Brett Morris, MD, PhD

BACKGROUND: Multi-parametric MRI has shown great promise to rapidly derive multiple quantitative imaging biomarkers for treatment response assessment.

PURPOSE: To evaluate a novel Deep-Learning-enhanced MUlti-PArametric MR sequence (DL-MUPA) for treatment response assessment for brain metastases patients treated with stereotactic radiosurgery (SRS) and head-and-neck (HnN) cancer patients undergoing conventionally fractionation adaptive radiation therapy.

METHODS: DL-MUPA derives quantitative T1 and T2 relaxation time maps from a single 4-6-minute scan denoised via DL method using least-squares dictionary fitting. Longitudinal phantom benchmarking was performed on a NIST-ISMRM phantom over one year. In patients, longitudinal DL-MUPA data were acquired on a 1.5T MR-simulator, including pre-treatment (PreTx) and every ~3 months after SRS (PostTx) in brain, and PreTx, mid-treatment and 3 months PostTx in HnN. Delta analysis was performed calculating changes of mean T1 and T2 values within gross tumor volumes (GTVs), residual disease (RD, HnN), parotids, and submandibular glands (HnN) for treatment response assessment. Uninvolved normal tissues (normal appearing white matter in brain, masseter in HnN) were evaluated to quantify within-subject repeatability.

RESULTS: Phantom benchmarking revealed excellent inter-session repeatability (coefficient of variance <0.9% for T1, <6.6% for T2), suggesting reliability for longitudinal studies once systematic biases are adjusted. Uninvolved normal tissue suggested acceptable within-subject repeatability (brain |ΔT1mean|<36ms/5.0%, |ΔT2mean|<2ms/5.0%, HnN |ΔT1mean|<69ms/7.0%, |ΔT2mean|<4ms/17.8% due to low T2). In brain, remarkable changes were noted in resolved metastasis (4-month PostTx ΔT1mean=155ms/13.7%) and necrotic settings (ΔT1mean=214-502ms/17.6-39.7%, ΔT2mean=7-41ms/8.7-41.4%, 6-month to 3-month PostTx). In HnN, two base of tongue tumors exhibited T2 enhancement (PostTx GTV ΔT2mean>7ms/12.8%, RD ΔT2mean>10ms/18.1%). A case with nodal disease resolved PostTx (GTV ΔT1mean=-541ms/-39.5%, ΔT2mean=-24ms/-32.7%, RD ΔT1mean=-400ms/-29.2%, ΔT2mean=-25ms/-35.3%). Enhancement was found in involved parotids (PostTx ΔT1mean>82ms/12.4%, ΔT2mean>6ms/13.4%) and submandibular glands (PostTx ΔT1mean>135ms/14.6%, ΔT2mean>17ms/34.5%) while the uninvolved organs remained stable.

CONCLUSIONS: Preliminary results suggest promise of DL-MUPA for treatment response assessment and highlight potential endpoints for functional sparing.

PMID:40196149 | PMC:PMC11975303

BACKGROUND: Patients with grade 2 glioma exhibit highly variable survival. Re-irradiation for recurrent disease has limited mature clinical data. We report treatment results of pulsed reduced-dose rate (PRDR) radiation for patients with recurrent grade 2 glioma.

METHODS: A retrospective analysis of 58 patients treated with PRDR from 2000 to 2021 was performed. Radiation was delivered in 0.2 Gy pulses every 3 minutes encompassing tumor plus margin. Survival outcomes and prognostic factors on outcome were Kaplan-Meier and Cox regression analyses.

RESULTS: The median survival from the date of initial surgery was 8.6 years (95% CI: 5.5-11.8 years). 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI: 8.3-17.0 months) and progression-free survival was 6.2 months (95% CI: 3.8-8.6 months). Overall response rate based on post-PRDR MRI was 36%. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months with 5 patients remaining disease-free, the longest at 8.2 and 11.4 years. PRDR was generally well tolerated.

CONCLUSIONS: To the best of our knowledge, this is the largest reported series of patients with recurrent grade 2 gliomas treated with PRDR radiation for disease recurrence. We demonstrate promising survival and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (>5 years) is observed in selected patients. For the entire cohort, 1p19q codeletion, KPS, and longer time from initial diagnosis to PRDR were associated with improved survival.

