Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Matrix anisotropy promotes angiogenesis in a density-dependent manner.

Angiogenesis is necessary for wound healing, tumorigenesis, implant inosculation, and homeostasis. In each situation, matrix structure and mechanics play a role in determining whether new vasculatures can establish transport to new or hypoxic tissues. Neovessel growth and directional guidance are sensitive to three-dimensional (3-D) matrix anisotropy and density, although the individual and integrated roles of these matrix features have not been fully recapitulated in vitro. We developed a tension-based method to align 3-D collagen constructs seeded with microvessel fragments in matrices of three levels of collagen fibril anisotropy and two levels of collagen density. The extent and direction of neovessel growth from the parent microvessel fragments increased with matrix anisotropy and decreased with density. The proangiogenic effects of anisotropy were attenuated at higher matrix densities. We also examined the impact of matrix anisotropy in an experimental model of neovessel invasion across a tissue interface. Matrix density was found to dictate the success of interface crossing, whereas interface curvature and fibril alignment were found to control directional guidance. Our findings indicate that complex configurations of matrix density and alignment can facilitate or complicate the establishment or maintenance of vascular networks in pathological and homeostatic angiogenesis. Furthermore, we extend preexisting methods for tuning collagen anisotropy in thick constructs. This approach addresses gaps in tissue engineering and cell culture by supporting the inclusion of large multicellular structures in prealigned constructs.NEW & NOTEWORTHY Matrix anisotropy and density have a considerable effect on angiogenic vessel growth and directional guidance. However, the current literature relies on 2-D and simplified models of angiogenesis (e.g., tubulogenesis and vasculogenesis). We present a method to align 3-D collagen scaffolds embedded with microvessel fragments to different levels of anisotropy. Neovessel growth increases with anisotropy and decreases with density, which may guide angiogenic neovessels across tissue interfaces such as during implant inosculation and tumorigenesis.

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Fitness cost and realized heritability of resistance to spinosad in Chrysoperla carnea (Neuroptera: Chrysopidae).

The common green lacewing Chrysoperla carnea is a key biological control agent employed in integrated pest management (IPM) programs for managing various insect pests. Spinosad is used for the management of pests in ornamental plants, fruit trees, vegetable and field crops all over the world, including Pakistan. A field-collected population of C. carnea was selected with spinosad and fitness costs and realized heritability were investigated. After selection for five generations, C. carnea developed 12.65- and 73.37-fold resistance to spinosad compared to the field and UNSEL populations. The resistant population had a relative fitness of 1.47, with substantially higher emergence rate of healthy adults, fecundity and hatchability and shorter larval duration, pupal duration, and development time as compared to a susceptible laboratory population. Mean relative growth rate of larvae, intrinsic rate of natural population increase and biotic potential was higher for the spinosad-selected population compared to the susceptible laboratory population. Chrysoperla species are known to show resistance to insecticides which makes the predator compatible with most IPM systems. The realized heritability (h 2) value of spinosad resistance was 0.37 in spinosad-selected population of C. carnea.

Quality of Care for Prostate Cancer in Kashmir, India: A Real-World Study.

Purpose Despite the importance of quality care for patients with prostate cancer, significant gaps exist in healthcare delivery, including diagnosis and treatment. Our objective was to assess the quality of care (QoC) using retrospective data from prostate care patients in our center. Methods We performed a retrospective study of prostate cancer patients registered at a dedicated cancer care center in the Kashmir region from 2012 to 2020. A set of 15 quality indicators representing crucial facets of diagnosis, pathology, and treatment was identified from a comprehensive list developed and validated by other researchers. Results The final analysis of all indicators was conducted on 46 patients with a median age of 70 years (52-92 years). In the majority of patients, the diagnosis (89.1%) was made through a prostatic biopsy, while only five patients were diagnosed solely based on the prostate-specific antigen. Transrectal ultrasound (TRUS) or transurethral resection (TURP)-guided biopsy was documented in 84.8% of patients, with Gleason grading documented in 87.5% of patients. However, the number of positive cores was mentioned for only 25.7% of patients. Radical prostatectomy was the primary treatment for most patients with localized prostate cancer (58.3%). The majority of patients with metastatic prostate cancer were treated with orchidectomy (55%), owing to easy access and the lower cost of surgical castration. Conclusion The study demonstrated a lack of compliance with many QoC indicators at the diagnostic and therapeutic levels. However, large-scale, population-based studies are needed to establish the compliance of prostate cancer QoC in Kashmir. The quality indicator assessment can guide the necessary actions required to improve QoC for prostate cancer patients.

