Pulmonary Open, Robotic, and Thoracoscopic Lobectomy (PORTaL) Study: Survival Analysis of 6646 Cases.

OBJECTIVE: The aim of this study was to analyze overall survival (OS) of robotic-assisted lobectomy (RL), video-assisted thoracoscopic lobectomy (VATS), and open lobectomy (OL) performed by experienced thoracic surgeons across multiple institutions. SUMMARY BACKGROUND DATA: Surgeons have increasingly adopted RL for resection of early-stage lung cancer. Comparative survival data following these approaches is largely from single-institution case series or administrative data sets. METHODS: Retrospective data was collected from 21 institutions from 2013 to 2019. Consecutive cases performed for clinical stage IA-IIIA lung cancer were included. Induction therapy patients were excluded. The propensity-score method of inverse-probability of treatment weighting was used to balance baseline characteristics. OS was estimated using the Kaplan-Meier method. Multivariable Cox proportional hazard models were used to evaluate association among OS and relevant risk factors. RESULTS: A total of 2789 RL, 2661 VATS, and 1196 OL cases were included. The unadjusted 5-year OS rate was highest for OL (84%) followed by RL (81%) and VATS (74%); P =0.008. Similar trends were also observed after inverse-probability of treatment weighting adjustment (RL 81%; VATS 73%, OL 85%, P =0.001). Multivariable Cox regression analyses revealed that OL and RL were associated with significantly higher OS compared with VATS (OL vs. VATS: hazard ratio=0.64, P <0.001 and RL vs. VATS: hazard ratio=0.79; P =0.007). CONCLUSIONS: Our finding from this large multicenter study suggests that patients undergoing RL and OL have statistically similar OS, while the VATS group was associated with shorter OS. Further studies with longer follow-up are necessary to help evaluate these observations.

Pulmonary Open, Robotic, and Thoracoscopic Lobectomy (PORTaL) Study: An Analysis of 5721 Cases.

OBJECTIVE: The aim of this study was to analyze outcomes of open lobectomy (OL), VATS, and robotic-assisted lobectomy (RL). SUMMARY BACKGROUND DATA: Robotic-assisted lobectomy has seen increasing adoption for treatment of early-stage lung cancer. Comparative data regarding these approaches is largely from single-institution case series or administrative datasets. METHODS: Retrospective data was collected from 21 institutions from 2013 to 2019. All consecutive cases performed for clinical stage IA-IIIA lung cancer were included. Neoadjuvant cases were excluded. Propensity-score matching (1:1) was based on age, sex, race, smoking-status, FEV1%, Zubrod score, American Society of Anesthesiologists score, tumor size, and clinical T and N stage. RESULTS: A total of 2391 RL, 2174 VATS, and 1156 OL cases were included. After propensity-score matching there were 885 pairs of RL vs OL, 1,711 pairs of RL vs VATS, and 952 pairs of VATS vs OL. Operative time for RL was shorter than VATS ( P < 0.0001) and OL ( P = 0.0004). Compared to OL, RL and VATS had less overall postoperative complications, shorter hospital stay (LOS), and lower transfusion rates (all P <0.02). Compared to VATS, RL had lower conversion rate ( P <0.0001), shorter hospital stay ( P <0.0001) and a lower postoperative transfusion rate ( P =0.01). RL and VATS cohorts had comparable postoperative complication rates. In-hospital mortality was comparable between all groups. CONCLUSIONS: RL and VATS approaches were associated with favorable perioperative outcomes compared to OL. Robotic-assisted lobectomy was also associated with a reduced length of stay and decreased conversion rate when compared to VATS.

Are Routine Chest Radiographs After Chest Tube Removal in Thoracic Surgery Patients Necessary?

