Experimental high thoracic spinal cord injury impairs the cardiac and cerebrovascular response to orthostatic challenge in rats.

Spinal cord injury (SCI) impairs the cardiovascular responses to postural challenge, leading to the development of orthostatic hypotension (OH). Here, we apply lower body negative pressure (LBNP) to rodents with high-level SCI to demonstrate the usefulness of LBNP as a model for experimental OH studies, and to explore the effect of simulated OH on cardiovascular and cerebrovascular function following SCI. Male Wistar rats (n = 34) were subjected to a sham or T3-SCI surgery and survived into the chronic period postinjury (i.e., 8 wk). Cardiac function was tracked via ultrasound pre- to post-SCI to demonstrate the clinical utility of our model. At study termination, we conducted left-ventricular (LV) catheterization and insonated the middle cerebral artery to investigate the hemodynamic, cardiac, and cerebrovascular response to a mild dose of LBNP that is sufficient to mimic clinically defined OH in rats with T3-SCI but not sham animals. In response to mimicked OH, there was a greater decline in stroke volume, cardiac output, maximal LV pressure, and blood pressure in SCI compared with sham (P < 0.034), whereas heart rate was increased in sham but decreased in SCI (P < 0.029). SCI animals also had an exaggerated reduction in peak, minimum and mean middle cerebral artery flow, for a given change in blood pressure, in response to LBNP (P < 0.033), implying impaired dynamic cerebral autoregulation. Using a preclinical SCI model of OH, we demonstrate that complete high thoracic SCI impairs the cardiac response to OH and disrupts dynamic cerebral autoregulation.NEW & NOTEWORTHY This is the first use of LBNP to interrogate the cardiac and cerebrovascular responses to simulated OH in a preclinical study of SCI. Here, we demonstrate the utility of our simulated OH model and use it to demonstrate that SCI impairs the cardiac response to simulated OH and disrupts dynamic cerebrovascular autoregulation.

Investigating the role of the IGF axis as a predictor of biochemical recurrence in prostate cancer patients post-surgery.

BACKGROUND: Between 20% and 35% of prostate cancer (PCa) patients who undergo treatment with curative intent (ie, surgery or radiation therapy) for localized disease will experience biochemical recurrence (BCR). Alterations in the insulin-like growth factor (IGF) axis and PTEN expression have been implicated in the development and progression of several human tumors including PCa. We examined the expression of the insulin receptor (INSR), IGF-1 receptor (IGF-1R), PTEN, and AKT in radical prostatectomy tissue of patients who developed BCR post-surgery. METHODS: Tissue microarrays (TMA) of 130 patients post-radical prostatectomy (65 = BCR, 65 = non-BCR) were stained by immunohistochemistry for INSR, IGF-1R, PTEN, and AKT using optimized antibody protocols. INSR, IGF1-R, PTEN, and AKT expression between benign and cancerous tissue, and different Gleason grades was assessed. Kaplan-Meier survival curves were used to examine the relationship between proteins expression and BCR. RESULTS: INSR (P < 0.001), IGF-1R (P < 0.001), and AKT (P < 0.05) expression was significantly increased and PTEN (P < 0.001) was significantly decreased in cancerous versus benign tissue. There was no significant difference in INSR, IGF-1R, or AKT expression in the cancerous tissue of non-BCR versus BCR patients (P = 0.149, P = 0.990, P = 0.399, respectively). There was a significant decrease in PTEN expression in the malignant tissue of BCR versus non-BCR patients (P = 0.011). Combinational analysis of the tissue proteins identified a combination of decreased PTEN and increased AKT or increased INSR was associated with worst outcome. We found that in each case, our hypothesized worst group was most likely to experience BCR and this was significant for combinations of PTEN+INSR and PTEN+AKT but not PTEN+IGF-1R (P = 0.023, P = 0.028, P = 0.078, respectively). CONCLUSIONS: Low PTEN is associated with BCR and this association is strongly modified by high INSR and high AKT expression. Measurement of these proteins could help inform appropriate patient selection for postoperative adjuvant therapy and prevent BCR.

Seek and ye shall find: the importance of careful macroscopic examination and thorough sampling in 2522 cholecystectomy specimens.