PMID:38845694 | PMC:PMC11154132 | DOI:10.1093/noajnl/vdae073

PURPOSE: Approximately 30% of patients with diffuse large B cell lymphoma (DLBCL) will develop relapsed or treatment-refractory disease after primary chemotherapy. Patients unable to undergo aggressive chemotherapy and stem cell transplant or chimeric antigen receptor T-cell (CAR T-cell) therapy have limited treatment options. Here, we investigated the safety and efficacy of combining obinutuzumab with cytoreductive radiation to all areas of disease in patients with relapsed DLBCL.

METHODS AND MATERIALS: A retrospective review of patients with treatment refractory DLBCL was performed. All patients were treated with external beam radiation to all sites of refractory disease with concurrent and adjuvant obinutuzumab. Toxicities were evaluated based on Common Terminology Criteria for Adverse Events v5.0 criteria. Kaplan-Meier analysis was used to calculate progression-free survival and overall survival.

RESULTS: Between 2016 and 2022, 7 patients with refractory DLBCL were treated with concurrent radiation and obinutuzumab. No grade 3 or greater treatment-related toxicity was observed. Four of the 7 patients had a complete response at the radiated site on first postradiation imaging. The median progression-free survival and overall survival were 30 months.

CONCLUSIONS: In this small cohort of treatment-refractory patients with DLBCL, the combination of radiation and obinutuzumab was well tolerated without excessive treatment-related toxicity. The combination resulted in durable disease control with a prolonged overall survival without additional treatment in a subset of patients.

PMID:38799107 | PMC:PMC11127189 | DOI:10.1016/j.adro.2024.101524

PURPOSE: Ablative local treatment of all radiographically detected metastatic sites in patients with oligometastatic non-small cell lung cancer (NSCLC) increases progression-free survival (PFS) and overall survival (OS). Prior studies demonstrated the safety of combining stereotactic body radiation therapy (SBRT) with single-agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy for patients with oligometastatic NSCLC.

METHODS AND MATERIALS: We conducted a phase 1b clinical trial in patients with oligometastatic NSCLC with up to 6 sites of extracranial metastatic disease. All sites of disease were treated with SBRT to a dose of 30 to 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days after completion of radiation using anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) immunotherapy for a total of 4 cycles followed by durvalumab alone until progression or toxicity.

RESULTS: Of the 17 patients enrolled in this study, 15 patients received at least 1 dose of combination immunotherapy per protocol. The study was closed early (17 of planned 21 patients) due to slow accrual during the COVID-19 pandemic. Grade 3+ treatment-related adverse events were observed in 6 patients (40%), of which only one was possibly related to the addition of SBRT to immunotherapy. Median PFS was 42 months and median OS has not yet been reached.

CONCLUSIONS: Delivering ablative SBRT to all sites of metastatic disease in combination with dual checkpoint immunotherapy did not result in excessive rates of toxicity compared with historical studies of dual checkpoint immunotherapy alone. Although the study was not powered for treatment efficacy results, durable PFS and OS results suggest potential therapeutic benefit compared with immunotherapy or radiation alone in this patient population.

PMID:38072321 | PMC:PMC10947887 | DOI:10.1016/j.ijrobp.2023.11.040

PURPOSE/OBJECTIVE(S): Approximately 30% of patients with diffuse large B cell lymphoma (DLBCL) will develop relapsed or treatment refractory disease following primary chemotherapy. Patients unable to undergo aggressive chemotherapy and stem cell transplant or CAR T-cell therapy have limited treatment options. Obinutuzumab, a type II CD-20 directed antibody, has been previously shown to have efficacy in these patients, though overall outcomes remain poor. Here, we investigated the safety and efficacy of combining obinutuzumab with cytoreductive radiation to all areas of disease in patients with relapsed DLBCL.

