Opportunity in Complexity: Harnessing Molecular Biomarkers and Liquid Biopsies for Personalized Sarcoma Care.

Due to their rarity and complexity, sarcomas represent a substantial therapeutic challenge. However, the incredible diversity within and across sarcoma subtypes presents an opportunity for personalized care to maximize efficacy and limit toxicity. A deeper understanding of the molecular alterations that drive sarcoma development and treatment response has paved the way for molecular biomarkers to shape sarcoma treatment. Genetic, transcriptomic, and protein biomarkers have become critical tools for diagnosis, prognostication, and treatment selection in patients with sarcomas. In the future, emerging biomarkers like circulating tumor DNA analysis offer the potential to improve early detection, monitoring response to treatment, and identifying mechanisms of resistance to personalize sarcoma treatment. Here, we review the current state of molecular biomarkers for sarcomas and highlight opportunities and challenges for the implementation of new technologies in the future.

Less than whole uterus irradiation for patients with locally advanced cervical cancer.

INTRODUCTION: Current consensus guidelines for definitive cervical cancer intensity modulated radiation therapy (IMRT) recommend inclusion of the entire uterus within the clinical target volume, however this is debated. We aimed to evaluate outcomes of patients with cervical cancer who were treated with less than whole uterus irradiation. METHODS: We identified 109 patients with FIGO Stage IB-IVA cervical cancer treated definitively with concurrent chemoradiation, including IMRT and brachytherapy, from 2010 to 2022 at a single institution where the practice was to include the gross cervix tumor with an internal target volume with differences in bladder filing accounted for, plus additional 5 mm planning target volume (PTV) margin. Local, regional, and distant recurrences were analyzed using competing risk methods, and a Wilcoxon rank sum test was performed to assess differences in dose to organs at risk based on the proportion of the uterus included in the PTV, with the median proportion of the uterus included (75 %) used as the cut-point. RESULTS: The median follow-up time was 65 months (range 3-352 months). The 2-year cumulative incidence of LR for the entire cohort was 4.2 % (95 % confidence interval [CI] 1.3-9.7). Compared with patients who had ≥ 75 % of the uterus included in the PTV, patients who had < 75 % of the uterus included in the PTV had significantly lower bowel D200cc (p = 0.02). The cumulative incidence of local failure (LR) was not significantly different between the two groups. CONCLUSIONS: Including less than the whole uterus for definitive cervix cancer IMRT does not seem to compromise local control. Less than whole uterus irradiation could be considered for carefully selected cervix cancer patients to decrease bowel dose and possible treatment-related toxicity.

Design approach and benefits of the 3D-printed vaginal individualized applicator (VIA).

PURPOSE: Interstitial gynecologic brachytherapy necessitates precise needle placement, requiring time and expertise. We aimed to simplify interstitial procedures and facilitate optimal needle distribution with individualized vaginal templates to guide interstitial needles. MATERIALS/METHODS: We developed the 3D-printed vaginal individualized applicator (VIA), a cylindrical template containing individualized internal channels that guide interstitial needles to cover the tumor extent. Eight patients underwent VIA only interstitial implants (VIA only), and five intact cervical cases were treated using tandem and customized VIA (VIA + T). Procedure length, number of needles utilized and dosimetric measures were evaluated. RESULTS: VIA was successfully designed and used clinically for 24 procedures (8 VIA only, 16 VIA + T). Average procedure needle insertion time reduced from 80.9 min for traditional interstitial to 42.9 min for VIA only, approximately 47% shorter with a similar mean high risk CTV volume (28.3 cc VIA only vs. 32.4 cc) and excellent dosimetry with average CTV V100% (94.3% and 94.4%). VIA + T was particularly useful in patients with small vaginal canals and large tumor size. For the five VIA + T patients average tumor size was 68.0cc (range 26.6-143.5 cc). VIA + T procedures were approximately 20% shorter than hybrid procedures with other applicators with mean length of 20.1 min and an average of 6.8 needles (range 3-12). CONCLUSION: Our novel 3D-printed VIA facilitates gynecologic interstitial brachytherapy by simplifying needle placement, reducing procedure time, and maintaining excellent dosimetry. VIA can be customized for various clinical scenarios, particularly beneficial for large tumors or small vaginal canals.

A systematic review of endometrial cancer clinical research in Africa.

