Predictors of Quality of Life Decline in Patients with Oligometastases treated with Stereotactic Ablative Radiotherapy: Analysis of the Population-Based SABR-5 Phase II Trial.

AIMS: Most patients experience stable quality of life (QoL) after stereotactic ablative radiotherapy (SABR) treatment for oligometastases. However, a subset of patients experience clinically relevant declines in QoL on post-treatment follow-up. This study aimed to identify risk factors for QoL decline. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases. Prospective QoL was measured using treatment site-specific tools at pre-treatment baseline and 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. The time to persistent QoL decline was calculated as the time from SABR to the first decline in QoL score meeting minimum clinically important difference with no improvement to baseline score on subsequent assessments. Univariable and multivariable logistic regression analyses were carried out to determine factors associated with QoL decline. RESULTS: One hundred and thirty-three patients were included with a median follow-up of 32 months (interquartile range 25-43). Thirty-five patients (26%) experienced a persistent decline in QoL. The median time until persistent QoL decline was not reached. The cumulative incidence of QoL decline at 2 and 3 years were 22% (95% confidence interval 14.0-29.6) and 40% (95% confidence interval 28.0-51.2), respectively. In multivariable analysis, disease progression (odds ratio 5.23, 95% confidence interval 1.59-17.47, P = 0.007) and adrenal metastases (odds ratio 9.70, 95% confidence interval 1.41-66.93, P = 0.021) were associated with a higher risk of QoL decline. Grade 3 or higher (odds ratio 3.88, 95% confidence interval 0.92-16.31, P = 0.064) and grade 2 or higher SABR-associated toxicity (odds ratio 2.24, 95% confidence interval 0.85-5.91, P = 0.10) were associated with an increased risk of QoL decline but did not reach statistical significance. CONCLUSIONS: Disease progression and adrenal lesion site were associated with persistent QoL decline following SABR. The development of grade 3 or higher toxicities was also associated with an increased risk, albeit not statistically significant. Further studies are needed, focusing on the QoL impact of metastasis-directed therapies.

Prospective Longitudinal Assessment of Quality of Life After Stereotactic Ablative Radiotherapy for Oligometastases: Analysis of the Population-based SABR-5 Phase II Trial.

AIMS: To evaluate longitudinal patient-reported quality of life (QoL) in patients treated with stereotactic ablative radiotherapy (SABR) for oligometastases. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases, conducted in six regional cancer centres in British Columbia, Canada from 2016 to 2020. Prospective QoL was measured using treatment site-specific QoL questionnaires at pre-treatment baseline and at 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. Patients with bone metastases were assessed with the Brief Pain Inventory (BPI). Patients with liver, adrenal and abdominopelvic lymph node metastases were assessed with the Functional Assessment of Chronic Illness Therapy-Abdominal Discomfort (FACIT-AD). Patients with lung and intrathoracic lymph node metastases were assessed with the Prospective Outcomes and Support Initiative (POSI) lung questionnaire. The two one-sided test procedure was used to assess equivalence between the worst QoL score and the baseline score of individual patients. The mean QoL at all time points was used to determine the trajectory of QoL response after SABR. The proportion of patients with 'stable', 'improved' or 'worsened' QoL was determined for all time points based on standard minimal clinically important differences (MCID; BPI worst pain = 2, BPI functional interference score [FIS] = 0.5, FACIT-AD Trial Outcome Index [TOI] = 8, POSI = 3). RESULTS: All enrolled patients with baseline QoL assessment and at least one follow-up assessment were analysed (n = 133). On equivalence testing, the patients' worst QoL scores were clinically different from baseline scores and met MCID (BPI worst pain mean difference: 1.8, 90% confidence interval 1.19 to 2.42]; BPI FIS mean difference: 1.68, 90% confidence interval 1.15 to 2.21; FACIT-AD TOI mean difference: -8.76, 90% confidence interval -11.29 to -6.24; POSI mean difference: -4.61, 90% confidence interval -6.09 to -3.14). However, the mean FIS transiently worsened at 9, 18 and 21 months but eventually returned to stable levels. The mean FACIT and POSI scores also worsened at 36 months, albeit with a limited number of responses (n = 4 and 8, respectively). Most patients reported stable QoL at all time points (range: BPI worst pain 71-82%, BPI FIS 45-78%, FACIT-AD TOI 50-100%, POSI 25-73%). Clinically significant stability, worsening and improvement were seen in 70%/13%/18% of patients at 3 months, 53%/28%/19% at 18 months and 63%/25%/13% at 36 months. CONCLUSIONS: Transient decreases in QoL that met MCID were seen between patients' worst QoL scores and baseline scores. However, most patients experienced stable QoL relative to pre-treatment levels on long-term follow-up. Further studies are needed to characterise patients at greatest risk for decreased QoL.

