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PURPOSE Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space. METHODS This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry. RESULTS A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression. CONCLUSION Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Perineural invasion is a frequent histological finding in pancreatic adenocarcinoma. However, perineural invasion by intraductal papillary mucinous neoplasm (IPMN), a precursor lesion of pancreatic adenocarcinoma, has not been reported so far. We report a unique case of perineural invasion by IPMN in a 60-year-old female who underwent pancreatoduodenectomy for high-risk features of IPMN. Histological evaluation showed increased nerve density in the connective tissue of IPMN with multiple foci of perineural invasion by IPMN. In addition, there was a discrete 2 mm focus of invasive carcinoma that did not show perineural invasion. Chemotherapy was started and the patient is disease-free at 29 months follow up. The case illustrates previously unreported neuroplastic alterations and neutrotropism in benign neoplastic component of a malignant IPMN.

Background Cancer of unknown primary (CUP) presenting as bone‐predominant (BCUP) or lymph node‐only disease (LNCUP) represents two clinically distinct subsets of nonvisceral CUP. These present a diagnostic challenge with a large differential of putative primary cancers and defy the “one‐treatment‐fits‐all” approach. Materials and Methods We identified patients with BCUP (n = 29) and LNCUP (n = 63) using a prospectively collected CUP database and tumor registry of patients seen at MD Anderson Cancer Center between 2001 to 2017. Clinicopathological characteristics, treatments, and outcomes were abstracted. A control group of non‐BCUP/LNCUP cases (n = 443) from the database was used for comparison. Kaplan‐Meier method was used to estimate overall survival and compared using log‐rank test. Results In this cohort, 64% and 60% patients had disseminated disease at diagnosis and 39% and 23% had Culine poor‐risk disease in BCUP and LNCUP, respectively. Median overall survival (OS) for BCUP was 14.5 months and for LNCUP was 32.6 months. For BCUP, gemcitabine plus platinum was the most common initial chemotherapy (54%). For LNCUP, carboplatin plus paclitaxel was the most common initial chemotherapy (38%). Radiation was given to 74% of patients with BCUP and 37% of those with LNCUP. On multivariate analysis, poor‐risk Culine group (hazard ratio [HR], 1.76; p < .001) and high neutrophil‐to‐lymphocyte ratio (HR, 2.38, p < .001) were associated with worse OS. Conclusion BCUP and LNCUP are rare subsets within CUP with varying prognosis. Poor‐risk Culine group and high neutrophil‐to‐lymphocyte ratio are associated with poor survival. Select patients with limited metastases can have long‐term survival with aggressive multimodality treatment. Careful clinicopathological review can facilitate chances of site‐directed therapy. Implications for Practice Cancer of unknown primary (CUP) rarely presents as bone‐predominant (BCUP) or lymph node‐only (LNCUP) disease. This article describes a cohort of each and compares with a larger CUP cohort. Patients with BCUP have unique issues with fractures and pain, often receiving radiation. Overall survival of 14.5 months was similar to a larger CUP comparison cohort. Patients with LNCUP had improved overall survival at 32.6 months, with longer survival in patients without disseminated disease. Culine poor‐risk group and neutrophil‐to‐lymphocyte ratio were associated with worse overall survival. Tips regarding diagnosis and management of these rare malignant subsets are provided., Considering the limited understanding of bone‐predominant or lymph‐node‐only cancers of unknown primary, this article describes the clinical features and outcome data of these two unique conditions.

Despite aggressive adjuvant management, a high percentage of patients who undergo appropriate surgical resection for pancreatic cancer will see their cancer recur and thus will not be cured. An important paradigm shift to achieve better outcomes has been therapy sequence, with neoadjuvant chemotherapy preceding surgery. Patients with a borderline resectable cancer, or patients with a resectable cancer but who have other high-risk features, are ideal candidates to consider for neoadjuvant chemotherapy. Among the high-risk features, a baseline elevated CA 19-9 concentration can be particularly useful, as its response trend during neoadjuvant chemotherapy can offer important insights into the prognosis after surgery. When selecting a neoadjuvant chemotherapy regimen, response data available for the use of FOLFIRINOX and gemcitabine and nabpaclitaxel in the metastatic setting support their use in this space. FOLFIRINOX is perhaps the preferred regimen, given its proven adjuvant benefit and possibly its superior tumor response rate; still, patient tolerance and thus ability to complete recommended treatment must be carefully considered. This review presents the evidence supporting neoadjuvant chemotherapy for resectable pancreatic cancer, the factors to consider when making such a recommendation, the selection of specific regimens, and our institutional approach using these tools.

