Validation of a nomogram to predict the risk of cancer in patients with intraductal papillary mucinous neoplasm and main duct dilatation of 10 mm or less.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is premalignant pancreatic lesion. International guidelines offer limited predictors of individual risk. A nomogram to predict individual IPMN malignancy risk was released, with good diagnostic performance based on a large cohort of Asian patients with IPMN. The present study validated a nomogram to predict malignancy risk and invasiveness of IPMN using both Eastern and Western cohorts. METHODS: Clinicopathological and radiological data from patients who underwent pancreatic resection for IPMN at four centres each in Eastern and Western countries were collected. After excluding patients with missing data for at least one malignancy predictor in the nomogram (main pancreatic duct diameter, cyst size, presence of mural nodule, serum carcinoembryonic antigen and carbohydrate antigen (CA) 19-9 levels, and age). RESULTS: In total, data from 393 patients who fit the criteria were analysed, of whom 265 were from Eastern and 128 from Western institutions. Although mean age, sex, log value of serum CA19-9 level, tumour location, main duct diameter, cyst size and presence of mural nodule differed between the Korean/Japanese, Eastern and Western cohorts, rates of malignancy and invasive cancer did not differ significantly. Areas under the receiver operating characteristic (ROC) curve values for the nomogram predicting malignancy were 0·745 for Eastern, 0·856 for Western and 0·776 for combined cohorts; respective values for the nomogram predicting invasiveness were 0·736, 0·891 and 0·788. CONCLUSIONS: External validation of the nomogram showed good performance in predicting cancer in both Eastern and Western patients with IPMN lesions.

ANTECEDENTES: La neoplasia mucinosa papilar intraductal (intraductal papillary mucinous neoplasm, IPMN) es una lesión pancreática premaligna. Las guías internacionales incluyen un número limitado de factores predictivos de riesgo individual. Para predecir el riesgo individual de malignidad del IPMN se ha propuesto un nomograma con un buen rendimiento diagnóstico, basado en una gran cohorte de pacientes asiáticos con IPMN. Este estudio validó el nomograma para predecir el riesgo de cáncer y de invasión de la IPMN utilizando cohortes tanto orientales como occidentales. MÉTODOS: Se recogieron datos clínico-patológicos y radiológicos de pacientes en los que se realizó una resección de páncreas por IPMN en 4 centros en países orientales y en 4 centros de países occidentales. Se excluyeron los pacientes en los que en el nomograma faltaba ≥ 1 factor(es) predictivo(s) de malignidad (diámetro del conducto pancreático principal, tamaño del quiste, presencia de nódulo mural, niveles séricos de CEA y CA19-9, y edad). RESULTADOS: En total, se analizaron datos de 393 pacientes que cumplían con los criterios de inclusión, de los cuales 265 eran de centros orientales y 128 de centros occidentales. Aunque la edad media, el sexo, el valor logarítmico del nivel sérico de CA19-9, la localización del tumor, el diámetro del conducto principal, el tamaño del quiste y la presencia de un nódulo mural difirieron entre las cohortes de Corea/Japón y las cohortes oriental y occidental, las tasas de malignidad y de cáncer invasivo no fueron significativamente diferentes. Las áreas bajo la curva operativa del receptor (area under the receiver operating curve, AUC) que mostró el nomograma para predecir la malignidad fueron: cohorte oriental: 0,745; cohorte occidental: 0,856 y cohortes combinadas: 0,776; y para predecir la invasión tumoral fueron: cohorte oriental: 0,736; cohorte occidental: 0,891, y cohortes combinadas: 0,788. CONCLUSIÓN: La validación externa del nomograma mostró un buen rendimiento en la predicción de cáncer, tanto en pacientes orientales como occidentales con lesiones IPMN.

Neoadjuvant therapy and vascular resection during pancreaticoduodenectomy: shifting the survival curve for patients with locally advanced pancreatic cancer.