INTRODUCTION: The routine use of chest x-ray (CXR) to evaluate the pleural space after chest tube removal is a common practice driven primarily by surgeon preference and institutional protocol. The results of these postpull CXRs frequently lead to additional interventions that serve only to increase health care costs and resource utilization. We investigated the utility of these postpull CXRs in thoracic surgery patients and assessed their effectiveness in predicting the need for tube replacement. METHODS: Single-institution retrospective study comprising thoracic surgery patients requiring postoperative chest tube drainage over a 3-y period. Demographics and surgical characteristics, including surgical approach, procedure, and procedure type, were recorded. Outcomes included postpull CXR findings, interventions resulting from radiographic abnormalities, and the additional health resource utilization incurred by obtaining these studies on asymptomatic patients. RESULTS: The study included 433 patients. Postpull CXRs were performed in 87.1% of patients, with 33.2% demonstrating an abnormality compared with the prior study. Among these, 65.7% resulted only in repeat imaging and 25.7% resulted in discharge delay. Overall, a total of 13 patients (3%) required chest tube replacement, three during the index hospitalization and the other 10 requiring readmission. Among those requiring chest tube replacement, 75% had normal postpull imaging, and all were symptomatic. CONCLUSIONS: Recurrent pneumothorax after chest tube removal requiring immediate tube reinsertion is relatively rare and does not occur in the absence of symptoms. Our study suggests that routine postpull CXRs have limited clinical utility and can be safely omitted in asymptomatic patients with appropriate clinical observation.

Utilization and costs of epidermal growth factor receptor mutation testing and targeted therapy in Medicare patients with metastatic lung adenocarcinoma.

BACKGROUND: Guidelines in 2013 and 2014 recommended Epidermal Growth Factor Receptor (EGFR) testing for metastatic lung adenocarcinoma patients as the efficacy of targeted therapies depends on the mutations. However, adherence to these guidelines and the corresponding costs have not been well-studied. METHODS: We identified 2362 patients at least 65 years old newly diagnosed with metastatic lung adenocarcinoma from January 2013 to December 2015 using the SEER-Medicare database. We examined the utilization patterns of EGFR testing and targeted therapies including erlotinib and afatinib. We further examined the costs of both EGFR testing and targeted therapy in terms of Medicare costs and patient out-of-pocket (OOP) costs. RESULTS: The EGFR testing rate increased from 38% in 2013 to 51% and 49% in 2014 and 2015 respectively. The testing rate was 54% among the 394 patients who received erlotinib, and 52% among the 42 patients who received afatinib. The median Medicare and OOP costs for testing were $1483 and $293. In contrast, the costs for targeted therapy were substantially higher with median 30-day costs at $6114 and $240 for erlotinib and $6239 and $471 for afatinib. CONCLUSION: This population-based study suggests that testing guidelines improved the use of EGFR testing, although there was still a large proportion of patients receiving targeted therapy without testing. The costs of targeted therapy were substantially higher than the testing costs, highlighting the need to improve adherence to testing guidelines in order to improve clinical outcomes while reducing the economic burden for both Medicare and patients.

Improving Lung Function in Severe Heterogenous Emphysema with the Spiration Valve System (EMPROVE). A Multicenter, Open-Label Randomized Controlled Clinical Trial.

Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema.Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management.Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control).Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment (n = 113) or control (n = 59). Mean FEV1 showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax.Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Chest Tube Drainage Devices.

Placement of a chest tube drains intrapleural fluid and air. The tube should be attached to a drainage system, such as one-, two-, or three-compartment devices, a one-way (Heimlich) valve for ambulatory drainage, a digital system, or a vacuum bottle. The frequently employed three-compartment systems, currently integrated disposable units, allow adjustment of negative pressure or no suction (water seal), and include an air leak meter on the water seal chamber to be used for demonstrating and quantifying air leak. These readings are subjective and prone to interobserver variability. Digital pleural drainage systems offer the benefits of quantification of any air leak and pleural pressure. Indwelling pleural catheters, typically utilized for malignant pleural effusion, can be drained using vacuum bottles. Knowledge of the design and functionality of each device in the setting of an individual patient's specific pleural process facilitates the selection of practical and financially prudent chest tube drainage strategies.

