Toward Precision Perioperative Therapy in GI Malignancies.

PURPOSE: The term precision oncology typically refers to molecularly guided therapies against cancer. Less appreciated but also critically important is molecular identification of patients with resectable disease who are most likely to benefit from perioperative drugs, and tailored selection of such drugs. We call this idea precision perioperative therapy. Over the past several years, use of precision perioperative approaches for patients with localized GI cancers has expanded in clinical trials and practice. Here, we summarize the status of the field and highlight areas of future innovation. METHODS: Using PubMed, we reviewed articles published from 2017 to 2023 in English. We used search terms "adjuvant," "perioperative," "neoadjuvant," and "precision medicine" for various types of GI malignancies. Information about ongoing clinical trials was accessed through ClinicalTrials.gov, accessed January 2023. RESULTS: Paradigms such as minimal residual disease detection via circulating tumor DNA and perioperative immunotherapy in lieu of chemotherapy for mismatch repair-deficient disease may lead to reduced toxicity and improved long-term outcomes in select populations. Molecularly targeted drugs that have shown activity against metastatic disease may also hold promise in the curable setting. CONCLUSION: The field is very much in development, but emerging data demonstrate early promise. We are optimistic that ongoing research efforts will increasingly bring precision perioperative therapy to patients with resectable GI malignancies.

Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.

In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.

Efficacy, Safety, and Regulatory Approval of Food and Drug Administration-Designated Breakthrough and Nonbreakthrough Cancer Medicines.

Purpose The breakthrough therapy program was established in 2012 to expedite the development and review of new medicines. We evaluated the times to approval, efficacy, and safety of breakthrough-designated versus non-breakthrough-designated cancer drugs approved by the US Food and Drug Administration (FDA). Methods We studied all new cancer drugs approved by the FDA between January 2012 and December 2017. Regulatory and therapeutic characteristics (time to FDA approval, pivotal trial efficacy end point, novelty of mechanism of action) were compared between breakthrough-designated and non-breakthrough-designated cancer drugs. Random-effects meta-regression was used to assess the association between breakthrough therapy designation and hazard ratios for progression-free survival (PFS), response rates (RRs) for solid tumors, serious adverse events, and deaths not attributed to disease progression. Results Between 2012 and 2017, the FDA approved 58 new cancer drugs, 25 (43%) of which received breakthrough therapy designation. The median time to first FDA approval was 5.2 years for breakthrough-designated drugs versus 7.1 years for non-breakthrough-designated drugs (difference, 1.9 years; P = .01). There were no statistically significant differences between breakthrough-designated and non-breakthrough-designated drugs in median PFS gains (8.6 v 4.0 months; P = .11), hazard ratios for PFS (0.43 v 0.51; P = .28), or RRs for solid tumors (37% v 39%; P = .74). Breakthrough therapy-designated drugs were not more likely to act via a novel mechanism of action (36% v 39%; P = 1.00). Rates of deaths (6% v 4%; P = .99) and serious adverse events (38% v 36%; P = 0.93) were also similar in breakthrough-designated and non-breakthrough-designated drugs. Conclusion Breakthrough-designated cancer drugs were associated with faster times to approval, but there was no evidence that these drugs provide improvements in safety or novelty; nor was there a statistically significant efficacy advantage when compared with non-breakthrough-designated drugs.

Reconstituting Mouse Lungs with Conditionally Reprogrammed Human Bronchial Epithelial Cells.

We developed methods for conditionally reprogramming (CR) primary human bronchial epithelial cells (HBECs) to extend their functional lifespan and permit their differentiation into both upper and lower airway lung epithelium. We also developed a bioreactor to support vascular perfusion and rhythmic breathing of decellularized mouse lungs reconstituted with CR HBECs isolated from patients with and without cystic fibrosis (CF). While conditionally reprogrammed cells only differentiate into an upper airway epithelium after 35 days at the air-liquid interface, in reconstituted lungs these cells differentiate into upper airway bronchial epithelium and lower airway alveolar structures after 12 days. Rapid scale-up and the ability to obtain clonal derivatives of primary patient-derived HBECs without the need for genetic manipulation may permit rapid reconstitution of the lung epithelium; facilitating the study of lung disease in tissue-engineered models.

