Navigating the labyrinth of peritoneal and extraperitoneal anatomy: abdominal spread made easy with a case based review.

Essential to understanding disease spread in abdomen is to separate the peritoneum from the extraperitoneum. These areas have distinct anatomy with well-define separate pathways. The peritoneum is comprised of connected recesses that are potential spaces, normally not imaged except when containing excess fluid or air. Peritoneal recesses are formed by the opposing peritoneal surfaces and subdivided by the attachments of the ligaments and mesenteries to the parietal peritoneum. Disease flows within the recesses by changes in abdominal pressure. This forms a distinct spread pattern. The extraperitoneum is traditionally stratified by the renal fascia into the anterior and posterior pararenal spaces and the perirenal space. The fascia contains and directs spread from the contained organs with the compartments. Each space has a unique spread pattern defined by the containing fascia. The extraperitoneum is connected to the mesenteries and ligaments forming the subperitoneal space. This space interconnects the extraperitoneum with the mesenteries allowing for the normal continuum of blood vessels, lymphatics, and nerves but also forms the pathways for bidirectional spread of disease.

Quantitation and predictors of short-term mortality following extrapleural pneumonectomy, pleurectomy/decortication, and nonoperative management for malignant pleural mesothelioma.

BACKGROUND: For malignant pleural mesothelioma (MPM), the benefit of resection, as well as the optimal surgical technique, remain controversial. In efforts to better refine patient selection, this retrospective observational cohort study queried the National Cancer Database in an effort to quantify and evaluate predictors of 30- and 90-day mortality between extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D), as well as nonoperative management. METHODS: After applying selection criteria, cumulative incidences of mortality by treatment paradigm were graphed for the unadjusted and propensity-matched populations, as well as for six a priori age-based intervals (≤60, 61-65, 66-70, 71-75, 76-80, and ≥81 years). The interaction between age and hazard ratio (HR) for mortality between treatment paradigms was also graphed. Cox multivariable analysis ascertained factors independently associated with 30- and 90-day mortality. RESULTS: Of 10,723 patients, 2,125 (19.8%) received resection (n=438 EPP, n=1,687 P/D) and 8,598 (80.2%) underwent nonoperative management. The unadjusted 30/90-day mortality for EPP, P/D, and all operated cases was 3.0%/8.0%, 5.4%/14.1%, and 4.9%/12.8%, respectively. There were no short-term mortality differences between EPP and P/D following propensity-matching, within each age interval, or between age subgroups on interaction testing (P>0.05 for all). Nonoperative patients had a crude 30- and 90-day mortality of 9.9% and 24.6%, respectively. Several variables were identified as predictors of short-term mortality, notably patient age (HR 1.022, P<0.001), Charlson-Deyo comorbidity index (HR 1.882, P<0.001), receipt of treatment at high-volume centers (HR 0.834, P=0.032) and induction chemotherapy (HR 1.735, P=0.025), among others. The patient (yearly) incremental increase in age conferred 2.0% (30 day) and 2.2% (90 day) increased risk of mortality (P<0.001). CONCLUSIONS: Quantitative estimates of age-associated 30- and 90-day mortality of EPP and P/D should be considered when potentially operable patients are counseled regarding the risks and benefits of resection.

Comparison of outcomes between metaplastic and triple-negative breast cancer patients.