Pleural space infections after image-guided percutaneous drainage of infected intraabdominal fluid collections: a retrospective single institution analysis.

BACKGROUND: Percutaneous drainage of infected intraabdominal fluid collections is preferred over surgical drainage due to lower morbidity and costs. However, it can be a challenging procedure and catheter insertion carries the potential to contaminate the pleural space from the abdomen. This retrospective analysis demonstrates the clinical and radiographic correlation between percutaneous drainage of infected intraabdominal collections and the development of iatrogenic pleural space infections. METHODS: A retrospective single institution analysis of 550 consecutive percutaneous drainage procedures for intraabdominal fluid collections was performed over 24 months. Patient charts and imaging were reviewed with regard to pleural space infections that were attributed to percutaneous drain placements. Institutional review board approval was obtained for conduct of the study. RESULTS: 6/550 (1.1%) patients developed iatrogenic pleural space infections after percutaneous drainage of intraabdominal fluid collections. All 6 patients presented with respiratory symptoms and required pleural space drainage (either by needle aspiration or chest tube placement), 2 received intrapleural fibrinolytic therapy and 1 patient had to undergo surgical drainage. Pleural effusion cultures revealed same bacteria in both intraabdominal and pleural fluid in 3 (50%) cases. A video with a dynamic radiographic sequence demonstrating the contamination of the pleural space from percutaneous drainage of an infected intraabdominal collection is included. CONCLUSIONS: Iatrogenic pleural space infections after percutaneous drainage of intraabdominal fluid collections occur at a low incidence, but the pleural empyema can be progressive requiring prompt chest tube drainage, intrapleural fibrinolytic therapy or even surgery. Expertise in intraabdominal drain placements, awareness and early recognition of this complication is critical to minimize incidence, morbidity and mortality in these patients.

Efficacy and safety of the Spiration Valve System™ for the treatment of severe emphysema in patients with Alpha-1 antitrypsin deficiency (EMPROVE).

OBJECTIVES: Alpha-1 antitrypsin deficiency (AATD) is a hereditary condition associated with emphysema. This study analyzed the efficacy and safety of Spiration Valve System TM (SVS) among AATD patients with severe emphysema. METHODS: This multicenter prospective study included 20 patients demonstrating AATD as assessed by quantitative levels of AAT and genotype containing two ZZ alleles. Most diseased lobe based on high resolution computed tomography was selected for treatment with endobronchial SVS. The change from baseline in forced expiratory volume in 1 s (FEV1) at 6 months (Primary outcome) and at 12 months, quality-of-life (QoL) measured by St. George's Respiratory Questionnaire (SGRQ) as health status, dyspnea scale measured by mMRC, Chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), 36-item Short Form Health Survey (SF-36) physical component summary (PCS) and safety were assessed. RESULTS: Lung function (FEV1) significantly improved at 6 months (P = 0.02); but did not reach statistical significance at 12 months (P = 0.22). Significant improvement was observed in dyspnea (at all time points), QoL measures (3, 6, and 12 months), CAT score and PCS of SF-36 (1, 3 and 6 months). Response rates based on minimal clinically important difference reached 50-80% for all variables. Overall, 4.4 valves/patient were used to isolate the target lobe, with a mean procedure time of 20.3 min. Serious adverse events included COPD exacerbations (5%), pneumonia (10%), pneumothorax (15%) and death (5%), occurring within first three months. CONCLUSION: SVS endobronchial valve treatment showed improvement in lung function, dyspnea, and QoL in AATD patients with severe emphysema.

Sustained Clinical Benefits of Spiration Valve System in Patients with Severe Emphysema: 24-Month Follow-Up of EMPROVE.

Rationale: Follow-up of patients with emphysema treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives: To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period. Methods: EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed. Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George's Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively. Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Esophagectomy vs Gastrectomy for Early Stage Adenocarcinoma of the Gastroesophageal Junction: What is the Optimal Oncologic Surgical Treatment?