Medicare Spending for Breast, Prostate, Lung, and Colorectal Cancer Patients in the Year of Diagnosis and Year of Death.

OBJECTIVE: To characterize spending patterns for Medicare patients with incident breast, prostate, lung, and colorectal cancer. DATA SOURCES/STUDY SETTING/STUDY DESIGN: 2007-2012 data from the Surveillance, Epidemiology, and End Results Program linked with Medicare fee-for-service claims. DATA COLLECTION/EXTRACTION METHODS: We calculate per-patient monthly and yearly mean and median expenditures, by cancer type, stage at diagnosis, and spending category, over the years of diagnosis and death. PRINCIPAL FINDINGS: Over the year of diagnosis, mean spending was $35,849, $26,295, $55,597, and $63,063 for breast, prostate, lung, and colorectal cancer, respectively. Over the year of death, spending was similar across different cancer types and stage at diagnosis. CONCLUSIONS: Characterization of Medicare spending according to clinically meaningful categories may assist development of oncology alternative payment models and cost-effectiveness models.

A Biomechanical Analysis of Interference Screw Versus Bone Tunnel Fixation of Flexor Hallucis Longus Tendon Transfers to the Calcaneus.

The flexor hallucis longus tendon transfer is commonly used to restore function in chronic Achilles tendon ruptures and chronic Achilles tendinopathy. The tendon is often secured to the calcaneus either through a bone tunnel or by an interference screw. We hypothesized that tenodesis using the bone tunnel method would be mechanically superior to interference screw fixation for flexor hallucis longus transfers. Eight matched pairs of cadaveric specimens were assigned randomly to the bone tunnel or interference screw technique and were loaded to failure. Biomechanical analysis was performed to evaluate the ultimate strength, peak stress, Young's modulus, failure strain, and strain energy. Unpaired comparison, paired comparison, and linear regression analyses were used to determine statistical significance. A slight 22% ± 9% decrease in Young's modulus and a 52% ± 18% increase of strain energy were found in the interference screw group. However, no differences in ultimate strength, peak stress, or failure strain were seen between the 2 groups on paired comparison. Our findings suggest that interference screw fixation provides similar spontaneous biomechanical properties to the use of a bone tunnel for flexor hallucis longus transfer to the calcaneus. The interference screw is a practical option for fixation of the flexor hallucis longus tendon to the calcaneus and can be performed through a single incision approach.

Hypovitaminosis D and Cervical Disk Herniation among Adults Undergoing Spine Surgery.

Study Design Single-center, retrospective study. Objective Suboptimal concentrations of vitamin D have been linked to hip and knee osteoarthritis in large, population-based cohort studies. We sought to examine the association of vitamin D levels with intervertebral disk disease. Methods From January 2010 through May 2011, 91 consecutive, eligible adult spine surgery patients who had undergone cervical magnetic resonance imaging (MRI) and preoperative serum 25-hydroxyvitamin D (s25D) measurement were retrospectively included. MRI was read for C2-T1 disk herniation and degeneration (grades I to V). Logistic regressions were performed. Results Compared with the 384 disks of nondeficient patients, 162 disks of vitamin D-deficient (< 20 ng/mL) patients were more frequently herniated (40% versus 27%, p = 0.004); deficiency was not predictive of individual disk grade (unadjusted odds ratio [uOR] = 0.98, p = 0.817). On regression analysis, deficiency was associated with increased number of herniations per patient (uOR = 2.17, 95% confidence interval [CI] = 1.22 to 3.87, p = 0.009; adjusted odds ratio [aOR] = 2.12, 95% CI = 1.11 to 4.03, p = 0.023). When disks were analyzed individually, and levels (e.g., C5 to C6), additionally controlled for, deficiency correlated with greater likelihood of herniation per disk (uOR = 1.81, 95% CI = 1.22 to 2.66, p = 0.003; aOR = 2.06, 95% CI = 1.25 to 3.41, p = 0.005). Conclusion Among adults undergoing spine surgery at our institution, vitamin D deficiency was associated with cervical disk herniation. Considering the current epidemics of vitamin D insufficiency and neck pain, further investigation is warranted, as these data were retrospectively collected and subject to sampling bias.