Perineurioma -a rare cause of proptosis.

Perineurioma is a rare benign soft tissue tumor arising from the peripheral nerve sheath. To date only two cases of orbital perineurioma have been reported in literature. A 45-year-old, with no comorbidities, presented with protrusion of the right eye since one-year. Examination revealed 8mm proptosis of the right eye. Dilated fundoscopy of the right eye showed a pale optic disc with choroidal folds temporal to it. Computerised Tomogram (CT) of the orbit showed a well-defined intraconal mass in the inferotemporal part of the orbit. A trans conjunctival orbitotomy with lateral canthotomy was performed and the tumor was removed en bloc. On immunohistochemistry, the tumour was negative for S-100 and showed patchy weak Epithelial Membrane Antigen positivity which was suggestive of a soft tissue perineurioma.

Isolated neurofibroma of the eyelid mimicking recurrent chalazion.

Neurofibroma is a peripheral nerve sheath tumor which is seen in neurofibromatosis type 1 and is characterized by various ophthalmic manifestations. Solitary neurofibroma of the eyelid is rare. We report a case of a 53-year-old female patient who presented with a painless swelling in the left upper lid of 4 years' duration. She had undergone surgery for the same lesion twice. The lesion was excised and histopathological examination revealed a solitary neurofibroma. She did not have any other features of generalized neurofibromatosis.

Primary squamous cell carcinoma arising from palpebral conjunctiva: A rare presentation.

Squamous cell carcinoma (SCC) of the conjunctiva usually arises from the limbal conjunctiva. Rarely, it can arise from the palpebral conjunctiva. We report a case of primary conjunctival SCC of the palpebral conjunctiva which was treated successfully.

Impact of malignancy on Clostridium difficile infection.

PURPOSE: The purpose of this study was to investigate the impact of malignancy and chemotherapy on the clinical and microbiological characteristics of Clostridium difficile infections (CDI). METHODS: CDI patients with a history of malignancy within 5 years were defined as the cancer group. The characteristics of the patients were compared according to the presence of malignancy. RESULTS: Of 580 patients with CDI, 159 (27.4 %) belonged to the cancer group and 421 (72.6 %) to the non-cancer group. More of the patients in the cancer group than those in the non-cancer group had been hospitalized within the prior 2 months (P < 0.001). Leukocytosis was more common in the non-cancer group (P = 0.034), while infection by PCR ribotype 017 strains was more common in the cancer group, with marginal significance (P = 0.07). Recurrence was more frequent in the cancer group (20.4 % vs. 9.5 %, P =0.005) and cancer was an independent risk factor for recurrence of CDI (OR = 2.66, 95 % CI 1.34-5.29, P =0.005). Age also contributed to the recurrence of CDI (OR = 1.03, 95 % CI 1.00-1.06, P =0.026). CONCLUSIONS: Malignancy and age are independent risk factors for recurrence of CDI. Cancer patients require careful observation for recurrence after treatment of CDI.

