Ammar A. Javed

Detection and localization of surgically resectable cancers with a multi-analyte blood test

SEEK and you may find cancer earlier Many cancers can be cured by surgery and/or systemic therapies when detected before they have metastasized. This clinical reality, coupled with the growing appreciation that cancers rapid genetic evolution limits its response to drugs, have fueled interest in methodologies for earlier detection of the disease. Cohen et al. developed a noninvasive blood test, called CancerSEEK that can detect eight common human cancer types (see the Perspective by Kalinich and Haber). The test assesses eight circulating protein biomarkers and tumor-specific mutations in circulating DNA. In a study of 1000 patients previously diagnosed with cancer and 850 healthy control individuals, CancerSEEK detected cancer with a sensitivity of 69 to 98% (depending on cancer type) and 99% specificity. Science, this issue p. 926; see also p. 866 A blood test that combines protein and DNA markers may allow earlier detection of eight common cancer types. Earlier detection is key to reducing cancer deaths. Here, we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69 to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was greater than 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.

Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers

Significance Few patients with pancreatic cancer survive longer than 5 y, in part because most patients are identified only after their disease has progressed to an advanced stage. In this study, we show how combining mutations in circulating tumor DNA (ctDNA) with protein markers can result in a screening test with improved sensitivity while retaining specificity. The combination of the ctDNA and protein markers was superior to any single marker. Moreover, the combination detected nearly two-thirds of pancreatic cancers that had no evidence of distant metastasis at the time of surgical resection. The strategy may represent an approach to detect cancers of many types at an earlier stage. The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient’s primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

Modified Staging Classification for Pancreatic Neuroendocrine Tumors on the Basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society Systems

Purpose The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) staging classifications are two widely used systems in managing pancreatic neuroendocrine tumors. However, there is no universally accepted system. Methods An analysis was performed to evaluate the application of the ENETS and AJCC staging classifications using the SEER registry (N = 2,529 patients) and a multicentric series (N = 1,143 patients). A modified system was proposed based on analysis of the two existing classifications. The modified system was then validated. Results The proportion of patients with AJCC stage III disease was extremely low for both the SEER series (2.2%) and the multicentric series (2.1%). For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage IIA disease, and patients with stage IIIB disease had a lower hazard ratio for death than did patients with stage IIIA disease. We modified the ENETS staging classification by maintaining the ENETS T, N, and M definitions and adopting the AJCC staging definitions. The proportion of patients with stage III disease using the modified ENETS (mENETS) system was higher than that of the AJCC system in both the SEER series (8.9% v 2.2%) and the multicentric series (11.6% v 2.1%). In addition, the hazard ratio of death for patients with stage III disease was higher than that for patients with stage IIB disease. Moreover, statistical significance and proportional distribution were observed in the mENETS staging classification. Conclusion An mENETS staging classification is more suitable for pancreatic neuroendocrine tumors than either the AJCC or ENETS systems and can be adopted in clinical practice.

Neutrophil-to-lymphocyte Ratio is a Predictive Marker for Invasive Malignancy in Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Objective: To evaluate the correlation between neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) values, and the presence of invasive carcinoma in patients with intraductal papillary mucinous neoplasm (IPMN). Background: NLR and (PLR) are inflammatory markers that have been associated with overall survival in patients with invasive malignancies, including pancreatic cancer. Methods: We retrospectively reviewed 272 patients who underwent surgical resection for histologically confirmed IPMN from January 1997 to July 2015. NLR and PLR were calculated and coevaluated with additional demographic, clinical, and imaging data for possible correlation with IPMN-associated carcinoma in the form of a predictive nomogram. Results: NLR and PLR were significantly elevated in patients with IPMN-associated invasive carcinoma (P < 0.001). In the multivariate analysis, NLR value higher than 4 (P < 0.001), IPMN cyst of size more than 3 cm (P < 0.001), presence of enhanced solid component (P = 0.014), main pancreatic duct dilatation of more than 5 mm (P < 0.001), and jaundice (P < 0.001) were statistically significant variables. The developed statistical model has a c-index of 0.895. Implementation of the statistically significant variables in a predictive nomogram provided a reliable point system for estimating the presence of IPMN-associated invasive carcinoma. Conclusions: NLR is an independent predictive marker for the presence of IPMN-associated invasive carcinoma. Further prospective studies are needed to assess the predictive ability of NLR and how it can be applied in the clinical setting.