Guidelines for the management of gastroesophageal junction (GEJ) adenocarcinoma recommend esophagectomy as the preferred surgical treatment. Gastrectomy has been proposed as an equivalent procedure. This study aims to compare the oncologic outcomes of these operations. The National Cancer Database was queried for patients with clinical T1N0M0 (all sizes) and T2N0M0 (≤2cm) GEJ adenocarcinoma from 2004-2017. Patients treated with surgery-only were included and were stratified by surgical treatment. Propensity-score matching (PSM) was used to create a balanced cohort. Multivariable logistic regression was performed to evaluate for factors predictive of treatment. Kaplan-Meier (KM) and Cox proportional hazards models were used to compare overall survival (OS). 2,446 patients were identified. 75.1% received esophagectomy, while 24.9% were treated with gastrectomy. Patients at high volume facilities were more likely to undergo esophagectomy (OR 1.750, P < 0.001). Factors associated with lower likelihood of undergoing esophagectomy included age ≥75 years (OR 0.588, P = 0.001), female sex (OR 0.706, P = 0.003), and non-White race (OR 0.430, P < 0.001), compared to age ≤50 years, male, and White race, respectively. In the unmatched cohort, gastrectomy was associated with a higher rate of positive margins (4.1% vs 2.3%, P = 0.022). PSM yielded 591 pairs. In the matched cohort, patients treated with esophagectomy had improved 5-year OS compared to gastrectomy (70.6% vs 66.5%, P = 0.030). Multivariable analysis showed improved OS in patients treated with esophagectomy compared to gastrectomy (HR 0.767, P = 0.010). Esophagectomy is associatedwith improved survival and a lower incidence of positive margins in patients with early-stage GEJ adenocarcinoma when compared to gastrectomy.

Outcomes after sublobar resection versus lobectomy in non-small cell carcinoma in situ.

OBJECTIVE: Guidelines for treatment of non-small cell lung cancer identify patients with tumors ≤2 cm and pure carcinoma in situ histology as candidates for sublobar resection. Although the merits of lobectomy, sublobar resection, and lymphoid (LN) sampling, have been investigated in early-stage non-small cell lung cancer, evaluation of these modalities in patients with IS disease can provide meaningful clinical information. This study aims to compare these operations and their relationship with regional LN sampling in this population. METHODS: The National Cancer Database was used to identify patients diagnosed with non-small cell lung cancer clinical Tis N0 M0 with a tumor size ≤2 cm from 2004 to 2017. The χ2 tests were used to examine subgroup differences by type of surgery. Kaplan-Meier method and Cox proportional hazard model were used to compare overall survival. RESULTS: Of 707 patients, 56.7% (401 out of 707) underwent sublobar resection and 43.3% (306 out of 707) underwent lobectomy. There was no difference in 5-year overall survival in the sublobar resection group (85.1%) compared with the lobectomy group (88.9%; P = .341). Multivariable survival analyses showed no difference in overall survival (hazard ratio, 1.044; P = .885) in the treatment groups. LN sampling was performed in 50.9% of patients treated with sublobar resection. In this group, LN sampling was not associated with improved survival (84.9% vs 85.0%; P = .741). CONCLUSIONS: We observed no difference in overall survival between sublobar resection and lobectomy in patients with cTis N0 M0 non-small cell lung cancer with tumors ≤2 cm. Sublobar resection may be an appropriate surgical option for this population. LN sampling was not associated with improved survival in patients treated with sublobar resection.

Multidisciplinary management of malignant pleural effusion.

Approximately 50% of patients with metastatic disease develop a malignant pleural effusion (MPE). Prompt clinical evaluation and treatment to achieve successful palliation are the main goals of management of MPE. Optimal treatment is still controversial and there is no universal standard approach. Management options include observation, thoracentesis, indwelling pleural catheter (IPC) or chest tube placement, pleurodesis, and surgical pleurectomy. The treatment for each patient should be based on symptoms, general condition, and life expectancy.