Gallbladder dysplasia and carcinoma (GBDC) vary greatly in incidence worldwide. We aimed to determine their prevalence in an Irish population, to assess the influence of tissue sampling protocols upon GBDC diagnosis, and to correlate various macroscopic and microscopic features with GBDC. We retrospectively reviewed histology reports of cholecystectomy specimens accessioned from 2000 to 2013. A total of 2522 cholecystectomy reports were reviewed, from 1860 female and 662 male patients. Male patients were significantly older (54.8 vs 46.8 years). There were 29 cases of dysplasia (1.15%) and 12 cases of carcinoma (0.48%), of which 10 were primary gallbladder cancers (0.4%). In 83.4% of cases, there was pathologic or radiologic evidence of cholelithiasis. Histologic findings included chronic (91.1%) or acute (15.4%) cholecystitis, cholesterosis (10.9%), adenomyomatous hyperplasia (2.1%), xanthogranulomatous inflammation (2.02%), and "porcelain" gallbladder (0.2%). Patients with GBDC were more likely to have a macroscopically identifiable lesion (29.4% vs 1.8%, positive predictive value, 18.18%, negative predictive value, 99.03%). Gallbladder dysplasia and carcinoma patients also had larger gallstones (median, 19 vs 12 mm) and were more likely to have adenomyomatous hyperplasia (8.8% vs 2.05%). When cases with a macroscopically identifiable lesion or clinical details suggestive of a gallbladder tumour were excluded (n = 2385), GBDC was significantly more frequently diagnosed if multiple tissue blocks had been sampled (2.91% vs 0.76%; relative risk (RR), 3.836). Rates of GBDC in Irish cholecystectomy specimens are low. The absence of a macroscopically identifiable lesion has a high (but not 100%) negative predictive value for GBDC. Sampling with more than 1 block significantly increases pickup rates of GBDC in these cases.

High-grade histologic features of DCIS are associated with R5 rather than R3 calcifications in breast screening mammography.

Mammographic calcification is an important radiologic feature of early breast carcinoma whose index of suspicion for malignancy may be reported by a five-tier R-category system. This study aims to describe the histologic diagnoses underlying screen-detected mammographic calcifications using both digital and screen-film mammography, and to correlate these findings with radiologic R-categories. Patients attending the Merrion Breast Screening Unit in Dublin between 2000 and 2011 were identified, who underwent needle-core biopsy for assessment of mammographic calcifications without associated mass or architectural distortion. Radiologic R-category was correlated with biopsy and excision histology reports. A total of 776 cases of calcification were identified, involving 769 individual patients. The radiologic R-categories were as follows: R3 513 (66.1%), R4 192 (24.7%), R5 71 (9.1%). The positive predictive values for malignancy were R3 32.6%, R4 69.8%, R5 95.8%. Several histologic features of DCIS were associated with R5 rather than R3 radiology: high nuclear grade, solid or cribriform architecture, necrosis, periductal inflammation or fibrosis, and associated microinvasive or invasive carcinoma. Mammographic lesions and histologic whole and invasive tumors increased in size from R3 to R5. Radiologic size of calcifications correlated with whole (but not invasive) tumor size, although it tended to underestimate it by several millimeters. Digital-detected calcifications were more likely than screen-film detected to be categorized as R3 and less likely R4 or R5, and there was no significant difference in positive predictive value between the two imaging techniques in any R-category. In conclusion, histologic features of DCIS, in particular those associated with high grade, are associated with R5 radiology. There is no significant difference in positive predictive value for malignancy in any R-category between digital and screen-film mammography.

Primary care provider-led cancer survivorship care in the first 5 years following initial cancer treatment: a scoping review of the barriers and solutions to implementation.

PURPOSE: To synthesize the barriers to primary care provider (PCP)-led cancer survivorship care (≤ 5 years after initial cancer treatment) experienced by healthcare systems around the world, and to explore potential solutions that would succeed within a developed country. METHODS: A scoping review of peer-reviewed articles and grey literature was conducted. Four electronic databases (Medline, Embase, Web of Science Core Collection, and Google Scholar) were searched for articles prior to April 2021. RESULTS: Ninety-seven articles published across the globe (USA, Canada, Australia, European Union, and UK) met the review inclusion/exclusion criteria. The four most frequently discussed barriers to PCP-led survivorship care in healthcare systems were as follows: (1) insufficient communication between PCPs and cancer specialists, (2) limited PCP knowledge, (3) time restrictions for PCPs to provide comprehensive survivorship care, and (4) a lack of resources (e.g., survivorship care guidelines). Potential solutions to combat these barriers were as follows: (1) improving interdisciplinary communication, (2) bolstering PCP education, and (3) providing survivorship resources. CONCLUSIONS: This scoping review identified and summarized key barriers and solutions to the provision of PCP-led cancer survivorship care. Importantly, the findings from this review provide insight and direction to guide optimization of cancer care practice within BC's healthcare system. IMPLICATIONS FOR CANCER SURVIVORS: Optimizing the PCP-led survivorship care model will be a valuable contribution to the field of cancer survivorship care and will hopefully lead to more widespread use of this model, ultimately lessening the growing demand for cancer-specific care by cancer specialists.