BACKGROUND: Women in Africa are experiencing a rising burden of endometrial cancer. Research and investment to improve treatment and outcomes are critically needed. We systematically reviewed and characterized endometrial cancer-related research within a clinically relevant context to help organize and assess existing endometrial cancer research in Africa. METHODS: According to PRISMA guidelines, we searched online databases for published endometrial cancer articles from African countries from January 1, 2011, to July 20, 2021. Based on our inclusion and exclusion criteria, independent reviewers documented the study design, country/region, human development index, focus of research, type of interventions performed, and histologic and molecular type to illustrate the breadth of research coverage in each region. RESULTS: A total of 18 research articles were included. With an average Human Development Index (HDI) in Africa of 0.536, the average HDI of the represented countries in this study was 0.709. The majority (88.9%) of prospective endometrial cancer research articles in Africa were from North Africa, with Egypt encompassing 83.3% of the papers. Most of these studies focused on endometrial cancer diagnosis. Research on the treatment of endometrial cancer is still emerging (33% of papers). Of all included articles, only 11.1% represented Sub-Saharan Africa, where the majority population of black Africans reside. CONCLUSIONS: Endometrial cancer research in Africa is extremely limited, with the majority being concentrated in African countries with higher HDIs. As the incidence of endometrial cancer rises in Sub-Saharan Africa, there is a pressing need for more prospective clinical research to tackle the growing disease burden and improve outcomes.

Patterns of Local Recurrence and Risk of Skin Recurrence in Soft Tissue Sarcomas After Surgical Resection.

PURPOSE: Although there is a theoretical risk of skin seeding during surgical resection of soft tissue sarcomas (STSs), current consensus guidelines recommend against routine use of bolus during radiation therapy (RT). However, the risk of skin recurrence has not been systematically assessed. We aimed to assess the patterns of local recurrence (LR) in patients with STS treated with surgery with or without RT. METHODS AND MATERIALS: We performed a retrospective analysis of adults with STSs evaluated at our institution between 2007 and 2021. For patients who developed LR, the depth was evaluated. Progression-free survival and overall survival were analyzed from time of first LR using the Kaplan-Meier method. Cumulative incidence of distant metastasis was calculated with competing risk analysis from date of LR. RESULTS: Of the 206 patients evaluated, 20 had LR (9.7%). Among patients with LR, 5 patients (25.0%) were treated with surgery alone and 15 patients (75.0%) with surgery and RT. In patients treated with RT, 46.7% had preoperative RT, 53.3% had postoperative RT, and bolus was used in 46.7%. Surgical margins were close (<1 mm) in 4 patients (20.0%) and positive in 10 patients (50.0%). LR occurred in the deep subfascial tissue in 9 patients (45%), subcutaneous tissue in 10 patients (50.0%), and skin in 1 patient (5.0%). The patient with a skin recurrence was treated with surgery alone, and the tumor involved the skin at presentation. In patients treated with RT, LR occurred within the RT field in 13 patients (86.7%). At 1 year after LR, progression-free survival was 70.3%, overall survival was 81.7%, and cumulative incidence of distant metastasis was 5.9%. CONCLUSIONS: Skin recurrences were rare after surgical resection of STSs and only occurred in a tumor that involved the skin at initial presentation. These findings support current recommendations against routine use of bolus in STSs not involving the skin at presentation.

Mapping of Radiation Oncology and Gynecologic Oncology Services Available to Treat the Growing Burden of Cervical Cancer in Africa.

PURPOSE: To meet the demand for cervical cancer care in Africa, access to surgical and radiation therapy services needs to be understood. We thus mapped the availability of gynecologic and radiation therapy equipment and staffing for treating cervical cancer. METHODS AND MATERIALS: We collected data on gynecologic and radiation oncology staffing, equipment, and infrastructure capacities across Africa. Data was obtained from February to July 2021 through collaboration with international partners using Research Electronic Data Capture. Cancer incidence was taken from the International Agency for Research on Cancer's GLOBOCAN 2020 database. Treatment capacity, including the numbers of radiation oncologists, radiation therapists, physicists, gynecologic oncologists, and hospitals performing gynecologic surgeries, was calculated per 1000 cervical cancer cases. Adequate capacity was defined as 2 radiation oncologists and 2 gynecologic oncologists per 1000 cervical cancer cases. RESULTS: Forty-three of 54 African countries (79.6%) responded, and data were not reported for 11 countries (20.4%). Respondents from 31 countries (57.4%) reported access to specialist gynecologic oncology services, but staffing was adequate in only 11 countries (20.4%). Six countries (11%) reported that generalist obstetrician-gynecologists perform radical hysterectomies. Radiation oncologist access was available in 39 countries (72.2%), but staffing was adequate in only 16 countries (29.6%). Six countries (11%) had adequate staffing for both gynecologic and radiation oncology; 7 countries (13%) had no radiation or gynecologic oncologists. Access to external beam radiation therapy was available in 31 countries (57.4%), and access to brachytherapy was available in 25 countries (46.3%). The number of countries with training programs in gynecologic oncology, radiation oncology, medical physics, and radiation therapy were 14 (26%), 16 (30%), 11 (20%), and 17 (31%), respectively. CONCLUSIONS: We identified areas needing comprehensive cervical cancer care infrastructure, human resources, and training programs. There are major gaps in access to radiation oncologists and trained gynecologic oncologists in Africa.