MATERIALS/METHODS: A retrospective review of patients with treatment refractory DLBCL was performed. All patients were treated with external beam radiation to all sites of refractory disease with concurrent and adjuvant obinutuzumab. Patients were treated with obinutuzumab 1600 mg on days 1 and 8 of cycle 1, followed by 800 mg on day 1 for 8 total cycles or until progression. Toxicities were evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Kaplan Meier analysis was utilized to calculate progression free survival (PFS) and overall survival (OS).

RESULTS: Between 2016 and 2022, 8 patients with refractory DLBCL were treated with concurrent radiation and obinutuzumab. The median age at time of treatment was 70. The most common radiation dose was 50 Gy in 25 fractions (range 37.5 - 50 Gy). No grade 3 or greater treatment related toxicity was observed. The median number of prior lymphoma treatments was 2 (range 1-5). Fifty percent of patients had a complete response at the irradiated site, and no patients progressed at the site of radiation. Median PFS and OS were 30 months, with two patients dying of unrelated disease without recurrence at 30 and 60 months. Four patients did not develop evidence of recurrence with only one patient receiving additional therapy (planned CAR-T following radiation completion).

CONCLUSION: In this small cohort of treatment refractory DLBCL patients, the combination of radiation and obinutuzumab was well tolerated without excessive treatment related toxicity. The combination resulted in durable disease control with prolonged overall survival without additional treatment in a subset of patients. Larger studies of this combination therapy in refractory DLBCL are warranted as bridging or definitive treatment.

PMID:37785514 | DOI:10.1016/j.ijrobp.2023.06.1694

PURPOSE/OBJECTIVE(S): The benefit of neoadjuvant radiation therapy for patients undergoing surgery for pancreatic ductal adenocarcinoma (PDAC) remains unclear. Stereotactic MR-guided adaptive radiation therapy (SMART) treatment to ablative doses is a newer technique that is well tolerated and has increased local control in unresectable pancreatic cancer. For resectable pancreatic cancer, neoadjuvant SMART has the potential to decrease local recurrence risk and positive margin rates. However, there is concern for perioperative risks associated with ablative dose treatments. We report the efficacy and safety of surgical resection in patients who have received neoadjuvant SMART at our institution.

MATERIALS/METHODS: We conducted a retrospective analysis of all consecutive patients diagnosed with PDAC who had noted vascular involvement of the celiac axis, superior mesenteric, and/or portal vessels between January 2016 and December 2022 at a single, high-volume, academic institution. Perioperative events were defined according to the Clavien-Dindo classification. The Kaplan Meier method was applied to estimate disease free survival (DFS) and overall survival (OS).

RESULTS: Seventeen patients with PDAC and vessel involvement at time of diagnosis who received SMART were included. Median follow-up time was 14.3 months; all patients underwent surgery, at a median time after radiation of 28 days (range: 15 - 90). Median length of postoperative stay was 7 days (range: 3 - 15). Five patients (29%) underwent vascular resection. Fifteen patients (88%) achieved R0 resection, with two R1 resections noted at the SMA and pancreatic neck respectively. Seven patients (41%) had adverse events attributable to surgery, with the majority being defined as abscess or infection (n = 5; 29%). One (6%) Clavien-Dindo grade III or higher toxicity was observed - a cortical cerebrovascular event following surgery. No major bleeding events requiring surgical intervention were noted. At time of event censorship, there were no observable locoregional failures. The median DFS and OS were not reached; however, 1-year DFS and OS were 62% and 87%, respectively.

CONCLUSION: Neoadjuvant SMART appears to be safe, with low rates of surgical complications and promising outcomes. Further identification of patients for this approach requires additional investigation.

PMID:37785155 | DOI:10.1016/j.ijrobp.2023.06.2370

PURPOSE/OBJECTIVE(S): Despite maximal treatment, nearly all patients with grade 4 gliomas develop recurrent disease. Treatment options for these patients are limited and overall survival is poor. Re-irradiation may be considered in certain patients, though risk of side effects often limits the effective dose able to be delivered. Pulsed reduced dose rate (PRDR) radiation is a treatment technique that reduces effective dose rate and increases treatment time allowing for intrafraction repair. Here, we report safety and efficacy of PRDR re-irradiation for recurrent grade 4 gliomas.