Orally active microtubule-targeting agent, MPT0B271, for the treatment of human non-small cell lung cancer, alone and in combination with erlotinib.

Microtubule-binding agents, such as taxanes and vinca alkaloids, are used in the treatment of cancer. The limitations of these treatments, such as resistance to therapy and the need for intravenous administration, have encouraged the development of new agents. MPT0B271 (N-[1-(4-Methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-1-oxy-isonicotinamide), an orally active microtubule-targeting agent, is a completely synthetic compound that possesses potent anticancer effects in vitro and in vivo. Tubulin polymerization assay and immunofluorescence experiment showed that MPT0B271 caused depolymerization of tubulin at both molecular and cellular levels. MPT0B271 reduced cell growth and viability at nanomolar concentrations in numerous cancer cell lines, including a multidrug-resistant cancer cell line NCI/ADR-RES. Further studies indicated that MPT0B271 is not a substrate of P-glycoprotein (P-gp), as determined by flow cytometric analysis of rhodamine-123 (Rh-123) dye efflux and the calcein acetoxymethyl ester (calcein AM) assay. MPT0B271 also caused G2/M cell-cycle arrest, accompanied by the up-regulation of cyclin B1, p-Thr161 Cdc2/p34, serine/threonine kinases polo-like kinase 1, aurora kinase A and B and the downregulation of Cdc25C and p-Tyr15 Cdc2/p34 protein levels. The appearance of MPM2 and the nuclear translocation of cyclin B1 denoted M phase arrest in MPT0B271-treated cells. Moreover, MPT0B271 induced cell apoptosis in a concentration-dependent manner; it also reduced the expression of Bcl-2, Bcl-xL, and Mcl-1 and increased the cleavage of caspase-3 and -7 and poly (ADP-ribose) polymerase (PARP). Finally, this study demonstrated that MPT0B271 in combination with erlotinib significantly inhibits the growth of the human non-small cell lung cancer A549 cells as compared with erlotinib treatment alone, both in vitro and in vivo. These findings identify MPT0B271 as a promising new tubulin-binding compound for the treatment of various cancers.

Clinical characteristics predicting early clinical failure after 72 h of antibiotic treatment in women with community-onset acute pyelonephritis: a prospective multicentre study.

In patients with community-onset acute pyelonephritis (CO-APN), assessing the risk factors for poor clinical response after 72 h of antibiotic treatment (early clinical failure) is important. The objectives of this study were to define those risk factors, and to assess whether early clinical failure influences mortality and treatment outcomes. We prospectively collected the clinical and microbiological data of women with CO-APN in South Korea from March 2010 to February 2012. The numbers of cases in the early clinical success and early clinical failure groups were 840 (79.1%) and 222 (20.9%), respectively. Final clinical failure and mortality were higher in the early clinical failure group than in the early clinical success group (14.9% vs 2.3%, p <0.001; 6.8% vs 0.1%, p 0.001, respectively). In a multiple logistic regression model, the risk factors for early clinical failure among the total 1062 patients were diabetes mellitus (OR 1.5; 95% CI 1.1-2.1), chronic liver diseases (OR 3.3; 95% CI 1.6-6.7), malignancy (OR 2.2; 95% CI 1.1-4.4), Pitt score ≥2 (OR 2.5; 95% CI 1.6-3.8), presence of azotaemia (OR 1.8; 95% CI 1.2-2.7), white blood cell count ≥20 000/mm(3) (OR 2.5; 95% CI 1.6-4.0), serum C-reactive protein level ≥20 mg/dL (OR 1.7; 95% CI 1.2-2.4), and history of antibiotic usage within the previous year (OR 1.5; 95% CI 1.1-2.2). Analysing the subgroup of 743 patients with CO-APN due to Enterobacteriaceae, fluoroquinolone resistance of the uropathogen was another factor associated with early clinical failure (OR 1.7; 95% CI 1.1-2.5). Simple variables of underlying diseases, previous antibiotic usage and initial laboratory test outcomes can be used to decide on the direction of treatment in CO-APN.