Hepatocellular carcinoma in Native South Asian Pakistani population; trends, clinico-pathological characteristics & differences in viral marker negative & viral-hepatocellular carcinoma

BackgroundHCC is the fifth most common cancer globally. Our study was conducted to (1)investigate the trends and clinico-pathological characteristics of Hepatocellular carcinoma among native South Asian patients in Pakistan, (2)to estimate the prevalence as well as the trends of viral marker negative HCC and (3) to compare the clinico-pathological, radiological characteristics, applicability of treatment at diagnosis and prognostic factors among patients with both viral marker negative and viral marker positive-HCC being consulted at Aga Khan University Hospital(AKUH), Karachi, Pakistan.MethodPatients ≥18 years, already diagnosed to have HCC and visiting AKUH during 1999–2009 were identified using ICD code 1550. The diagnosis of HCC was made in the presence of characteristic features of HCC on triple-phasic CT scan/MRI or with histological findings on biopsy.Results645 patients were enrolled. Of these 546(84.7%) were viral-HCC and 99(15.3%) were viral marker negative HCC. Among viral-HCC group underlying etiology of cirrhosis was HCV in 67.9%, HBV in 21.8% and concomitant HBV with HCV or HDV in 10.3% cases. Majority (62.8%) patients had advanced HCC. Larger tumor size (p < 0.001), shorter duration between diagnosis of cirrhosis and HCC (p 0.03), concomitant Diabetes Mellitus (p < 0.001) were found significant factors associated with viral marker negative HCC.ConclusionThe burden of hepatocellular carcinoma is rising among native South Asian Pakistani population and the viral marker negative HCC are not uncommon in our population. Viral marker negative HCC tend not to be under surveillance as compared to viral-HCC and are diagnosed mostly at advanced stage & when they became symptomatic.

Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

Tumor-Vessel Relationships in Pancreatic Ductal Adenocarcinoma at Multidetector CT: Different Classification Systems and Their Influence on Treatment Planning

Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a challenge, given its propensity for early systemic spread and growth into the adjacent vital vascular structures. With the advent of newer surgical techniques and chemoradiation therapies, multidetector computed tomography (CT) plays a crucial role in the identification of patients with borderline resectable disease who may benefit from such treatments. Stage III PDAC is divided into two categories-locally advanced, defined by arterial encasement or nonreconstructible portovenous axis involvement; and borderline resectable, defined by limited arterial involvement and/or reconstructible portovenous involvement. A consensus definition for stage III borderline resectable PDAC has been proposed by the Americas Hepato-Pancreato-Biliary Association, the Society of Surgical Oncology, and the Society for Surgery of the Alimentary Tract and has gained widespread use. Evaluation of borderline resectable disease involves the identification of the circumferential and longitudinal relationship of the tumor with its neighboring vessels, markers of vascular invasion, and aberrant anatomic structures that alter the surgical approach. Furthermore, the use of template-based radiology reporting may increase the objectivity of the evaluation and mandate the provision of all of the key descriptors required for a comprehensive evaluation of the disease. In this review, the staging of PDAC at multidetector CT is described, with reference to the evaluation of the tumor-vessel interface as it guides treatment planning, along with a discussion of the key descriptors of PDAC at multidetector CT and their importance. Examples are provided of the imaging findings of borderline resectable disease and different surgical approaches, along with a discussion on the importance of standardized terminology and template-based reporting. ©RSNA, 2016.

Characterization and Optimal Management of High-Risk Pancreatic Anastomoses During Pancreatoduodenectomy

Objective: The aim of this study was to identify the optimal fistula mitigation strategy following pancreaticoduodenectomy. Background: The utility of technical strategies to prevent clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreatoduodenectomy (PD) may vary by the circumstances of the anastomosis. The Fistula Risk Score (FRS) identifies a distinct high-risk cohort (FRS 7 to 10) that demonstrates substantially worse clinical outcomes. The value of various fistula mitigation strategies in these particular high-stakes cases has not been previously explored. Methods: This multinational study included 5323 PDs performed by 62 surgeons at 17 institutions. Mitigation strategies, including both technique related (ie, pancreatogastrostomy reconstruction; dunking; tissue patches) and the use of adjuvant strategies (ie, intraperitoneal drains; anastomotic stents; prophylactic octreotide; tissue sealants), were evaluated using multivariable regression analysis and propensity score matching. Results: A total of 522 (9.8%) PDs met high-risk FRS criteria, with an observed CR-POPF rate of 29.1%. Pancreatogastrostomy, prophylactic octreotide, and omission of externalized stents were each associated with an increased rate of CR-POPF (all P < 0.001). In a multivariable model accounting for patient, surgeon, and institutional characteristics, the use of external stents [odds ratio (OR) 0.45, 95% confidence interval (95% CI) 0.25–0.81] and the omission of prophylactic octreotide (OR 0.49, 95% CI 0.30–0.78) were independently associated with decreased CR-POPF occurrence. In the propensity score matched cohort, an “optimal” mitigation strategy (ie, externalized stent and no prophylactic octreotide) was associated with a reduced rate of CR-POPF (13.2% vs 33.5%, P < 0.001). Conclusions: The scenarios identified by the high-risk FRS zone represent challenging anastomoses associated with markedly elevated rates of fistula. Externalized stents and omission of prophylactic octreotide, in the setting of intraperitoneal drainage and pancreaticojejunostomy reconstruction, provides optimal outcomes.