MATERIALS/METHODS: We performed a retrospective review of patients treated with PRDR between 2001 and 2022. Patients were treated with reduced dose rate radiation delivered in 0.2 Gy pulses every 3 minutes in 2 Gy daily fractions. Both 3D conformal and step and shoot IMRT radiation plans were utilized. Toxicities were evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Kaplan Meier analysis was used to calculate overall survival (OS). Cox regression analysis was performed for multivariate analysis.

RESULTS: A total of 168 grade 4 glioma patients treated with PRDR re-irradiation were identified. The median age was 55 years old. The median initial radiation dose was 60 Gy (range 36 Gy - 72 Gy) and the median PRDR dose was 54 Gy (range 37.5 - 60 Gy). Seventy percent of patients received systemic therapy for recurrent disease prior to PRDR, while 30% received PRDR as first treatment for recurrent disease (or following re-resection without other treatment). The median survival following PRDR was 6.3 months. Multivariate analysis showed time since initial radiation of 14+ months (HR 0.66, p = 0.005, 95% CI 0.44 - 0.98), pre-PRDR use of steroids (HR 1.78, p = 0.005, 95% CI 1.2 - 2.66), and Karnofsky performance status of 70 or greater to be a significant predictor of survival (HR = 0.6, p = 0.008, 95% CI 0.44 - 0.98). No grade 4 or 5 toxicity was noted. Grade 3 new onset seizures was noted in 6% of patients, all subsequently controlled with medication. The most common grade 1-2 side effect after treatment was fatigue.

CONCLUSION: In this large, retrospective cohort, PRDR re-irradiation for recurrent grade 4 gliomas was well tolerated with low rates of grade 3 toxicity. Overall survival outcomes were encouraging, especially in heavily pre-treated patients. Prospective studies are ongoing to further evaluate the efficacy of PRDR for recurrent glioma treatment.

PMID:37784707 | DOI:10.1016/j.ijrobp.2023.06.946

PURPOSE/OBJECTIVE(S): For patients with soft tissue sarcoma (STS) who cannot or choose not to have surgery, radiation can provide local tumor control in both palliative and definitive settings. Conventionally fractionated radiation provides modest (< 50%) rates of local control (LC) for STS at 2 years. To our knowledge, no prospective studies to date have evaluated the safety and efficacy of dose-escalated hypofractionated radiation therapy as treatment of inoperable STS. We hypothesized that dose-escalated, hypofractionated radiation therapy (RT) for inoperable STS could achieve higher rates of LC than reported in trials of conventionally fractionated RT.

MATERIALS/METHODS: An IRB-approved single institution prospective phase II clinical trial of dose-escalated, hypofractionated RT as local control for STS was designed and completed planned accrual. Exclusion criteria included anti-cancer systemic therapy within the preceding two weeks. Patients underwent hypofractionated RT utilizing either CT-guided radiation (24, 50%) or MRI-guided radiation treatments (24, 50%). Data on patient characteristics, RT dose and fractionation, LC, toxicity, and overall survival (OS) was collected. The primary endpoint was local tumor control (stable, partial, or complete response according to RECIST) at 2-years after completion of radiation. Secondary endpoints were acute and late toxicity, rates of complete response, 5-year local tumor control, and progression-free and overall survival. Acute toxicity was graded on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale during treatment and at 3 months following RT.

RESULTS: Forty-eight patients were enrolled, 17 with non-metastatic localized disease and 31 with metastatic disease. Median patient age was 64. Twenty-five men and 23 women were treated. Ninety-six total lesions were treated (36 lung, 7 extremity, 37 abdominopelvic, 16 other). Radiation dose per fraction ranged from 6-12 Gy for a total of 1-12 fractions (median dose was 52.5 Gy in 6 fractions. Median patient follow-up is 8.6 months (range 1 - 36 months). Six patients (13%) did not complete initial 3-month follow-up imaging. Of the 40 patients who have undergone 3-month follow up imaging, 32 (80%) had stable disease, 5 (12.5%) had partial response, 0 had complete response, and 3 (7.5%) had disease progression. Median PFS was 17.2 months at time of last follow up. Median OS was 12.9 months at time of last follow up. Twenty-five patients (52%) experienced an acute toxicity likely or possibly related to radiation. Three (6%) patients experienced CTACE grade 3 or greater treatment-related toxicity (pain, weakness, decreased range of motion, dermatitis).