Meeting the health information needs of prostate cancer patients using personal health records.

BACKGROUND: There is interest in the use of health information technology in the form of personal health record (phr) systems to support patient needs for health information, care, and decision-making, particularly for patients with distressing, chronic diseases such as prostate cancer (pca). We sought feedback from pca patients who used a phr. METHODS: For 6 months, 22 pca patients in various phases of care at the BC Cancer Agency (bcca) were given access to a secure Web-based phr called provider, which they could use to view their medical records and use a set of support tools. Feedback was obtained using an end-of-study survey on usability, satisfaction, and concerns with provider. Site activity was recorded to assess usage patterns. RESULTS: Of the 17 patients who completed the study, 29% encountered some minor difficulties using provider. No security breaches were known to have occurred. The two most commonly accessed medical records were laboratory test results and transcribed doctor's notes. Of survey respondents, 94% were satisfied with the access to their medical records, 65% said that provider helped to answer their questions, 77% felt that their privacy and confidentiality were preserved, 65% felt that using provider helped them to communicate better with their physicians, 83% found new and useful information that they would not have received by talking to their health care providers, and 88% said that they would continue to use provider. CONCLUSIONS: Our results support the notion that phrs can provide cancer patients with timely access to their medical records and health information, and can assist in communication with health care providers, in knowledge generation, and in patient empowerment.

Incontinentia pigmenti.

Incontinentia pigmenti is an X- linked dominant condition characterized by cutaneous lesions associated with developmental defects of the eye, skeletal system and central nervous system. We report a case of incontinentia pigmenti in a 30 day old female infant who presented to us with skin eruptions over bilateral upper limbs, lower limbs and trunk since birth. She had linear verrucous plaques and vesicles distributed along the Blaschko's lines in addition to macular hyperpigmentation in a linear and whorled pattern involving the concerned areas. On ophthalmological examination, proliferative retinopathy in the right eye was noted.

Congenital angiomyoma of the tongue: case report.

Angiomyomas of the oral cavity are rare benign vascular neoplasms. In particular, the congenital form has not been reported before in the English language literature. We present a congenital angiomyoma of the tongue that was found on the posterior middle of the tongue in an infant. On MRI, the mass showed an isointense signal to muscle on the T1 weighted image and a slightly hyperintense signal on the T2 weighted image. Immunohistochemically, tumour cells were positive to desmin and smooth muscle actin, but negative to vimentin and S100. The treatment was surgical excision and no recurrence was found during the 26 month follow-up period.

Population-based study of biochemical and survival outcomes after permanent 125I brachytherapy for low- and intermediate-risk prostate cancer.

OBJECTIVES: To analyze the biochemical and survival outcomes after permanent low-dose-rate prostate brachytherapy in a large, consecutive, population-based cohort of patients. METHODS: A total of 1006 consecutive implants were performed from July 20, 1998 to October 23, 2003 for men with low-risk and "low-tier" intermediate-risk prostate cancer. The prescribed minimal peripheral dose was 144 Gy, using 0.33 mCi (125)I sources and a preplan technique with a strong posterior-peripheral dose bias. Most patients (65%) had received 6 months of androgen deprivation therapy. Supplemental external beam radiotherapy was not used. The prognostic features, dose metrics, and follow-up data were prospectively collected. Kaplan-Meier and Cox regression analyses were used to assess the factors associated with freedom from biochemical recurrence and survival. RESULTS: The median patient age at treatment was 66 years. The median follow-up was 54 months for biochemical outcomes and 66 months for survival. The actuarial freedom from biochemical recurrence rate was 95.6% +/- 1.6% at 5 years and 94.0% +/- 2.2% at 7 years. On multivariate analysis, the pretreatment prostate-specific antigen level (P = .03) and androgen deprivation therapy use (P = .04) were predictive of the freedom from biochemical recurrence. The actuarial rates of distant metastasis and disease-specific death at 5 years were both <1%. The overall survival rate at 5 years was 95.2% +/- 1.4% and was 93.4% +/- 1.8% at 7 years. On multivariate analysis, only age was predictive of overall survival (P = .011). CONCLUSIONS: When consistently planned and delivered, low-dose-rate brachytherapy, without supplemental external beam radiotherapy or intraoperative planning, can produce cancer-specific outcomes for men with low- and "low-tier" intermediate-risk prostate cancer at least equal to that produced by dose-escalated external beam radiotherapy or surgical prostatectomy.