The Extent of Axillary Lymph Node Clearance Required Following Detection of Sentinel Node Micrometastases.

Sentinel node (SN) micrometastases are an indication to proceed to axillary clearance. The aim of this study is to determine the extent and level of axillary clearance required for patients with SN micrometastases. All patients with SN micrometastases which were followed by axillary clearances from 1999 to 2007 were identified. Slides were reviewed by a histopathologist to detail characteristics of SN micrometastases including size and site. The SN micrometastases and primary tumor characteristics were correlated with the presence and level of non-SN micrometastases. Fifty patients who had micrometastases followed by axillary clearances were identified. Of those 18% (n = 9) had non-SN metastases.Seven patients had metastases to level I, one patient had metastases to level I and III and one patient had non-SN metastases to level III only. No patient had metastases to level II. Patients with non-SN metastases had very limited number of non-SNs involved (maximum 2 non-SNs). No variable, including site of the micrometastasis, was predictive of non-SN metastases. In patients with SN micrometastases, a limited level I axillary clearance can be justified in view of the low number of additional nodes involved and in particular, the low (4%) rate of spread to level II / III nodes.

Exercise and Prostate Cancer: Evidence and Proposed Mechanisms for Disease Modification.

Exercise has many potential benefits in relation to cancer. Apart from primary prevention, these include improvement of nonspecific cancer-related symptoms, amelioration of symptoms and cardiovascular risk factors related to cancer treatment, and improvements in various quality-of-life-related factors. Increasing evidence also points toward improved cancer-free and overall survival in cancer patients who undertake regular exercise, findings which should encourage further research in this area. Obesity is known to be associated with a proinflammatory, prothrombotic humoral milieu, which may promote aggressiveness in prostate cancer through interactions with NK-cell-mediated killing of circulating tumor cells, through platelet-circulating tumor cell interactions, and through alterations in adipokine and myokine profile among others. Physical activity reduces levels of systemic inflammatory mediators and so exercise may represent an accessible and cost-effective means of ameliorating the proinflammatory effects of obesity in cancer patients. This review outlines the evidence for the benefits of exercise in these patients, focusing on prostate cancer, and delineates current theories of the underlying biological mechanisms. Cancer Epidemiol Biomarkers Prev; 25(9); 1281-8. ©2016 AACR.

Kidney volume correlates with tumor diameter in renal cell carcinoma and is associated with histological poor prognostic features.

We aimed to correlate kidney volume (KV) in renal cell carcinoma nephrectomy specimens with tumor diameter (TD), macroscopic growth pattern, and histological features associated with poor prognosis. Histopathology reports, macroscopic specimen photographs, and selected glass slides were retrospectively reviewed. KV was approximated to the volume of an ellipsoid. A total of 273 specimens were identified with median KV 245 cm(3). Kidneys larger than this contained larger tumors (7.5 vs 4.5 cm). KV was significantly greater in tumors of high grade, involving perinephric fat, exhibiting venous invasion, and involving renal sinus. There was a robust linear correlation between KV and TD (r = 0.602) and a weaker correlation between kidney diameter (KD) and TD (r = 0.53). In pT1 tumors, KV (r = 0.40) also correlated better with TD than did KD (r = 0.27). By multiple regression analysis, both TD and venous invasion independently predicted both KD (R (2) = 38.27%) and KV (R (2) = 51.97%). KV and KD correlate well with TD and histopathological features of aggressiveness, although KD correlates better overall and in the pT1 subset.

Rectal site and suboptimal nodal yield predict systemic recurrence in resected colorectal carcinoma: a case-control study.