The cost of treatments for retained traumatic hemothorax: A decision analysis.

INTRODUCTION: Early video-assisted thorascopic surgery (VATS) is the recommended intervention for retained hemothorax in trauma patients. Alternative options, such as lytic therapy, to avoid surgery remain controversial. The purpose of this decision analysis was to assess expected costs associated with treatment strategies. METHODS: A decision tree analysis estimated the expected costs of three initial treatment strategies: 1) VATS, 2) intrapleural tissue plasminogen activator (TPA) lytic therapy, and 3) intrapleural non-TPA lytic therapy. Probability parameters were estimated from published literature. Costs were based on National Inpatient Sample data and published estimates. Our model compared overall expected costs of admission for each strategy. Sensitivity analyses were conducted to explore the impact of parameter uncertainty on the optimal strategy. RESULTS: In the base case analysis, using TPA as the initial approach had the lowest total cost (U.S. $37,007) compared to VATS ($38,588). TPA remained the optimal initial approach regardless of the probability of complications after VATS. TPA was an optimal initial approach if TPA success rate was >83% regardless of the failure rate with VATS. VATS was the optimal initial strategy if its total cost of admission was <$33,900. CONCLUSION: Lower treatment costs with lytic therapy does not imply significantly lower total cost of trauma admission. However, an initial approach with TPA lytic therapy may be preferred for retained traumatic hemothorax to lower the total cost of admission given its high probability of avoiding the operating room with its resultant increased costs. Future studies should identify differences in quality of life after recovery from competing interventions.

Multidisciplinary management of early and locally advanced esophageal cancer.

Clinical management of esophageal cancer is a multidisciplinary challenge. Diagnosis is associated with a high mortality and approximately 40% of patients have locally advanced disease at clinical presentation. Surgery remains one of the fundamental parts of treatment, but multimodal approaches including chemotherapy and radiation are associated with improved outcomes. This comprehensive review addresses the multidisciplinary management of early and locally advanced esophageal cancer.

Mediastinal IgG4-Related Disease Manifesting as Superior Vena Cava Syndrome.

Immunoglobulin G4 (IgG4)-related disease was first identified as a systemic condition in 2003 when extrapancreatic manifestations were identified in patients with autoimmune pancreatitis. Its peak incidence occurs in the fifth or sixth decades of life. Isolated extraaortic mediastinal involvement is extremely rare. This report describes a case of isolated extraaortic mediastinal IgG4-related disease encasing the superior vena cava (SVC) and manifesting as SVC syndrome in a 25-year-old man with no personal or family history of autoimmune disease. Resection with SVC reconstruction was performed.

Postoperative chemotherapy and radiation improve survival following cardiac sarcoma resection.

OBJECTIVE: Cardiac sarcoma represents a rare and aggressive form of cancer with a paucity of data to produce outcome-driven evidence-based guidelines. Current surgical management consists of resection with postoperative therapy (chemotherapy, radiation, or both) offered on a selective, individualized basis. This study was designed to determine whether postoperative therapy was associated with improved overall survival after resection. METHODS: The National Cancer Database was used to identify patients with cardiac sarcoma between 2004 and 2015. Patient characteristics were stratified by treatment (surgical, nonsurgical, and none), and treatment was analyzed by stage. Overall survival, assessed with Kaplan-Meier methodology, was compared between patients who received postoperative therapy and those who did not following resection. Multivariable survival modeling using a Weibull model identified risk factors associated with survival while controlling for confounders. RESULTS: The study included 617 patients diagnosed with cardiac sarcoma. Only 24% (149/617) of patients were diagnosed with early-stage disease. Angiosarcoma represented 48% (298/617) of cases and was the most commonly identified histologic subtype. 60% (372/617) underwent surgical resection and 58% (216/372) of those patients were treated with postoperative therapy. Following surgery, median survival was more than doubled for patients treated with postoperative therapy (19 months vs 8 months, P = .026). However, 5-year overall survival was similar between the groups. Multivariable analysis confirmed an improvement in survival with postoperative therapy (hazard ratio, 0.68; 95% confidence interval, 0.51-0.91, P = .009). CONCLUSIONS: Postoperative therapy is associated with better median survival following resection of cardiac sarcoma. However, at 5 years, the difference in overall survival is not statistically significant.