Multimodality therapy (MMT) is recommended for patients with resectable gastric cancer, but no single approach has been established as standard. Little is presently known about current national practice patterns and sequencing of MMT.Retrospective cohort study of patients with gastric cancer aged 18 to 80 y in the National Cancer Database (2006-2014) with ≥T2 and/or node-positive disease (i.e., stage Ib to III) treated with MMT. Clinical nodal staging accuracy was ascertained among those treated with upfront surgery by comparing clinical and pathologic nodal staging. Multivariable Cox regression was used to evaluate the association between overall risk of death and MMT approach (i.e., radiation used versus not and treatment sequence).Among 5817 patients, 16.1% received perioperative MMT, 50.6% preoperative only, and 33.3% postoperative only. The sensitivity, specificity, positive predictive value, and negative predictive values of clinical nodal staging were 68.4%, 88.8%, 91.1%, and 62.7%, respectively. Current clinical nodal staging modalities understage 37.3% of clinically node-negative patients. Over time, radiation utilization decreased (74.3% in 2006 versus 53.9% in 2014; trend test, P 0.001), perioperative MMT increased (8.9% versus 22.2%%; trend test, P 0.001), and postoperative MMT decreased (43.1% versus 21.0%; trend test, P 0.001). Neither type of MMT nor treatment sequence is associated with risk of death.One-third of patients with gastric cancer who are candidates to receive MMT are treated with upfront surgery. Given the high false negative rate of clinical nodal staging and high noncompletion rate of postoperative treatment, efforts should be directed at improving and optimizing preoperative therapy utilization.

Biotherapeutics are attractive anti-cancer agents due to their high specificity and limited toxicity compared to conventional small molecules. Antibodies are widely used in cancer therapy, either directly or conjugated to a cytotoxic payload. Peptide therapies, though not as prevalent, have been utilized in hormonal therapy and imaging. The limitations associated with unmodified forms of both types of biotherapeutics have led to the design and development of novel structures, which incorporate key features and structures that have improved the molecules' abilities to bind to tumor targets, avoid degradation, and exhibit favorable pharmacokinetics. In this review, we highlight the current status of monoclonal antibodies and peptides, and provide a perspective on the future of biotherapeutics using novel constructs.

To determine the association between neoadjuvant chemotherapy and chemoradiation therapy on completeness of pathologic response and to assess the impact of primary tumor versus nodal response on survival after esophagectomy.Patients aged 18 to 80 years in the National Cancer Data Base (2006-2016) with clinically staged, locally advanced (cT2-4 or cN+) esophageal adenocarcinoma who underwent an R0 esophagectomy after neoadjuvant chemotherapy or chemoradiation therapy were included. Multivariable Cox proportional hazards regression models were constructed to assess the association between treatment response and survival.Among 2870 patients, there was a significant dose-response association between completeness of response and overall survival: no response (reference), partial response (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.72-0.91), and complete response (HR, 0.55; 95% CI, 0.47-0.65). Compared with neoadjuvant chemotherapy alone, neoadjuvant chemoradiation was associated with higher pathologic primary tumor (33.9% vs 21.3%; P .001) and pathologic nodal response rates (55.9% vs 32.7%; P .001). Both a primary and nodal response were associated with improved survival. However, among patients with a primary but no nodal response, primary tumor response was not associated with risk of death (HR, 0.88; 95% CI, 0.69-1.11). In contrast, among patients who had a nodal but no primary response, the survival benefit of a nodal response was maintained (HR, 0.66; 95% CI, 0.58-0.76).Pathologic nodal (rather than primary tumor) response to neoadjuvant therapy is associated with improved survival. These data suggest a need to optimize neoadjuvant strategies associated with more complete nodal response rates and to consider more aggressive adjuvant treatment for patients with residual nodal disease after esophagectomy.

The optimal adjuvant management of patients with resectable gastric cancer remains a therapeutic challenge. Although the benefit of adjuvant therapy for these patients is clearly established, recurrence and mortality rates remain high despite such treatment. Moreover, surgical comorbidities and treatment toxicities result in high rates of failure to complete treatment after surgery. Two divergent approaches to adjuvant treatment have emerged as standard: postoperative chemoradiotherapy and perioperative chemotherapy. Because these approaches have never been compared directly, recommendations for adjuvant treatment require multidisciplinary discussion. During this discussion, the characteristics of the symptoms, the histology, location, and stage of the tumor, and the feasibility of the patient's completing all recommended therapy may be considered. In our own practice, we favor perioperative chemotherapy for patients with asymptomatic, proximal, higher-stage disease and adjuvant chemoradiotherapy for patients with symptomatic, distal, lower-stage disease. Herein, we summarize the available data for approaches to the adjuvant treatment of gastric cancer, with special consideration of the characteristics of the patients enrolled in the various studies. We also describe how we developed our paradigm for recommending a particular approach to adjuvant treatment for each patient.

The curative surgical resection of metastatic disease in patients with stage IV colorectal cancer with a limited tumor burden is standard of care. However, the role for neoadjuvant medical therapy and the ideal composition of that therapy are not established. Several neoadjuvant medical therapies, including standard advanced colorectal cancer chemotherapy regimens-such as folinic acid, fluorouracil (5-FU), and oxaliplatin (FOLFOX); folinic acid, 5-FU, and irinotecan (FOLFIRI); and folinic acid, 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI)-have been evaluated, as has the addition of the biologic agents bevacizumab, panitumumab, and cetuximab. Those patients who are immediate surgical candidates do not seem to benefit from a neoadjuvant medical approach and should proceed directly to surgical resection. Those patients who are not surgical candidates at presentation can in some instances achieve a conversion of disease to a curable state with systemic therapy. Here, we review the studies that have explored different treatment regimens, therapeutic sequencing, and biologic inclusions for the treatment of these patients, with neoadjuvant intent. We also describe how we have established our own treatment paradigm for the management of potentially curable metastatic colorectal cancer.