CONCLUSION: In this initial report of a prospective, single-institution clinical trial of hypofractionated RT for STS not undergoing resection, we report low rates of acute grade 3 or greater toxicity and high rates of tumor response. We will continue to follow these patients to assess late toxicity and durability of tumor control.

PMID:37784374 | DOI:10.1016/j.ijrobp.2023.06.564

PURPOSE/OBJECTIVE(S): Aggressivelocal treatment to a limited number of metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies have shown the safety of combining high dose stereotactic body radiation therapy (SBRT) with single agent anti-PD1/PD-L1 therapy. Here, we report secondary survival endpoint outcomes from a phase Ib clinical trial investigating the safety of combining ablative, high dose radiation with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC.

MATERIALS/METHODS: Patients with up to 6 sites of extracranial metastatic disease were eligible for trial enrollment. All sites of disease were treated with stereotactic body radiation therapy to a dose of 30 - 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (Tremelimumab) and anti-PD-L1 (Durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until dose limiting toxicity or progression was observed. Primary toxicity outcomes were previously reported. Progression free and overall survival was analyzed using Kaplan Meier statistical methods.

RESULTS: Fifteen patients were treated with SBRT and received at least one dose of dual agent immunotherapy per protocol. The median follow up was 43 months. The median number of extracranial metastatic sites was 2. Seven patients had 3 or more sites of extracranial disease. The most commonly treated sites were separate metastatic pulmonary lesions or osseous metastatic lesions. Median progression free survival (PFS) was 42 months and median overall survival (OS) was 48 months. Seven patients remain alive without evidence of progressive disease. Prior history of brain metastases was associated with significantly worse PFS (Median PFS 4 months vs 42 months, HR 6.1 (95% CI 1.6 - 37.0) p = 0.0248), but no difference in OS (Median OS 24 vs 42 months, HR 1.9 (95% CI 0.3 - 10.4).

CONCLUSION: Ablative SBRT radiation to up to 6 sites of disease followed by dual checkpoint immunotherapy in oligometastatic NSCLC resulted in a favorable progression free survival (42 months) and overall survival (48 months) compared to historical controls. These findings suggest potential benefit to patient outcomes compared to immunotherapy or radiation alone in this patient population and warrant further investigation.

PMID:37784329 | DOI:10.1016/j.ijrobp.2023.06.475

PURPOSE: The recently reported FLAME trial demonstrated a biochemical disease-free survival benefit to using a focal intraprostatic boost to multiparametric magnetic resonance imaging (mpMRI)-identified lesions in men with localized prostate cancer treated with definitive radiation therapy. Prostate-specific membrane antigen (PSMA)-directed positron emission tomography (PET) may identify additional areas of disease. In this work, we investigated using both PSMA PET and mpMRI in planning focal intraprostatic boosts using stereotactic body radiation therapy (SBRT).

METHODS AND MATERIALS: We evaluated a cohort of patients (n = 13) with localized prostate cancer who were imaged with 2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-2-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL) PET/MRI on a prospective imaging trial before undergoing definitive therapy. The number of lesions concordant (overlapping) and discordant (no overlap) on PET and MRI was assessed. Overlap between concordant lesions was evaluated using the Dice and Jaccard similarity coefficients. Prostate SBRT plans were created fusing the PET/MRI imaging to computed tomography scans acquired the same day. Plans were created using only MRI-identified lesions, only PET-identified lesions, and the combined PET/MRI lesions. Coverage of the intraprostatic lesions and doses to the rectum and urethra were assessed for each of these plans.

RESULTS: The majority of lesions (21/39, 53.8%) were discordant between MRI and PET, with more lesions seen by PET alone (12) than MRI alone (9). Of lesions that were concordant between PET and MRI, there were still areas that did not overlap between scans (average Dice coefficient, 0.34). Prostate SBRT planning using all lesions to define a focal intraprostatic boost provided the best coverage of all lesions without compromising constraints on the rectum and urethra.