Pancreatic Fistula and Delayed Gastric Emptying After Pancreatectomy: Where do We Stand?

Pancreatic resection has become a feasible treatment of pancreatic neoplasms, and with improvements in surgical techniques and perioperative management, mortality associated with pancreatic surgery has decreased considerably. Despite this improvement, a high rate of complications is still associated with these procedures. Among these complications, delayed gastric emptying (DGE) and postoperative pancreatic fistula (POPF) have a substantial impact on patient outcomes and burden our healthcare system. Technical modifications and postoperative approaches have been proposed to reduce rates of both POPF and DGE in patients undergoing pancreatectomy; however, to date, their rates have remained unchanged. In the present study, we summarize the findings of the most significant studies that have investigated these complications. In particular, several studies focused on technical modifications including extent of dissection, stent placement, nature of anastomosis, type of reconstruction, and application of biological or non-biological agents to site of anastomosis. Moreover, postoperatively, drain placement, duration of drain usage, postoperative feeding, and use of pharmacological agents were studied to reduce rates of POPF and DGE. In this review, we summarize the most relevant literature on this fundamental aspect of pancreatic surgery. Despite studies identifying the potential benefit of technical modifications and postoperative approaches, these findings remain controversial and suggest need for further extensive investigation. Most importantly, we recommend that all surgeons performing these procedures base their practice on the most updated and highest available level of evidence.

The misuse of the terminology "standard of care" hampers innovations in surgery.

S tandard of care is defined by how a “reasonably prudent physician [with the same qualifications] would act in the same or similar circumstances.”1 It is very similarly defined as “the skill and care that is ordinarily used by reasonably well-qualified doctors in similar cases . . . .”2(p40) In the context of medicine, it is a legal term created to judge medical negligence, that is, in a condition where a practitioner provides treatment similar to that provided by his or her fellow practitioners, he or she would not be liable to negligence.3 However, this legal term is no longer confined to dealing with legal matters alone and is frequently used freely by insurers to determine reimbursement or coverage of treatments for patients. Despite modifications to the actual definition, which was coined in Britain 1957 after the case of Bolam v Friern Hospital Management, the prevailing concept has remained constant4,5; it being the minimal acceptable level of care in the determination of negligence.5 It is so difficult to define, in fact, that in practicality, the definition of standard of care for any problem is defined at the time of litigation by the “testimony of expert witnesses,” the so-called “Bolam test.”5 This legal, nonmedical term is now being used by health care providers both in their practice, as they communicate with one another and teach students and residents, and in medical literature.5 Instead of its true role in litigation, it now plays a pivotal part in determining patient care by impacting physician decision making and controlling payment or reimbursement.6 The insurance providers often only fund the treatment that is considered to be the “standard of care” and disregard the newer innovative techniques, which are labeled as being experimental instead of innovative. Another consideration is that, given its definition and subjective nature, “standard of care” is prone to vary both across practitioners and across geographic locations. The need therefore arises both to free ourselves of the use of such terminology in clinical medicine and to define and differentiate experimental treatment options from the more novel but suitable ones for a particular patient. In 1994, Stanley Reiser wrote that an intermediate category was necessary to denote therapies that were between experimental and standard ones, which he denoted as “crossover” therapies.6 The author stated that both scientific (indications of use, outcomes, requirements for use, and certification to deliver a therapy) and social factors comprise the criteria to categorize a treatment option as being a suitable one.6 One must also consider that it is only when these innovative techniques become more prevalent that we can gain enough knowledge about them to determine some of these variables. Given this dynamic nature there should ideally be a smooth transition across a spectrum and not a sudden jump between being