Patterns of Recurrence After Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation.

BACKGROUND: Improved treatment strategies are needed for patients with locally advanced gastric cancer with poor response to neoadjuvant chemotherapy. We aimed to describe patterns of failure for patients with no or partial response (NR, PR) to preoperative chemotherapy. PATIENTS AND METHODS: We analyzed patients with locally advanced gastric cancer treated from 2008 to 2022 with preoperative chemotherapy followed by surgery with D2 resection. We excluded patients who received radiation. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated. For patients with recurrent abdominal disease, hypothetical radiation clinical treatment volumes (CTV) were contoured on postoperative scans and compared with patterns of recurrence. RESULTS: A total of 60 patients were identified. The most used preoperative chemotherapy was FLOT (38.6%), followed by FOLFOX (30%) and ECF/ECX/EOX (23.3%). Four (6.7%), 40 (66.7%), and 9 patients (15%) had a complete pathologic response (CR), PR, and NR to neoadjuvant therapy, respectively. Among patients without a CR, 3-year overall and progression-free survival rates were 62.3% (95% CI 48-76.6%) and 51.3% (95% CI 36.9-65.7%), respectively. Three-year cumulative incidence of LRF and DM were 8.4% (95% CI 0.4-16.4%) and 41.0% (95% CI 26.3-55.4%), respectively. Absolute rates of patients having the first site of recurrence encompassed by a postoperative radiation CTV was 2.0% for patients without a CR and 0% for patients with NR. CONCLUSIONS: Patients with locally advanced gastric cancer with less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival.

Racial Disparities in Brachytherapy Treatment among Women with Cervical and Endometrial Cancer in the United States.

Brachytherapy improves clinical outcomes among women diagnosed with cervical and endometrial cancers. Recent evidence demonstrates that declining brachytherapy boosts for women with cervical cancer were associated with higher mortality. In this retrospective cohort study, women diagnosed with endometrial or cervical cancer in the United States between 2004 and 2017 were selected from the National Cancer Database for evaluation. Women ≥18 years of age were included for high intermediate risk (PORTEC-2 and GOG-99 definition) or FIGO Stage II-IVA endometrial cancers and FIGO Stage IA-IVA-non-surgically treated cervical cancers. The aims were to (1) evaluate brachytherapy treatment practice patterns for cervical and endometrial cancers in the United States; (2) calculate rates of brachytherapy treatment by race; and (3) determine factors associated with not receiving brachytherapy. Treatment practice patterns were evaluated over time and by race. Multivariable logistic regression assessed predictors of brachytherapy. The data show increasing rates of brachytherapy for endometrial cancers. Compared to non-Hispanic White women; Native Hawaiian and other Pacific Islander (NHPI) women with endometrial cancer and Black women with cervical cancer were significantly less likely to receive brachytherapy. For both NHPI and Black women, treatment at community cancer centers was associated with a decreased likelihood of brachytherapy. The data suggest racial disparities among Black women with cervical cancer and NHPI women with endometrial cancer and emphasize an unmet need for brachytherapy access within community hospitals.

Real world experience of poly (ADP-ribose) polymerase inhibitor use in a community oncology practice.