BACKGROUND: Neoadjuvant therapy and vascular resection may offer patients with locally advanced pancreatic cancer potential cure. METHODS: We reviewed medical records of patients with ductal adenocarcinoma who underwent pancreaticoduodenectomy (PD) from 1992 through 2011. We identified patients who received neoadjuvant therapy (NA+) or required vascular resection (VR+) for locally advanced disease and compared outcomes to those who did not. RESULTS: Of the 643 patients who were initially explored, 506 (143 NA+ and 363 NA- patients) ultimately underwent PD. There were no significant differences in R0 resection or morbidity. Mortality was higher in the NA+ versus NA- group (7.0 vs 3.0 %, p = 0.04). More NA+ patients underwent PD VR+ (p < 0.001). Among VR+ patients, neoadjuvant therapy resulted in significantly lower R1 resection. Among resected patients, survival of NA+ patients was significantly longer than both NA- patients (27.3 vs 19.7 months, p < 0.05) and patients abandoned because of locally advanced disease. Age, tumor grade, lymph node ratio, and R1 resection were independent predictors of poor survival. CONCLUSIONS: Neoadjuvant therapy and vascular resection offer patients with locally advanced pancreatic cancer the chance for cure with acceptable morbidity and mortality. These patients have improved survival over patients deemed locally inoperable by traditional criteria.

Two-stage operative cytoreduction and intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma: Operative morbidity and mortality in phase I and II trials.

AIMS: The standard of care for diffuse malignant peritoneal mesothelioma involves operative cytoreduction and intraperitoneal chemotherapy. Most centers favor aggressive operative cytoreduction, accepting high morbidity and mortality. In our trials, patients underwent less extensive cytoreduction followed by prolonged intraperitoneal chemotherapy. Patients underwent a second cytoreduction with heated intraperitoneal chemotherapy. We hypothesized this would result in lower operative morbidity and mortality with similar survival. METHODS: Hospital records, discharge summaries, microbiology, radiography, and office records were retrospectively reviewed to supplement a prospective database. 30-day morbidity and mortality were categorized, and classified according to the Clavien methodology. RESULTS: 47 first and 39 second operations were performed with 13% and 26% morbidity, respectively. Mortality was 2%. Infections comprised 59% of the morbidity. Inclusive of both operations, formal peritonectomy was performed in 16% of patients, resection of isolated lesions in less than half, and only 19% had a visceral organs other than the spleen resected. At the completion of the protocol, only 3% of patients had visible intraperitoneal disease. The mean total length of stay for both operations combined was 16 ± 23 days. Overall median survival was 54.9 months, and median survival for the epithelioid subtype was 70.2 months. CONCLUSIONS: A two-stage cytoreduction with intraperitoneal chemotherapy offers median survival comparable to one-stage protocols, with relatively low morbidity, mortality, visceral resections and length of stay despite two operations. This series supports that our protocol is a feasible and safe approach.

An aggressive resectional approach to cystic neoplasms of the pancreas.

BACKGROUND: Prognosis is good after curative resection for serous and mucinous cystic neoplasms of the pancreas. There has been a recent trend to resect all cystic neoplasms, without attempts to preoperatively determine the exact histologic subtype. Our purpose is to report on the results of such an aggressive surgical approach to all cystic neoplasms of the pancreas. METHODS: This is a retrospective cohort analysis of 25 patients with cystic neoplasms of the pancreas treated between July 1991 and July 1998. Data include patient demographics, presenting symptom, operative procedure, pathologic diagnosis, periop morbidity and mortality, survival, and symptomatic follow-up data. RESULTS: Twenty-one patients were women, with a mean age of 60 for the entire cohort. Mean follow-up was 24 months (range 6 months to 4.3 years) with complete follow-up possible in 92%. Twenty-three patients had curative resections and 2 had palliative resections. One patient with an uncinate mass had a partial pancreatectomy; 4 patients underwent distal pancreatectomy and 9 had distal pancreatectomy with splenectomy; 11 patients required a pancreatoduodenectomy, and of these, 4 had tumors involving the portal vein, necessitating a portal vein resection. Pathologic analysis revealed 12 serous cystadenomas, 4 mucinous cystadenomas, 3 mucinous cystadenocarcinomas, 5 intraductal papillary cystic neoplasms, and 1 serous cystadenocarcinoma. The overall perioperative complication rate was 40% with 5 major and 5 minor complications. In the 11 pancreatoduodenectomy patients alone, there were 1 major and 4 minor complications. There were no pancreatic fistulas or portal vein thromboses and no operative mortalities. Two patients, both with mucinous cystadenocarcinomas, died of their disease at 6 and 16 months postoperatively. All 11 pancreatoduodenectomy patients have only mild pancreatic insufficiency relieved by daily enzyme replacement. CONCLUSIONS: The good outcomes in this study support an aggressive surgical approach to all patients diagnosed with a cystic neoplasm of the pancreas, if medically fit to tolerate surgery. This approach is justified for the following reasons: (1) preoperative differentiation of a benign versus malignant tumor is unreliable and routine testing for this purpose is of questionable utility; (2) potential adverse consequences of nonresectional therapy are significant; (3) perioperative morbidity and mortality of pancreatic surgery is low; and (4) prognosis with curative resection is good.

