should lead to the analysis of the CYP19 gene for diagnostic confirmation and implementation of appropriate management.

Cytoplasmic beta-catenin is lacking in a subset of melanoma-associated naevi, but is detectable in naevus-associated melanomas: potential implications for melanoma tumorigenesis?

BACKGROUND: An excess of intracellular beta-catenin protein is triggered by various genetic alterations in melanoma cell lines, and has been suggested to play a role in melanoma tumorigenesis. OBJECTIVES: To investigate the role played in vivo by beta-catenin in melanoma tumorigenesis, we compared the cytoplasmic detection of beta-catenin in benign melanocytic cells vs. malignant melanoma cells presumably generated from these benign melanocytic cells. For this purpose, melanocytic naevi occurring in association with melanoma, which were suggested to be melanoma precursors, were compared with their associated melanoma for beta-catenin cytoplasmic immunoreactivity. METHODS: Fifty-seven consecutive cases of primary cutaneous melanoma were considered, and 15 of them were found to be associated with a melanocytic naevus portion. The naevus portion showed features of acquired melanocytic naevus (total 12 cases: five dysplastic, seven intradermal) or congenital growth pattern naevus (total three cases: one superficial, two deep). All specimens were immunohistochemically investigated for beta-catenin. RESULTS: Virtually all primary cutaneous melanomas, including those associated with a naevus portion, showed cytoplasmic beta-catenin positivity. However, the intradermal naevus portion was consistently cytoplasmic beta-catenin negative, while both the dysplastic and the congenital naevus portions were cytoplasmic beta-catenin positive. CONCLUSIONS: Beta-catenin excess may play a role in melanoma tumorigenesis, because beta-catenin cytoplasmic reactivity was found in primary cutaneous melanoma but not in its associated intradermal naevus precursor. As, however, beta-catenin cytoplasmic reactivity was detected not only in primary cutaneous melanoma but also in its associated dysplastic/congenital naevus precursors, beta-catenin stabilization alone is not sufficient to play a decisive role for melanoma onset.

Methyl group metabolism gene polymorphisms as modifier of breast cancer risk in Italian BRCA1/2 carriers.

BRCA1 and 2 are major cancer susceptibility genes but their penetrance is highly variable. The folate metabolism plays an important role in DNA methylation and its alterated metabolism is associated with cancer risk. The role of allele variants 677T and 1298C (MTHFR gene) and 2756G (MS gene) has been investigated as potentially modifying factors of BRCA gene penetrance, evaluated as age at first diagnosis of cancer, in 484 BRCA1/BRCA2 carriers and in 108 sporadic breast cancer cases as a control group. The genotype analysis has been performed by means of PCR/RFLP's. The analysis of association between a particular genotype and disease risk was performed using Cox Regression with time to breast or ovarian cancer onset as the end-point. The presence of 677T allele confers an increased risk of breast cancer in BRCA1 carriers (P = 0.007) and the presence of 1298C allele confers an increased risk of breast cancer in sporadic cases (P = 0.015).

Proton affinity of diastereoisomers of modified prolines using the kinetic method and density functional theory calculations: role of the cis/trans substituent on the endo/exo ring conformation.

The proton affinity (PA) of cis/trans-3-prolinoleucines and cis/trans-3-prolinoglutamic acids have been studied by the kinetic method and density functional theory (DFT) calculations. Several conformations of the neutral and the protonated modified prolines, in particular the endo and exo ring conformations, were analyzed with respect to their contribution to the PA values. When the substituent is an alkyl, both the diastereoisomers have the same PA value. However, the PA values for the diastereoisomers are different when the substituted chain contains functional groups (e.g. a carboxyl group). This variation in PA values could be attributed to the existence of intramolecular hydrogen bonds.

Proton affinity ladder for uridine and analogs: influence of the hydroxyl group on the sugar ring conformation.

A ladder of relative proton affinities (PA) for a series of modified uridines (e.g. araU, ddU, 5BrU, 5BrdU and 5IU) was established from competitive dissociations of proton-bound heterodimers using Cooks and co-workers' kinetic method. The studied heterodimers are constituted of a modified nucleoside and either an amino acid or a nucleoside with known PA value. These non-covalent heterodimers were prepared under electrospray conditions to be selected and dissociated into the ion-trap analyzer. These results allowed our PA ladder of uridine and deoxyuridine analogs substituted at the C-5 position in the uracil ring to be extended. From this scale, it was showed that the substitution of hydrogen atom at the C-2' position in the sugar ring by a hydroxyl group involves a decrease of about 7 kJ mol(-1). The experimental values for U, 5MeU, dU, 5MedU, ddU and araU are consistent with those obtained by DFT calculations (B3P86/6-31+G//B3LYP/6-31G(.)). Several neutral and protonated conformations of these compounds were considered, in particular the ring conformation of furanose and the orientation of the base with respect to the sugar ring. These calculated results showed the influence of sugar substituent on the conformation of the neutral form of theses nucleosides. However, the most stable protonated structure is the same for all the studied nucleosides except for araU, where the position of the anti 2'-OH group imposes a specific conformation.

A computational and experimental study of cation affinity (Na+) of nucleobases and modified nucleobases by electrospray ionization ion trap mass spectrometry.

Gas-phase Na+ affinities of modified or unmodified nucleobases were determined theoretically at the density functional theory level, with the B3P86 functional and the 6-31 + G* basis set, and experimentally using electrospray ionization ion trap mass spectrometry (ESI-ITMS) and the kinetic method. For the calculations, the sodium cation affinities (SCA) were obtained from energies of the most stable complexes of the free nucleobases. Experimentally and theoretically relative scales of cation affinities were determined using eight modified and unmodified nucleobases and a very good agreement was obtained.

Ab initio calculations of proton affinities of glycine, proline, cysteine and phenylalanine: comparison with the experimental values obtained using an electrospray ionisation ion trap mass spectrometer.

The proton affinities of four characteristic amino acids, glycine, proline, cysteine and phenylalanine, have been calculated using three different types of wave function, HF, DFT and MP2. These wave functions were combined with several basis sets using the valence double- or triple-xi with polarisation functions, and included or not a diffuse d function on heavy atoms. Calculations were carried out using Gaussian 98 on a LINUX system (2 GHz, 2 GB of RAM). The calculated results have been compared with the experimental values obtained using Cooks' kinetic method, in particular on an electrospray ionisation ion trap mass spectrometer. An excellent agreement was found between the experimental values and the theoretical results obtained using the B3P86/6-31+G*//B3LYP/6-31G* level.

Proton affinity of proline and modified prolines using the kinetic method: role of the conformation investigated by ab initio calculations.

The proton affinities of proline, cis-3-methylproline and cis-3-ethylproline have been measured by the kinetic method using an ion trap instrument; the values obtained are 936, 940.5, and 943 kJ mol(-1), respectively. The experimental values are consistent with those obtained by high-level ab initio calculations (B3LYP/6-31+G*//B3LYP/6-31G* and B3P86/6-31+G*//B3LYP/6-31G*). Several conformations of neutral and protonated proline were considered, in particular the endo and exo ring structure and the position of the carboxyl group. These results show the importance of the position of the hydrogen atom of the carboxyl group in determining the most stable protonated proline structure.