Design and testing of a miniature broadband frequency domain photon migration instrument.

A board-level broadband frequency domain photon migration (mini-FDPM) instrument has been constructed to replace a conventional network-analyzer-based FDPM instrument. The mini-FDPM instrument with four wavelengths (681, 783, 823, and 850 nm), matches conventional FDPM instrument in performance (-88 dBm noise level, 100 dB dynamic range) and bandwidth (1 GHz), and recovers the same optical properties within about 6% in absorption and 4% in reduced scattering for liquid phantoms covering a wide range of relevant optical properties. Compared to the conventional FDPM instrument, the mini-FDPM instrument is more than 5x faster (approximately 200 ms per 401 modulation frequencies) and several orders of magnitude less in size and cost. Standard fiber-optic-based probes can be used with the mini-FDPM instrument, which increases applications in a number of clinically relevant measurement scenarios. By drastically reducing size and cost, FDPM miniaturization lowers barriers to access and will help promote FDPM in clinical research problems. The mini-FDPM instrument forms the core of a modular broadband diffuse optical spectroscopy instrument that can be used for a variety of clinical problems in imaging and functional monitoring (i.e., breast/skin cancer, brain activation, and exercise physiology).

Unique cytochromes P450 in human brain: implication in disease pathogenesis.

Cytochromes P450 is a family of heme proteins that metabolize xenobiotics including drugs. Unique human brain cytochrome P450 enzymes metabolize xenobiotics including drugs to active/inactive metabolites through biotransformation pathways that are different from the well-characterized ones in liver. We have identified an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 in human brain but not in liver or kidney from the same individual. Genotyping revealed the presence of the frame-shift mutation 138delT only in those subjects who expressed the brain variant CYP2D7, which metabolizes codeine exclusively to morphine unlike hepatic CYP2D6 that metabolizes codeine to nor codeine and morphine. CYP1A1 bioactivates polycyclic aromatic hydrocarbons to reactive DNA binding metabolites and initiates carcinogenesis. We have identified a unique splice variant of CYP1A1 having deletion of 87 bp of exon 6 which is present in human brain but not in liver of the same individual. We present evidence for the existence of biotransformation pathways in human brain that are dissimilar from known pathways in liver. Identification and characterization of novel CNS-specific P450 enzymes generated by alternate splicing of known genes or as yet unidentified genes may help predict consequences of exposure to xenobiotics including pesticides in the brain.

The expression of NMDA receptor 1 is associated with clinicopathological parameters and prognosis in the oral squamous cell carcinoma.

BACKGROUND: Glutamate activates the N-methyl-d-aspartate (NMDA) receptors and this receptor is involved in the proliferation and migration of various tumour cells in vitro. However, the relationship between NMDA receptor expression and clinical parameters in cancer patients is unclear. Therefore, NMDA receptor 1 (NMDAR1) expression along with its clinical significance was examined in patients with oral squamous cell carcinoma (OSCC). METHODS: Eighty-one tumour specimens from OSCC patients were used to determine the NMDAR1 expression level by immunohistochemical staining. The control was obtained from a matched normal adjacent mucosa. The cases were considered to be positive if reactivity was displayed in >25% of the cells. RESULTS: The NMDAR1 reactivity was positive in 50 of 81 cases, while it was negative in the control. NMDAR1 expression was significantly associated with a lymph node metastasis (P = 0.008), the tumour size (P < 0.001), and the cancer stage (P = 0.034). The patients whose tumours expressed NMDAR1 had a significantly poorer survival than the patients who were NMDAR1-negative (log-rank = 6.45, d.f. = 1, P = 0.011). CONCLUSIONS: The NMDAR1 overexpression was significantly associated with the prognosis-related factors. Therefore, it might be one of the prognostic markers of OSCC.