Genetic basis and realized heritability of laboratory selected spirotetramat resistance for insecticide resistance management in Oxycarenus hyalinipennis Costa (Hemiptera: Lygaeidae).

Dusky cotton bug, Oxycarenus hyalinipennis Costa (Hemiptera: Lygaeidae) is become a major pest of cotton. It causes damage to cotton by sucking the cell sap or by staining the cotton seed. Insect pests in Pakistan are mainly managed by use of insecticides, applying this practice leads to resistance development. In this study, O. hyalinipennis was selected with spirotetramat under laboratory conditions to investigate genetic mode of resistance to spirotetramat. Selection with spirotetramat for eleven generations resulted in a 727-fold resistance compared to the susceptible strain. The LC50 values of spirotetramat in both reciprocal crosses were significantly different from each other and degree of dominanace values were 0.25 for cross-1 and 0.01 for cross-2. Monogenic model proved the contribution of more than one gene in controlling the spirotetramat resistance. Moreover, the value for realized heritability of spirotetramat resistance was 0.13. It can be concluded that spirotetramat resistance was sex linked, polygenic and incompletely dominant. These findings could be helpful in management of spirotetramat resistance in O. hyalinipennis as incompletely dominant and polygenic resistance tend to develop slowly and is manageable.

Determination of the Genetic and Synergistic Suppression of a Methoxyfenozide-Resistant Strain of the House Fly Musca domestica L. (Diptera: Muscidae).

Musca domestica Linnaeus (house fly, Diptera: Muscidae) is a major veterinary and medical important pest all over the world. These flies have ability to develop resistance to insecticides. The present trial was performed to discover the inheritance mode (autosomal, dominance, number of genes involved) and preliminary mechanism of methoxyfenozide resistance in order to provide basic information necessary to develop resistance management strategy for this pest. A strain of M. domestica (MXY-SEL) was exposed to methoxyfenozide for 44 generations which developed a 5253.90-fold level of resistance to methoxyfenozide. The overlapping fiducial limits of LC50 values of the reciprocal crosses, F1 (MXY-SEL ♂ × Susceptible ♀) and F1† (MXY-SEL ♀ × Susceptible ♂), suggest that inheritance of methoxyfenozide resistance was an autosomal and likely completely dominant trait (DLC = 0.93 and 0.94 for F1 and F1†, respectively). Backcrosses of the F1 with the parental MXY-SEL or Susceptible population predict a polygenic mode of inheritance. Piperonyl butoxide significantly altered the LC50 values, suggesting enhanced detoxification by cytochrome P450-dependent monooxygenases is a major mechanism of resistance to methoxyfenozide in the MXY-SEL strain. The estimated realized heritability was 0.07 for methoxyfenozide. These results would be helpful for the better management of M. domestica.

Correction to: Determination of the Genetic and Synergistic Suppression of a Methoxyfenozide-Resistant Strain of the House Fly Musca domestica L. (Diptera: Muscidae).

Due to an unfortunate turn of events, the surname of the last author appeared incorrectly in the original publication as the name should have read Binyameen.

An outbreak of wound infection in cardiac surgery patients caused by Enterobacter cloacae arising from cardioplegia ice.