We assessed the contribution of histopathological features to systemic recurrence (SR) in patients with colorectal cancer, using a case-control design: 71 cases and 184 controls were included, with a mean time until SR of 1.4 ± 0.1 years and a mean follow-up of controls of 1.6 ± 0.06 years. Cases had significantly greater odds of rectal site (odds ratio [OR] = 1.82), stage ≥ pT3 (OR = 2.11), suboptimal (<12) lymph node yield (OR = 4.6), stage ≥ pN1 (OR = 2.46), KRAS mutation (OR = 2.76), and extramural venous invasion (OR = 1.97). By multiple regression analysis, rectal site, stage ≥ pT3, suboptimal lymph node yield, and lymph node positivity independently predicted SR. Rectal cancers were more likely to have a suboptimal node yield than nonrectal cancers (relative risk = 1.6) among the entire cohort. We conclude that rectal cancers have greater risk of SR than colon cancers. A lower yield of lymph nodes in rectal cancer specimens may contribute to this.

Microinvasive lobular carcinoma arising in a fibroadenoma.

A 51-year-old woman had a 35 mm circumscribed calcified lesion identified on screening mammography, designated R4. Excision showed a fibroadenoma with multiple foci of lobular neoplasia (atypical lobular hyperplasia and classical lobular carcinoma in situ [LCIS]). A focus of microinvasive lobular carcinoma (MILC) was also present, confirmed on immunohistochemistry. The MILC cells were ER positive, Her-2-negative, and e-cadherin negative. Microinvasive carcinoma, defined as "invasive carcinoma with no focus measuring >1 mm" (TNM UICC 7th edition) is usually encountered in ductal carcinoma in situ but may occur with classical, florid, or pleomorphic LCIS. In one series MILC constituted 0.4% of all invasive lobular carcinomas and was present in 0.4% of all LCIS. MILC is a histologically subtle lesion, the identification of which lends further weight to the concept of lobular neoplasia as a precursor lesion. MILC has been observed in hamartoma but, to our knowledge, has not previously been reported in fibroadenoma.

Case report of a symptomatic giant renal oncocytoma.

Renal oncocytomas are benign tumours, often asymptomatic, and picked incidentally on radiological imaging. We present a case report of a symptomatic giant renal oncocytoma in a 61-year old man having lower back/right flank pain. A large right renal mass was identified on abdominal CT scan. Radiological features were not sufficient to differentiate this lesion from renal cancer. Right radical nephrectomy was performed. Typical features of oncocytoma, without evidence of malignancy, were seen on histological examination of the specimen. In this report, we discuss literature review of radiological, genetic, and pathological characteristics of renal oncocytoma.

Intranodal hybrid benign nerve sheath tumor.

Spindle cell lesions within lymph nodes generally raise concern for metastasis. We report the 1st intranodal hybrid schwannoma/perineurioma arising in an inguinal lymph node in a 13-year-old boy. Presentation comprised a painless, slowly enlarging mass in a patient with no clinical features of neurofibromatosis.

Axillary fine needle aspiration cytology for pre-operative staging of patients with screen-detected invasive breast carcinoma.

INTRODUCTION: Fine needle aspiration cytology (FNAC) of radiologically abnormal axillary lymph nodes in patients with breast cancer can identify patients suitable for primary axillary clearance (AC) rather than sentinel node biopsy, enabling surgical axillary staging by a single operation. This study assessed the accuracy of FNAC in predicting positive axillary lymph nodes. METHODS: 161 patients with screen-detected invasive carcinoma and who had pre-operative FNAC of a radiologically abnormal axillary lymph node were identified from two screening units, The axillary FNAC reports were correlated with sentinel node biopsy and AC reports, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated. RESULTS: FNAC had a moderate sensitivity (66.3%) and NPV (71.8%), and a high specificity (98.7%) and PPV (98.3%). Most patients (86%) had a single axillary operation. The sensitivity was highest in grade 3 (81.8%) and ductal type (77.8%) tumours. The sensitivity was lower in tumours of special type (34.8%), grade 1 tumours (50%) and those without lymphovascular invasion (LVI) (55.9%). The NPV was highest in pT1 (86.7%) and in grade 1 (84.5%) tumours, and lowest (44%) in tumours with LVI. The PPV was 100% in grade 1 and 3 tumours, stage pT2 and pT3 tumours and those without LVI, and was high (>96%) in all other groups. In lymph-node-positive patients, the mean number of lymph nodes involved was higher in the case of a positive (6.4) than negative FNAC (4.4). CONCLUSIONS: FNAC of ultrasonically abnormal axillary lymph nodes achieved surgical staging by a single operation in most patients with screen-detected invasive breast carcinoma, with moderate sensitivity and high specificity.