The shooty callus induced by suppression of tobacco CHRK1 receptor-like kinase is a phenocopy of the tobacco genetic tumor.

CHRK1 encodes a tobacco receptor-like kinase that contains a chitinase-like sequence in the extracellular domain. In a previous study, CHRK1-suppressed transgenic tobacco plants exhibited pleiotropic developmental abnormalities including spontaneous growth of shooty callus from emerging embryos in the absence of any exogenous hormones. In this study, we show that the CHRK1 shooty callus mimics tobacco genetic tumors in its morphology, physiology, and gene expression profiles. Similar to CHRK1 shooty callus, tobacco genetic tumors exhibit shooty callus morphology and hormone-independent shoot organogenesis. Both the CHRK1 callus and genetic tumors constitutively expressed KNOTTED1-type homeobox genes at the high levels, consistent with their vigorous shoot formation. These two types of calli exhibited cell death phenotypes, accompanied by high H2O2 production, increased ion leakage, and callose accumulation. Consistently, both types of calli constitutively expressed high levels of defense genes induced during pathogen-mediated HR cell death. These results, together with previous reports that both the CHRK1 shooty callus and tobacco genetic tumor contained high levels of cytokinin, indicate that CHRK1 shooty callus is a phenocopy of tobacco genetic tumor. CHRK1-mediated signal transduction may play a role in the formation of the genetic tumor in tobacco.

Infusion of beta-endorphin improves insulin resistance in fructose-fed rats.

In an attempt to probe the effect of beta-endorphin on insulin resistance, we used Wistar rats that were fed fructose-rich chow to induce insulin resistance. Insulin action on glucose disposal rate (GDR) was measured using the hyperinsulinemic euglycemic clamp technique, in which glucose (variable), insulin (40 mU/kg/min), and beta-endorphin (6 ng/kg/min) or vehicle were initiated simultaneously and continued for 120 min. A marked reduction in insulin-stimulated GDR was observed in fructose-fed rats compared to normal control rats. Infusion of beta-endorphin reversed the value of GDR, which was inhibited by naloxone and naloxonazine each at doses sufficient to block opioid mu-receptors. Opioid mu-receptors may therefore be activated by beta-endorphin to improve insulin resistance. Next, soleus muscle was isolated to investigate the effect of beta-endorphin on insulin signals. Insulin resistance in rats induced by excess fructose was associated with the impaired insulin receptor (IR), tyrosine autophosphorylation, and insulin receptor substrate (IRS)-1 protein content in addition to the significant decrease in IRS-1 tyrosine phosphorylation in soleus muscle. This impaired glucose transportation was also due to signaling defects that included an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and Akt serine phosphorylation. However, IR protein levels were not markedly changed in rats with insulin resistance. beta-endorphin infusion reversed the fructose-induced decrement in the insulin-signaling cascade with increased GDR. Apart from IR protein levels, infusion of beta-endorphin reversed the decrease in protein expression for the IRS-1, p85 regulatory subunit of PI3-kinase, and Akt serine phosphorylation in soleus muscle in fructose-fed rats. The decrease in insulin-stimulated protein expression of glucose transporter subtype 4 (GLUT 4) in fructose-fed rats returned to near-normal levels after beta-endorphin infusion. Infusion of beta-endorphin may improve insulin resistance by modulating the insulin-signaling pathway to reverse insulin responsiveness.