OBJECTIVE: This study aims to describe the real-world experience, including the clinical and financial burden, associated with PARP inhibitors in a large community oncology practice. METHODS: Retrospective chart review identified patients prescribed olaparib, niraparib or rucaparib for maintenance therapy or treatment of recurrent ovarian, primary peritoneal or fallopian tube cancer across twelve gynecologic oncologists between December 2016 and November 2018. Demographic, financial and clinical data were extracted. One PARP cycle was defined as a single 28-day period. For patients treated with more than one PARPi, each course was described separately. RESULTS: A total of 47 patients and 506 PARP cycles were identified (122 olaparib, 24%; 89 rucaparib, 18%; 294 niraparib, 58%). Incidence of grade ≥ 3 adverse events were similar to previously reported. Toxicity resulted in dose interruption, reduction and discontinuation in 69%, 63% and 29% respectively. Dose interruptions were most frequent for niraparib but resulted in fewer discontinuations (p-value 0.01). Mean duration of use was 7.46 cycles (olaparib 10.52, rucaparib 4.68, niraparib 7.34). Average cost of PARPi therapy was $8018 per cycle. A total of 711 phone calls were documented (call rate 1.4 calls/cycle) with the highest call volume required for care coordination, lab results and toxicity management. CONCLUSIONS: Although the toxicity profile was similar to randomized clinical trials, this real-world experience demonstrated more dose modifications and discontinuations for toxicity management than previously reported. Furthermore, the clinical and financial burden of PARP inhibitors may be significant and future studies should assess the impact on patient outcomes.

Contributing factors and short-term surgical outcomes of patients with early-onset rectal cancer.

INTRODUCTION: The aim of this study was to evaluate patient factors that contribute to increased incidence of early onset rectal cancer and analyze the short-term surgical outcomes of patients undergoing surgery. METHODS: A 2-year review (2015-2016) of the ACS-NSQIP included patients with rectal cancer who underwent surgical management. Patients were stratified into early-onset RC (<50-years) and late-onset RC (≥50-years). RESULTS: We included a total of 7538 patients in the analysis. Overall, 14% of the patients had early-onset RC. Patients with early-onset RC were more likely to be Black and Hispanic. Additionally, they were more likely to present with higher TNM stages. Patients with early-onset RC had lower 30-day complications and lower 30-day mortality. There was no difference between the two groups regarding hospital length of stay or 30-day readmission. On regression analysis, there was no difference between the two groups regarding patient outcomes. CONCLUSIONS: Racial disparities do exist in the incidence of RC. Young patients tend to have more aggressive disease, however, surgical outcomes between the two groups are comparable.

Does it matter where you get your surgery for colorectal cancer?

BACKGROUND: The influence of hospital-related factors on outcomes following colorectal surgery is not well-established. The aim of our study was to evaluate the relationship between hospital factors on outcomes in surgically managed colorectal cancer patients. METHODS: We performed a 2-year (2014-2015) analysis of the NIS database. Adult (> 18 years) patients who underwent open or laparoscopic colorectal resection were identified using ICD-9 codes. Patients were stratified based on hospital: volume (low vs. high), teaching status, and location (urban vs. rural). Outcome measures were complications and mortality. Multivariate logistic regression was performed. RESULTS: A total of 153,453 patients with CRC were identified of which 35.3% underwent surgical management. Mean age was 69 ± 13 years, 51.6% were female, and 67% were white. Twenty-seven percent of the patients were managed at a high-volume center, 48% at intermediate-volume center while 25% at a low-volume center. Complications and mortality rates were lower in patients who were managed at high-volume centers and urban hospitals, while no difference was noticed based on teaching status. On regression analysis, patients managed at high-volume centers (OR 0.76 [0.56-0.89]) and urban hospitals (OR 0.83 [0.64-0.91]) have lower odds of complications; similarly, high-volume centers (OR 0.79 [0.65-0.90]) and urban facility (OR 0.87 [0.70-0.92]) were associated with lower odds of mortality. However, there was no association between teaching status and outcomes. CONCLUSION: Hospital factors significantly influence outcomes in patients with CRC managed surgically. High-volume centers and urban facilities have relatively better outcomes. Regionalization of care along with the appropriate availability of resources may improve outcomes in patients with CRC. LEVEL OF EVIDENCE: Level III, Retrospective Observational Study.

Colon cancer in the young: contributing factors and short-term surgical outcomes.