Indications and approach to surgical resection of lung metastases.

Pulmonary metastasectomy is a curative option for selected patients with cancer spread to the lungs. Complete surgical removal of pulmonary metastases can improve survival and is recommended under certain criteria. Specific issues that require consideration in a multidisciplinary setting when planning pulmonary metastasectomy include: adherence to established indications for resection, the surgical strategy including the use of minimally invasive techniques, pulmonary parenchyma preservation, and the role of lymphadenectomy.

The Impact of Minimally Invasive Gastrectomy on Survival in the USA.

BACKGROUND: Minimally invasive surgical approaches for gastric adenocarcinoma are increasing in prevalence. Although recent studies suggest such approaches are associated with improvements in short-term outcomes, long-term outcomes have not been well studied. This study aimed to evaluate the impact of minimally invasive gastrectomy on long-term survival. METHODS: The National Cancer Database (NCDB) was used to identify patients who underwent gastrectomy for adenocarcinoma between 2010 and 2015. Patient characteristics were stratified by open and minimally invasive approaches and compared using chi-square and t tests. Unadjusted survival functions were estimated using Kaplan-Meier methodology. Multivariable modeling of risks factors for survival was analyzed with Cox proportional hazard models. Covariate imbalance was controlled using propensity score matching. RESULTS: The study included 17,449 patients who underwent gastrectomy. Cox proportional hazard modeling demonstrated that minimally invasive surgery improved survival (hazard ratio = 0.86, P < 0.0001). Predictors of worsened survival included community facility type, comorbidities, tumor size, extent of gastrectomy, clinical T and N staging (P < 0.0060 for all). After propensity score matching, minimally invasive surgery had a significantly improved survival at 5 years compared to an open approach, 51.9% versus 47.7% (P < 0.0001). Survival was not significantly different between propensity score-matched patients who received laparoscopic and robotic approaches (P = 0.2611). CONCLUSIONS: Minimally invasive approaches for gastric carcinoma are associated with improved long-term survival. There was no significant difference in survival when comparing laparoscopic to robotic gastrectomy. The mechanisms that drive these improvements deserve further investigation.

Distinct action of the retinoblastoma pathway on the DNA replication machinery defines specific roles for cyclin-dependent kinase complexes in prereplication complex assembly and S-phase progression.

The retinoblastoma (RB) and p16ink4a tumor suppressors are believed to function in a linear pathway that is functionally inactivated in a large fraction of human cancers. Recent studies have shown that RB plays a critical role in regulating S phase as a means for suppressing aberrant proliferation and controlling genome stability. Here, we demonstrate a novel role for p16ink4a in replication control that is distinct from that of RB. Specifically, p16ink4a disrupts prereplication complex assembly by inhibiting mini-chromosome maintenance (MCM) protein loading in G1, while RB was found to disrupt replication in S phase through attenuation of PCNA function. This influence of p16ink4a on the prereplication complex was dependent on the presence of RB and the downregulation of cyclin-dependent kinase (CDK) activity. Strikingly, the inhibition of CDK2 activity was not sufficient to prevent the loading of MCM proteins onto chromatin, which supports a model wherein the composite action of multiple G1 CDK complexes regulates prereplication complex assembly. Additionally, p16ink4a attenuated the levels of the assembly factors Cdt1 and Cdc6. The enforced expression of these two licensing factors was sufficient to restore the assembly of the prereplication complex yet failed to promote S-phase progression due to the continued absence of PCNA function. Combined, these data reveal that RB and p16ink4a function through distinct pathways to inhibit the replication machinery and provide evidence that stepwise regulation of CDK activity interfaces with the replication machinery at two discrete execution points.