Treatment of primary peritoneal mesothelioma by hyperthemic intraperitoneal chemotherapy.

Perfusion of the peritoneal cavity with chemotherapy agents under hyperthermic conditions has been utilized by several investigators in the treatment of intra-abdominal malignancies. Based on the concept that hyperthermia may potentiate the cytotoxic effects of chemotherapeutic agents, we embarked on a clinical trial of two-stage peritoneal chemotherapy for patients with primary peritoneal mesothelioma, a neoplasm unresponsive to traditional systemic chemotherapeutic regimens. In stage I, patients underwent surgical debulking of gross disease and placement of an intraperitoneal infusion catheter, through which intraperitoneal chemotherapy was administered for four months. Stage II consisted of debulking of residual tumor, placement of two transabdominal perfusion cannulae and administration of high-dose intraperitoneal chemotherapy at 40 degrees C using a simple, disposable perfusion circuit. Flow rates were maintained at 1 l/min, and inflow and outflow temperatures maintained at 42 and 40 degrees C, respectively. To date, three patients have undergone both phases of the protocol, with no perioperative complications related to either hyperthermia or end-organ toxicity. One patient died of progressive disease after three months, and two patients are alive and well. One patient developed a small bowel anastomotic leak three weeks after operation. In summary, intraoperative hyperthermic peritoneal chemotherapy may play a role in novel approaches to the treatment of peritoneal malignancies previously unresponsive to traditional chemotherapeutic regimens.

Risk factors for biliary tract cancers.

OBJECTIVE: Little is known regarding risk factors for biliary tract cancer, i.e., gallbladder carcinoma and extrahepatic bile duct carcinoma. This is the first case-control study conducted in the U.S. regarding risk factors for these cancers. METHODS: In this hospital-based case-control study, we reviewed the medical records of 69 patients with primary biliary tract cancer who were admitted to Columbia-Presbyterian Medical Center for surgery between January 1, 1980, and April 4, 1994, and of 138 controls, consisting of patients admitted for surgery for benign conditions. RESULTS: We found a significant association between cholelithiasis and biliary tract cancers (odds ratio, 19.5; 95% confidence interval, 6.4-59.4). Risk factors associated with gallbladder cancer included female gender, age, cigarette smoking, and postmenopausal status in women. Risk factors associated with extrahepatic bile duct cancer included history of cholecystectomy and hysterectomy in women. CONCLUSION: The risk factors for biliary tract cancers that have been identified in our study delineate a high-risk population, which in the future may be targeted for preventive measures.

Transthoracic, transdiaphragmatic excision of simultaneous lung and adrenal lesions.

Simultaneous adrenal and pulmonary lesions frequently present a therapeutic challenge to the thoracic surgeon. We describe 2 cases in which a transthoracic, transdiaphragmatic approach was used to establish tissue diagnosis and complete removal of gross tumor. In 1 case an intraoperative decision to perform a pneumonectomy was dictated by the tissue diagnosis of the adrenal mass, which was obtained with relative ease via this method. In both cases the morbidity of traditional approaches for adrenal operation was avoided.

An overview of adenocarcinoma of the small intestine.

Even though the small intestine contains 90% of the gastrointestinal tract mucosa and is located between the stomach and large intestine, two organs with a high cancer incidence, adenocarcinoma of the small intestine is 1/50th as common as adenocarcinoma of the large bowel. In several other respects, small-intestinal adenocarcinoma resembles large bowel adenocarcinoma; eg, it arises from adenomatous polyps, co-occurs in the same individuals, and has a similar pattern of incidence rates by country. Small-intestinal adenocarcinoma is diagnosed prior to surgery in only about 50% of cases and often occurs in conjunction with small bowel obstruction. The mainstay of treatment is surgery; prognosis depends on stage at presentation. Little is known about the use of radiotherapy and chemotherapy in this malignancy, but most physicians utilize therapeutic strategies modeled on the management of large-intestinal adenocarcinoma. Clarification of the reason for the low incidence of small-intestinal adenocarcinoma could lead to new interventions for the prevention of colorectal cancer.

The mechanism of UVB prevention of graft versus host disease.