PURPOSE: Metaplastic breast cancer (MBC) is a rare, aggressive variant of breast cancer that has been associated with poor clinical outcomes, as has triple-negative breast (TNBC) cancer. Limited studies compare the clinical characteristics and prognosis of MBC to TNBC. This study uses a large, contemporary US cancer database to compare clinical characteristics and survival outcomes for patients with MBC to those with TNBC. METHODS: The National Cancer Database was queried for women with cT1-4N1-3M0 MBC or TNBC diagnosed between 2004 and 2013 and treated with definitive surgery. Chi-squared analysis was performed to determine differences between the cohorts. Kaplan-Meier curves compared overall survival (OS), and Cox regression determined patient factors associated with OS. RESULTS: Altogether, 55,847 patients met the inclusion criteria; 50,705 (90.8%) had TNBC and 5,142 (9.2%) had MBC. Most patients had no comorbid conditions (82%), N0 disease (71%), poorly differentiated histology (77%), received chemotherapy (87%), and received radiation therapy (60%). Amongst all patients, patients with TNBC disease were observed to have greater OS than those with MBC (5-year OS 72.0% vs 55.8%, p < 0.001). The greater observed OS for patients with TNBC persisted when controlling for stage and when comparing propensity score matched cohorts. On Cox regression, lower age, T1 status, N0 status, chemotherapy, TNBC disease, and radiation therapy (RT) were associated with improved OS. CONCLUSIONS: MBC had an association with poorer OS compared to TNBC, while RT and chemotherapy receipt were associated with improved OS for patients regardless of stage. Further studies are needed to corroborate the conclusions herein.

Hydrogel Spacer Reduces Rectal Dose during Proton Therapy for Prostate Cancer: A Dosimetric Analysis.

PURPOSE: Proton therapy for prostate cancer may reduce bowel dose and risk of bowel symptoms relative to photon-based methods. Here, we determined the effect of using a biodegradable, injectable hydrogel spacer on rectal dose on plans for treating prostate cancer with intensity-modulated proton therapy (IMPT) or passive scattering proton therapy (PSPT). MATERIALS AND METHODS: Pairs of IMPT and PSPT plans for 9 patients were created from fused computed tomography/magnetic resonance imaging scans obtained before and after spacer injection. Calculated values of rectal V40, V60, V70, V80, and maximum dose (Dmax) were compared with Wilcoxon signed rank tests. Displacements at the base (BP), midgland (MP), and apex (AP) of the prostate relative to the anterior rectal wall with the spacer in place were averaged for each patient and correlated with V70 by using linear regression models. RESULTS: The presence of a spacer reduced all dosimetric parameters for both PSPT and IMPT, with the greatest difference in V70, which was 81.1% lower for PSPT-with-spacer than for IMPT-without-spacer. Median displacements at BP, MP, and AP were 12 mm (range 7-19), 2 mm (range 0-4), and 1 mm (range 0-5) without the spacer and 19 mm (range 12-23), 10 mm (range 8-16), and 7 mm (range 2-12) with the spacer. Modest linear trends were noted between rectal V70 and displacement for IMPT-with-spacer and PSPT-with-spacer. When displacement was ≥8 mm, V70 was ≤5.1% for IMPT-with-spacer and PSPT-with-spacer. CONCLUSION: Use of biodegradable hydrogel spacers for prostate cancer treatment provides a significant reduction of radiation dose to the rectum with proton therapy. Significant reductions in rectal dose occurred in both PSPT and IMPT plans, with the greatest reduction for IMPT-with-spacer relative to PSPT alone. Prospective studies are ongoing to assess the clinical impact of reducing rectal dose with hydrogel spacers.

Definitive hyperfractionated, accelerated proton reirradiation for patients with pelvic malignancies.