This paper describes an outbreak of postoperative sternal wound infections. A cardiac surgeon noted a cluster of serious infections leading to wound dehiscence, despite the fact that none of his colleagues had noticed a rise in infection rates. The infections were predominantly with Enterobacter cloacae, and molecular typing and serotyping showed these isolates to be indistinguishable. Observation of the surgeon's practice revealed nothing untoward, and there were no infections among his patients operated on in another hospital. There appeared to be no significant difference between the modes of operation of the different surgeons. The operating theatres were screened to exclude an environmental source, with samples cultured on CHROMagar Orientation, a selective/differential medium designed for urine samples. Further questioning revealed one difference between the practices of the different surgeons; this surgeon used semi-frozen Hartmann's solution to achieve cardioplegia. The freezer used for this was swabbed and yielded E. cloacae, indistinguishable from the clinical isolates. It is hypothesized that this organism contaminated the freezer, and that the contamination was passed on to the ice/slush solution, thus infecting the patients. There have been no more cases since the freezer was replaced, a rigorous cleaning schedule instituted, and steps taken to reduce the possibility of any further contamination.

Characterization of Phenacoccus solenopsis (Tinsley) (Homoptera: Pseudococcidae) Resistance to Emamectin Benzoate: Cross-Resistance Patterns and Fitness Cost Analysis.

Cotton mealybug Phenacoccus solenopsis (Tinsley) (Homoptera: Pseudococcidae) is a sucking pest of worldwide importance causing huge losses by feeding upon cotton in various parts of the world. Because of the importance of this pest, this research was carried out to select emamectin resistance in P. solenopsis in the laboratory to study cross-resistance, stability, realized heritability, and fitness cost of emamectin resistance. After selection from third generation (G3) to G6, P. solenopsis developed very high emamectin resistance (159.24-fold) when compared to a susceptible unselected population (Unsel pop). Population selected to emamectin benzoate conferred moderate (45.81-fold), low (14.06-fold), and no cross-resistance with abamectin, cypermethrin, and profenofos, respectively compared to the Unsel pop. A significant decline in emamectin resistance was observed in the resistant population when not exposed to emamectin from G7 to G13. The estimated realized heritability (h (2)) for emamectin resistance was 0.84. A high fitness cost was associated with emamectin resistance in P. solenopsis. Results of this study may be helpful in devising insecticide resistance management strategies for P. solenopsis.

Stability of Field-Selected Resistance to Conventional and Newer Chemistry Insecticides in the House Fly, Musca domestica L. (Diptera: Muscidae).

The house fly, Musca domestica L. (Diptera: Muscidae), is a pest of livestock and has the ability to develop resistance to different insecticides. We assessed the fluctuations in seasonal stability of house fly resistance to insecticides from poultry facility populations in Pakistan. House fly populations were collected from poultry facilities located at Khanewal, Punjab, Pakistan in three seasons (July, November, and March) to investigate the fluctuations in their resistance to conventional (organophosphate, pyrethroid) and novel chemistry (spinosyn, oxadiazine, neonicotinoid) insecticides. Laboratory bioassays were performed using the feeding method of mixing insecticide concentrations with 20% sugar solutions, and cotton pads dipped in insecticide solutions were provided to tested adult flies. Bioassay results showed that all house fly populations had varying degrees of susceptibility to tested insecticides. Comparisons between populations at different seasons showed a significant fluctuation in susceptibility to organophosphate, pyrethroid, spinosyn, oxadiazine, and neonicotinoid insecticides. Highest resistant levels were found for organophosphate when compared with other tested insecticides. The resistance to conventional insecticides decreased significantly in March compared with July and November, while resistance to oxadiazine and avermectins decreased significantly in November. However, resistance to spinosad and imidacloprid remained stable throughout the seasons. All conventional and novel chemistry insecticides were significantly correlated with each other in all tested seasons except nitenpyram/lambda-cyhalothrin and nitenpyram/imidacloprid. Our data suggests that the variation in house fly resistance among seasons could be due to fitness costs or to the cessation of selection pressure in the off-season. These results have significant implications for the use of insecticides in house fly management.

Early experience with the Toronto stentless porcine valve.