CONCLUSIONS: Using both mpMRI and PSMA-directed PET may better identify all areas of gross disease within the prostate. Using both imaging modalities could improve the planning of focal intraprostatic boosts.

PMID:37250282 | PMC:PMC10209128 | DOI:10.1016/j.adro.2023.101241

PURPOSE: In this prospective phase 2 trial, we investigated the toxicity and patient-reported quality-of-life outcomes in patients treated with stereotactic body radiation therapy (SBRT) to the prostate gland and a simultaneous focal boost to magnetic resonance imaging (MRI)-identified intraprostatic lesions while also de-escalating dose to the adjacent organs at risk.

METHODS AND MATERIALS: Eligible patients included low- or intermediate-risk prostate cancer (Gleason score ≤7, prostate specific antigen ≤20, T stage ≤2b). SBRT was prescribed to 40 Gy in 5 fractions delivered every other day to the prostate, with any areas of high disease burden (MRI-identified prostate imaging reporting and data system 4 or 5 lesions) simultaneously escalated to 42.5 to 45 Gy and areas overlapping organs at risk (within 2 mm of urethra, rectum, and bladder) constrained to 36.25 Gy (n = 100). Patients without a pretreatment MRI or without MRI-identified lesions were treated to dose of 37.5 Gy with no focal boost (n = 14).

RESULTS: From 2015 to 2022, a total of 114 patients were enrolled with a median follow-up of 42 months. No acute or late grade 3+ gastrointestinal (GI) toxicity was observed. One patient developed late grade 3 genitourinary (GU) toxicity at 16 months. In patients treated with focal boost (n = 100), acute grade 2 GU and GI toxicity was seen in 38% and 4% of patients, respectively. Cumulative late grade 2+ GU and GI toxicities at 24 months were 13% and 5% respectively. Patient-reported outcomes showed no significant long-term change from baseline in urinary, bowel, hormonal, or sexual quality-of-life scores after treatment.

CONCLUSIONS: SBRT to a dose of 40 Gy to the prostate gland with a simultaneous focal boost up to 45 Gy is well tolerated with similar rates of acute and late grade 2+ GI and GU toxicity as seen in other SBRT regimens without intraprostatic boost. Moreover, no significant long-term changes were seen in patient-reported urinary, bowel, or sexual outcomes from pretreatment baseline.

PMID:37179035 | DOI:10.1016/j.ijrobp.2023.05.004

PMID:36704191 | PMC:PMC9871068 | DOI:10.1016/j.adro.2022.101168

Radiation induced brachial plexopathy (RIBP) is an unfortunate complication of radiation involving the axilla and supraclavicular fossa. This case report highlights development of RIBP in a patient 15 years after initial radiation and 11 years after pulsed low dose rate (PRDR) re-irradiation for recurrent disease. PRDR is a radiation technique believed to lower normal tissue toxicity due to improved sublethal intrafraction damage repair of these tissues at low radiation dose rates with good reported long term locoregional control in the re-irradiation setting. However, RIBP, as seen in this patient, is a devastating side effect of high dose radiation to this region, with no effective treatment options outside of symptom management and control. In this case, the patient has remained disease free following her recurrence but has had continued RIBP with minimal improvement using pentoxyfilline for management.

PMID:34171539 | DOI:10.1016/j.prro.2021.06.003

Increased breast density attributed to collagen I deposition is associated with a 4-6 fold increased risk of developing breast cancer. Here, we assessed cellular metabolic reprogramming of mammary carcinoma cells in response to increased collagen matrix density using an in vitro 3D model. Our initial observations demonstrated changes in functional metabolism in both normal mammary epithelial cells and mammary carcinoma cells in response to changes in matrix density. Further, mammary carcinoma cells grown in high density collagen matrices displayed decreased oxygen consumption and glucose metabolism via the tricarboxylic acid (TCA) cycle compared to cells cultured in low density matrices. Despite decreased glucose entry into the TCA cycle, levels of glucose uptake, cell viability, and ROS were not different between high and low density matrices. Interestingly, under high density conditions the contribution of glutamine as a fuel source to drive the TCA cycle was significantly enhanced. These alterations in functional metabolism mirrored significant changes in the expression of metabolic genes involved in glycolysis, oxidative phosphorylation, and the serine synthesis pathway. This study highlights the broad importance of the collagen microenvironment to cellular expression profiles, and shows that changes in density of the collagen microenvironment can modulate metabolic shifts of cancer cells.