INTRODUCTION: Pelvic reirradiation (re-RT) presents challenges due to concerns for late toxicity to tissues-at-risk including pelvic bone marrow (PBM). We routinely utilize a hyperfractionated, accelerated re-RT for recurrent rectal or anal cancer in the setting of prior radiation. We hypothesized that proton beam radiation (PBR) is uniquely suited to limit doses to pelvic non-target tissues better than photon-based approaches. MATERIALS AND METHODS: All patients who received hyperfractionated, accelerated PBR re-RT to the pelvis from 2007 to 2017 were identified. Re-RT was delivered twice daily with a 6 h minimum interfraction interval at 1.5 Gray Relative Biological Effectiveness (Gy(RBE)) per fraction to a total dose of 39-45 Gy(RBE). Concurrent chemotherapy was given to all patients. Comparison photon plans were generated for dosimetric analysis. Dosimetric parameters compared using a matched-pair analysis and the Wilcoxon signed-rank test. Survival analysis was performed Kaplan Meier curves. RESULTS: Fifteen patients were identified, with a median prior pelvic RT dose of 50.4 Gy (range 25-80 Gy). Median time between the initial RT and PBRT re-RT was 4.7 years (range 1.0-36.1 years). In comparison to corresponding photon re-RT plans, PBR re-RT plans had lower mean PBM dose, and lower volume of PBM getting 5 Gy, 10 Gy, 20 Gy, and 30 Gy (p < 0.001, p < 0.001, p < 0.001, and p = 0.033, respectively).With median 13.9 months follow-up after PBR re-RT, five patients had developed local recurrences, and four patients had developed distant metastases. One-year overall survival following PBR re-RT was 67.5% and one-year progression free survival was 58.7%. No patients developed acute or late Grade 4 toxicity. CONCLUSION: PBR re-RT affords improved sparing of PBM compared with photon-based re-RT. Clinically, PBR re-RT is well-tolerated. However, given modest control rates with definitive re-RT without subsequent surgical resection, a multidisciplinary approach should be favored in this setting when feasible.

Stereotactic body radiation therapy versus conventionally fractionated radiation therapy for early stage non-small cell lung cancer.

PURPOSE: To date, no published randomized trials have shown stereotactic body radiation therapy (SBRT) to offer superior outcomes to conventionally fractionated radiation therapy (CFRT) for early-stage non-small cell lung cancer (NSCLC). The largest study to date, this investigation of a contemporary national database sought to evaluate practice patterns and survival between CFRT and SBRT. METHODS: The National Cancer Database was queried (2004-2015) for histologically-confirmed cT1-2aN0M0 NSCLC undergoing definitive CFRT or SBRT. Multivariable logistic regression ascertained factors associated with SBRT administration. Kaplan-Meier analysis evaluated overall survival (OS) before and following propensity matching. Cox proportional hazards modeling determined variables associated with OS. RESULTS: Of 23,088 patients, 2286 (10%) patients received CFRT and 20,802 (90%) SBRT. SBRT was less often delivered in African-Americans, patients with lower incomes, urban location, greater comorbidities, at non-academic centers, in larger tumors, and squamous histology (p < 0.05 for all). Patients treated with SBRT had a higher median OS (38.8 months vs. 28.1 months, p < 0.001). At median follow-up of 44.6 months, the median OS for the SBRT group was 38.8 months, versus 28.1 months for CFRT (p < 0.001). These findings persisted following propensity matching. Subgroup analyses demonstrated improved OS in multiple subcohorts (T2, Charlson comorbidity score 2-3, squamous histology). SBRT was also independently associated with OS on Cox multivariate analysis (p < 0.001). CONCLUSIONS: The largest such study to date (comprising of over 23,000 patients), this investigation demonstrates the survival benefit to ablative radiotherapy for early-stage NSCLC. Maturation of comparative prospective trials is eagerly awaited.

Adjuvant Management of Pathologic Node-Positive Disease After Definitive Surgery for Clinical T1-2 N0 Rectal Cancer.