Failed healing of rotator cuff repair correlates with altered collagenase and gelatinase in supraspinatus and subscapularis tendons.

BACKGROUND: Despite improvements in arthroscopic rotator cuff repair technique and technology, a significant rate of failed tendon healing persists. Improving the biology of rotator cuff repairs may be an important focus to decrease this failure rate. The objective of this study was to determine the mRNA biomarkers and histological characteristics of repaired rotator cuffs that healed or developed persistent defects as determined by postoperative ultrasound. HYPOTHESIS: Increased synovial inflammation and tendon degeneration at the time of surgery are correlated with the failed healing of rotator cuff tendons. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Biopsy specimens from the subscapularis tendon, supraspinatus tendon, glenohumeral synovium, and subacromial bursa of 35 patients undergoing arthroscopic rotator cuff repair were taken at the time of surgery. Expression of proinflammatory cytokines, tissue remodeling genes, and angiogenesis factors was evaluated by quantitative real-time polymerase chain reaction. Histological characteristics of the affected tissue were also assessed. Postoperative (>6 months) ultrasound was used to evaluate the healing of the rotator cuff. General linear modeling with selected mRNA biomarkers was used to predict rotator cuff healing. RESULTS: Thirty patients completed all analyses, of which 7 patients (23%) had failed healing of the rotator cuff. No differences in demographic data were found between the defect and healed groups. American Shoulder and Elbow Surgeons shoulder scores collected at baseline and follow-up showed improvement in both groups, but there was no significant difference between groups. Increased expression of matrix metalloproteinase 1 (MMP-1) and MMP-9 was found in the supraspinatus tendon in the defect group versus the healed group (P = .006 and .02, respectively). Similar upregulation of MMP-9 was also found in the subscapularis tendon of the defect group (P = .001), which was consistent with the loss of collagen organization as determined by histological examination. From a general linear model, the upregulation of MMP-1 and MMP-9 was highly correlated with failed healing of the rotator cuff (R(2) = .656). CONCLUSION: The upregulation of tissue remodeling genes in the torn rotator cuff at the time of surgery provides a snapshot of the biological environment surrounding the torn rotator cuff that is closely related to the healing of repaired rotator cuffs.

Musculoskeletal effects of obesity.

PURPOSE OF REVIEW: The problem of obesity has become a global concern, with increased prevalence reported in the literature. Numerous comorbid conditions are known to be associated with obesity; its relationship with the development and function of the musculoskeletal system in the growing child is poorly understood. This article reviews the current literature on the various musculoskeletal effects associated with obesity in children and adolescents. RECENT FINDINGS: The association between obesity and various musculoskeletal disorders such as slipped capital femoral epiphysis and Blount disease is well reported. Its effects on the structure and function of the musculoskeletal system have not been well documented. Recent studies suggest an increased association between obesity and musculoskeletal pain and increased fracture risk. The limitations imposed by increasing body mass appear to be directly reflected in the child's level of activity and overall functional capacity. SUMMARY: Obesity continues to pose a serious health concern. Its impact on the development of the child's musculoskeletal system is still poorly understood. Recent data suggests that obesity affects the child's locomotor system both functionally and structurally. As the obesity epidemic grows, newer studies will be needed to help us fully understand the true impact of obesity on the musculoskeletal system of the growing child.