We have previously demonstrated that Ultraviolet B (UVB) irradiation of Lewis donor bone marrow (BM) allografts prevents graft versus host disease (GVHD) in ACI recipients while allowing full engraftment. In a one-way GVHD model of parent to Lewis X BN (F1) rats, the site and mechanism of the action of UVB irradiation was assessed by adding nonirradiated isolated cell subsets, isolated by monoclonal antibodies (Mab) to cell surface markers, to the reconstituting UVB-irradiated bone marrow inoculum. GVHD was assessed primarily on clinical grounds by observation of posture, alopecia, skin erythema, and weight loss. The addition of nonirradiated spleen cells or non-UVB-irradiated T-cell subsets (both CD4 and CD8 positive) to the otherwise UVB-irradiated donor inoculum consistently resulted in acute GVHD. In contrast, UVB irradiation of these cells resulted in full engraftment without acute GVHD. Mixed lymphocyte culture (MLC) assays confirmed responsiveness by BM transplanted hosts to third party stimulators while coculture assays failed to show any in vitro suppressor activity in the host. We conclude that UVB acts on both the T-lymphocyte and antigen presenting cell (APC) subsets to prevent acute GVHD. We also propose a model to explain tolerance based on clonal anergy produced by modified antigen presentation by UVB-irradiated APC's or by a modified response to processed antigen.

UVB pretreatment of rat bone marrow allografts. Prevention of GVHD and induction of allochimerism and donor-specific unresponsiveness.

Ultraviolet B irradiation has been used to pretreat blood and islets to prevent subsequent graft rejection. In this study the optimal dose of UVB irradiation of bone marrow was determined in syngeneic recipients and was subsequently applied to in-vitro treatment of bone marrow allografts. UVB pretreatment of donor bone marrow inoculum led to complete prevention of GVHD in allogeneic rat recipients without major marrow or other toxicity. Long-standing recipients of allogeneic UVB-BM became stable adult chimeras. The recipients of allogeneic BM were populated by donor-type peripheral blood lymphocytes and did not reject host or donor-type heart grafts. The BM allograft recipients were immunocompetent as measured by their ability to normally reject third-party cardiac allografts. We suggest that the prevention of GVHD and induction of stable chimerism in adult recipients of allogeneic UVB-BM may be mediated by suppressor mechanisms.

Early colonic dysplasia: comparison of differential mucin staining and tritiated thymidine labeling.

Controversy has arisen regarding the interpretation and significance of histochemical changes in the mucin produced by the globlet cells in colonic mucosa. The shift from sulfomucin to sialomucin, which is readily identified utilizing high iron diamine-alcian blue staining techniques, has been alternately interpreted as a specific, early dysplastic and premalignant change or a nonspecific generalized response to trauma and inflammation, among others. An attempt to clarify this issue was made by comparing mucin changes identified by high iron diamine-alcian blue staining techniques with increases in DNA synthetic activity identified utilizing autoradiographic analysis of tritiated thymidine uptake. Male Holtzman rats were treated with 15 weekly subcutaneous injections of dimethylhydrazine (30 mg/kg per week) (10 rats) or placebo (10 rats). The colons were prepared and fixed, sequential sections were stained with hematoxylin-eosin or high iron diamine-alcian blue, autoradiography was performed. Analyses of labeling index showed no difference in normal background crypts between the control and treatment groups nor in crypts adjacent to those displaying abnormal mucin staining. Crypts with abnormal mucin production (sialomucin dominant) had significantly higher labeling indexes when compared with those of control animals (p less than 0.005). These findings indicate that the shifts in mucin production identified with high iron diamine-alcian blue staining represent crypts with increased and abnormally distributed mitotic activity that is an early dysplastic response to the carcinogenic stimulus.

Differential mucin staining in colorectal neoplasms. Potential clinical application.

Screening techniques that can identify histochemically different mucin production by colonic mucosa have been claimed to be able to identify early dysplastic changes in the colon and rectum. Controversy has arisen regarding interpretation of these changes, and this study has attempted to address this issue. Utilizing a high iron diamine-alcian blue staining technique, several benign and malignant pathologic conditions of the colon were evaluated. Significantly abnormal staining patterns were identified at the resection margins of all patients in whom either anastomotic recurrence or metachronous carcinomas developed compared with patients who were without recurrence for more than 5 years. It is postulated that this technique may be useful in prospectively identifying this group of patients at high risk for the development of recurrence.