PMID:27743905 | PMC:PMC5264313 | DOI:10.1016/j.ebiom.2016.10.012

Historically, most cellular processes have been studied in only 2 dimensions. While these studies have been informative about general cell signaling mechanisms, they neglect important cellular cues received from the structural and mechanical properties of the local microenvironment and extracellular matrix (ECM). To understand how cells interact within a physiological ECM, it is important to study them in the context of 3 dimensional assays. Cell migration, cell differentiation, and cell proliferation are only a few processes that have been shown to be impacted by local changes in the mechanical properties of a 3-dimensional ECM. Collagen I, a core fibrillar component of the ECM, is more than a simple structural element of a tissue. Under normal conditions, mechanical cues from the collagen network direct morphogenesis and maintain cellular structures. In diseased microenvironments, such as the tumor microenvironment, the collagen network is often dramatically remodeled, demonstrating altered composition, enhanced deposition and altered fiber organization. In breast cancer, the degree of fiber alignment is important, as an increase in aligned fibers perpendicular to the tumor boundary has been correlated to poorer patient prognosis(1). Aligned collagen matrices result in increased dissemination of tumor cells via persistent migration(2,3). The following is a simple protocol for embedding cells within a 3-dimensional, fibrillar collagen hydrogel. This protocol is readily adaptable to many platforms, and can reproducibly generate both aligned and random collagen matrices for investigation of cell migration, cell division, and other cellular processes in a tunable, 3-dimensional, physiological microenvironment.

PMID:27213771 | PMC:PMC4942088 | DOI:10.3791/53989

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer.

METHODS: One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data.

RESULTS: Among patients taking ACEIs/ARBs in the UW data set, a significant 3-fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P = .001) was observed. This finding was confirmed in the UH data set, in which a significant 2-fold-increased pCR rate (24% vs 12%, P = .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06-7.82; P < .001).

CONCLUSIONS: The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487-95. © 2016 American Cancer Society.

PMID:27203227 | PMC:PMC4998053 | DOI:10.1002/cncr.30079

INTRODUCTION: Contralateral lung tumors in non-small-cell lung cancer (NSCLC) are classified as stage M1a yet may represent hematogenous metastases or synchronous primary tumors. The impact of these tumors on overall survival (OS) is poorly understood. Here, we aim to determine whether NSCLC patients with M1a disease due only to a contralateral tumor nodule exhibit a favorable prognosis relative to other M1a or M1b patients.

METHODS: Retrospective evaluation of the impact of contralateral tumor nodules on OS in NSCLC stratified by primary tumor size and N stage attained from Surveillance, Epidemiology, and End Results database.

RESULTS: Of 173,640 patients, 5161 M1a-contra patients were identified. Median and 3-year OS for these patients exceeded that of patients with M1b (p < 0.0001) or other M1a disease (p < 0.0001). Primary tumor size and N stage were strongly associated with OS in M1a-contra patients. Three-year OS demonstrated a delayed convergence between M1a-contra and other M1a patients with primary tumors greater than or equal to 3 cm or mediastinal lymph node involvement. Proportional hazard modeling indicated that T1-2N0-1M1a-contra patients exhibit OS not significantly different (p = 0.258) from that predicted with comparable T and N stage disease plus a second early-stage primary.

CONCLUSIONS: Contralateral tumors in NSCLC carry a more favorable prognosis than other M1a or M1b disease. Primary tumor size and N stage may help distinguish M1a-contra patients with hematogenous metastasis from those with a synchronous, second primary.

PMID:26317917 | PMC:PMC4636460 | DOI:10.1097/JTO.0000000000000655