Stentless porcine valves in the aortic position offer many theoretic advantages, but their clinical performance has not been adequately defined. We evaluated the clinical and echocardiographic results of 103 patients who had aortic valve replacement with the Toronto stentless porcine valve over a 2-year period. There were 67 men with a mean age of 68 years. The predominant native valve lesion was aortic stenosis (64%), and 4 patients had prosthetic valve dysfunction. Forty-two patients had concomitant procedures. The 30-day mortality rate was 3.3% (n = 2) for isolated valve replacement and 5.8% (n = 6) for the series. The sole determinant of early death was poor left ventricular function. There were three late deaths due to non-valve-related complications over a median follow-up of 11.87 months. In addition, prosthetic valve endocarditis developed in 1 patient, necessitating a homograft valve replacement at 6 weeks. Doppler echocardiography performed at 3 to 6 months showed low peak and mean transvalvular gradients, with no substantial change at 1 year. None of the patients showed signs of clinically significant aortic regurgitation, although echocardiography demonstrated trivial or mild regurgitation in 12 patients at discharge or early follow-up, which was less marked or absent at 1 year. We conclude that the Toronto stentless porcine valve appears to offer promising early results.

Malignant lymphoma in Al-Qassim, Saudi Arabia, reclassified according to the WHO classification.

OBJECTIVE: To determine the frequency of various types of malignant lymphoma (ML) in the Al-Qassim region of Kingdom of Saudi Arabia (KSA) according to recently introduced the WHO classification. METHODS: For this retrospective analysis, material was available in 385 out of 519 cases diagnosed as ML from 1988-2007. Morphological assessment was followed by immunohistochemistry using a panel of antibodies. The study was conducted at Prince Faisal Oncology Centre (PFOC) of King Fahad Specialist Hospital (KFSH), Buraidah, Al-Qassim, KSA. RESULTS: Out of 385 cases reviewed, 251 (65.2%) had non-Hodgkin lymphoma (NHL) and 117 (30.4%) had Hodgkin lymphoma (HL). Male preponderance (male to female ratio 1.6:1) and a wide age range was observed (6 months to 103 years). B cell neoplasms were the most common NHL seen (81.6%) and diffuse large B cell lymphoma (DLBCL) was the most frequent type of NHL encountered (50.1%). Indolent lymphomas like follicular lymphoma (FL) and small lymphocytic lymphoma (SLL) were rather uncommon (13.2%). T cell lymphoma comprised 18.3% of the NHL. The most common type of HL was nodular sclerosis classical Hodgkin lymphoma (NSCHL) (68.3%). CONCLUSION: In Al-Qassim region of KSA, NHL is the most common ML seen and DLBCL the most common type. Unlike other parts of KSA and Middle East, NSCHL is the most common type of HL encountered.

Self-dilatation of cervical oesophagogastric anastomotic stricture: a simple and effective technique.

Anastomotic stricture causing recurrent dysphagia is a serious problem occurring in patients after total oesophagectomy and cervical oesophagogastrostomy. We have developed a technique of self-dilatation of these strictures using a Foley catheter and have effectively managed ten patients. The technique is simple, painless, safe, cost-effective, and, as a domiciliary technique, patient acceptability is high.

Intragastric bile acid and symptoms in patients with an intrathoracic stomach after oesophagectomy.

Bile acid concentration and symptoms were evaluated in 24 patients after total oesophagectomy and gastric pull-up. Patients were randomly allocated to receive pyloroplasty or not. After operation all were followed for a minimum of 6 months. Bile acid concentration in the gastric juice was estimated. The mean(s.d.) bile acid concentration 6 months after surgery was similar in patients with and without pyloroplasty (34.9(30.1) and 25.0(24.2) mg/dl respectively). Postprandial discomfort and bilious eructations were the two most commonly observed symptoms in both groups. Other features noted were vomiting, anaemia and anorexia. These did not however seem to be related to intragastric bile acid concentration of individual patients in either group and occurred irrespective of whether pyloroplasty was performed or not.

Eyelid replantation eight months after traumatic avulsion.

We present a case in which a lower eyelid avulsed during trauma, was assumed to be lost, and was fortuitously discovered within a fistulous tract in the temporal fascia. The ectopic located lower eyelid was then replanted to its original location. The replanted lower eyelid and several lashes survived. We offer that in the rare instance when eyelid tissue cannot be immediately replanted after injury, temporary ectopic storage and future replantation may be a viable option.