BACKGROUND: The incidence in young patients has increased significantly over the last few decades. The aim of this study is to evaluate demographic and tumor characteristics of young patients and analyze the short-term surgical outcomes of patients undergoing surgery. METHODS: We performed a 2-year review (2015-2016) of the ACS-NSQIP and included all patients with CC who underwent surgical management. Patients were stratified into two groups: early-onset CC (< 50 years old) and late-onset CC (≥ 50 years old). Outcome measures were hospital length of stay, 30-day complications, mortality, and readmission. RESULTS: We included a total of 15,957 patients in the analysis. Mean age was 65 ± 13 years, and 52% were male. Overall 10% of the patients had early-onset CC. Patients with early-onset CC were more likely to be black (11% vs 7%, p = 0.04) and Hispanic (8% vs 4%, p = 0.02). Additionally, they presented with a more aggressive tumor and higher TNM staging. Patients with early onset CC had lower 30-day complications (18% vs 22%, p = 0.02), shorter hospital length of stay (6[3-8] vs 8[5-11], p = 0.03) and lower 30-day mortality (0.4% vs 1.8%, p = 0.04) compared to their counterparts. However, there was no difference between the two groups regarding 30-day readmission. On regression analysis, there was no difference between the two groups regarding study outcomes. CONCLUSIONS: Racial disparity does exist in the incidence of colon cancer in the young with higher incidence in blacks. Younger patients with CC tend to have better surgical outcomes on univariate analysis. On regression analysis, the surgical outcomes between the two groups are comparable.

Rectal cancer in the young: analysis of contributing factors and surgical outcomes.

BACKGROUND: Rectal cancer (RC) among young patients (≤50 years) is on the rise. The factors associated with development of RC are established however; factors leading to early RC remain unclear. The aim of this study was to assess factors associated with RC among young patients. METHODS: National estimates for patients with RC were abstracted from the National Inpatient Sample (NIS) database [2010-2012]. Patients were divided into two groups: young (≤50 years) and old (>50 years). Demographic, comorbidities, procedures performed, and hospital outcomes were collected. Regression analysis was performed to compare both groups. RESULTS: A total of 68,699 patients with RC were included. Incidence of RC among young patients increased significantly over the study period (2.4% vs. 3.4%; P=0.04). Majority of young patients with RC were white females. Bleeding was the most common presentation among young patients (P=0.03). Younger patients were more likely to have a family history of RC (P=0.01) and were more likely to undergo elective surgery (P=0.04) and laparoscopic surgery (P=0.02) compared to the older patients. Younger patients with RC were also more likely to use alcohol (P=0.03), be obese (P=0.02) compared to elder patients. There was no difference in the other co-morbidities between the two groups. After controlling for all factors in a regression model, younger patients had a lower complication rate (P=0.01), hospital LOS (P=0.02), and mortality rate (P=0.04). CONCLUSIONS: RC in younger patients appears as a different disease with different outcomes. There appears to be multifactorial and environmental factors contributing to this trend. Race and gender also play a role in the incidence of RC in the young. Identifying these risk factors will lead to a more robust intervention plan to help improve care among younger patients with RC.

Increasing Incidence of Colon Cancer in the Young: Assessing the Tumor Biology.

BACKGROUND: The overall incidence of colon cancer (CC) is decreasing, but with increasing early-onset colon cancer (EOCC < 50 years old). Our recent study revealed unique overexpression of cartilage oligomeric matrix protein (COMP) in EOCC and its association with aggressiveness. The aim of this study was to assess CC biology, especially in the young, by evaluating the role of COMP in CC carcinogenesis and cancer progression, detecting COMP in serum and its association with disease stage. STUDY DESIGN: Cancer and matching noninvolved tissue blocks from 12 sporadic EOCC and late-onset colon cancer (LOCC) patients of 4 disease stages were obtained from pathology archives. Ribonucleic acid expression profiling of 770 cancer-related genes using nCounter platform was performed. The COMP levels from 16 EOCC and LOCC serum samples were measured by ELISA. Carcinoembryonic antigen levels from these 16 samples were taken at the time of diagnosis. Transwell assay was performed to elucidate the role of COMP in motility and metastases. RESULTS: Expression profiling revealed increased COMP levels in higher disease stage. There was 7-fold higher COMP expression (p ≤ 0.05) in stage III compare to stage I and its coexpression with GAS1, VEGFC, MAP3K8, SFRP1, and PRKACA. Higher COMP expression was seen in stage II compared with stage I (p = 0.07) and its coexpression withTLR2, IL8, RIN1, IRAK3, and CACNA2D2, and COMP was detectable in serum and showed significantly higher levels in EOCC compared with LOCC. Similar correlation was seen with CEA levels, but the difference was not significant. Transwell assay revealed significantly increased motility of HT-29 cells after treatment with recombinant COMP. CONCLUSIONS: These findings suggest different tumor biology between EOCC and LOCC. Cartilage oligomeric matrix protein plays a significant role in CC carcinogenesis and has potential as biomarker for CC, especially aggressive EOCC.