INTRODUCTION: Patients with cT1-2N0M0 rectal cancer are often treated with up-front surgical resection, with adjuvant treatment reserved for patients upstaged with pathologic node-positive (pN+) disease at surgery. This study evaluates practice patterns and clinical outcomes when comparing different forms of adjuvant treatment for this patient population. METHODS: The National Cancer Data Base was queried for cT1-2N0M0 rectal cancer patients between 2004 and 2015 with postoperative pN+ disease treated without neoadjuvant treatment. Patients were divided into groups receiving observation, chemotherapy, or chemoradiotherapy (CRT). Multivariable logistic regression determined factors associated with receipt of adjuvant treatment. Kaplan-Meier curves compared overall survival (OS), and Cox regression determined patient factors associated with OS. RESULTS: Altogether, 1466 patients met the inclusion criteria; 536 patients (36.6%) received adjuvant chemotherapy, 413 (28.2%) received adjuvant CRT, and 517 (35.3%) were observed postoperatively. Use of adjuvant treatment was associated with superior median OS (124.1 vs. 51.1 months, P < .001), persisting after propensity score matching (124.0 vs. 61.9 months, P < .001), but not between adjuvant CRT versus chemotherapy on subset analysis. Patients with positive surgical margins receiving adjuvant CRT showed a trend toward OS improvement compared to patients managed with chemotherapy (54.9 vs. 47.4 months, P = .10). Increased age, pN2 status, positive margin status, and observation were associated with poorer OS. CONCLUSION: Most patients found to have pN+ disease after up-front surgery for cT1-2N0 rectal cancer receive adjuvant treatment, which is associated with improved OS. Chemotherapy or CRT are appropriate options, although there was a trend toward higher OS for patients with positive surgical margins receiving CRT.

Three-Dimensional Mechanical Loading Modulates the Osteogenic Response of Mesenchymal Stem Cells to Tumor-Derived Soluble Signals.

Dynamic mechanical loading is a strong anabolic signal in the skeleton, increasing osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) and increasing the bone-forming activity of osteoblasts, but its role in bone metastatic cancer is relatively unknown. In this study, we integrated a hydroxyapatite-containing three-dimensional (3D) scaffold platform with controlled mechanical stimulation to investigate the effects of cyclic compression on the interplay between breast cancer cells and BM-MSCs as it pertains to bone metastasis. BM-MSCs cultured within mineral-containing 3D poly(lactide-co-glycolide) (PLG) scaffolds differentiated into mature osteoblasts, and exposure to tumor-derived soluble factors promoted this process. When BM-MSCs undergoing osteogenic differentiation were exposed to conditioned media collected from mechanically loaded breast cancer cells, their gene expression of osteopontin was increased. This was further enhanced when mechanical compression was simultaneously applied to BM-MSCs, leading to more uniformly deposited osteopontin within scaffold pores. These results suggest that mechanical loading of 3D scaffold-based culture models may be utilized to evaluate the role of physiologically relevant physical cues on bone metastatic breast cancer. Furthermore, our data imply that cyclic mechanical stimuli within the bone microenvironment modulate interactions between tumor cells and BM-MSCs that are relevant to bone metastasis.

In vivo tibial compression decreases osteolysis and tumor formation in a human metastatic breast cancer model.

Bone metastasis, the leading cause of breast cancer-related deaths, is characterized by bone degradation due to increased osteoclastic activity. In contrast, mechanical stimulation in healthy individuals upregulates osteoblastic activity, leading to new bone formation. However, the effect of mechanical loading on the development and progression of metastatic breast cancer in bone remains unclear. Here, we developed a new in vivo model to investigate the role of skeletal mechanical stimuli on the development and osteolytic capability of secondary breast tumors. Specifically, we applied compressive loading to the tibia following intratibial injection of metastatic breast cancer cells (MDA-MB231) into the proximal compartment of female immunocompromised (SCID) mice. In the absence of loading, tibiae developed histologically-detectable tumors with associated osteolysis and excessive degradation of the proximal bone tissue. In contrast, mechanical loading dramatically reduced osteolysis and tumor formation and increased tibial cancellous mass due to trabecular thickening. These loading effects were similar to the baseline response we observed in non-injected SCID mice. In vitro mechanical loading of MDA-MB231 in a pathologically relevant 3D culture model suggested that the observed effects were not due to loading-induced tumor cell death, but rather mediated via decreased expression of genes interfering with bone homeostasis. Collectively, our results suggest that mechanical loading inhibits the growth and osteolytic capability of secondary breast tumors after their homing to the bone, which may inform future treatment of breast cancer patients with advanced disease.