The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer

Excess body weight, as defined by the body mass index (BMI), has been associated with several diseases and includes subjects who are overweight (BMI≥25–29.9 kg/m2) or obese (BMI≥30 kg/m2). Overweight and obesity constitute the fifth leading risk for overall mortality, accounting for at least 2.8 million adult deaths each year. In addition around 11% of colorectal cancer (CRC) cases have been attributed to overweight and obesity in Europe. Epidemiological data suggest that obesity is associated with a 30–70% increased risk of colon cancer in men, whereas the association is less consistent in women. Similar trends exist for colorectal adenoma, although the risk appears lower. Visceral fat, or abdominal obesity, seems to be of greater concern than subcutaneous fat obesity, and any 1 kg/m2 increase in BMI confers additional risk (HR 1.03). Obesity might be associated with worse cancer outcomes, such as recurrence of the primary cancer or mortality. Several factors, including reduced sensitivity to antiangiogenic-therapeutic regimens, might explain these differences. Except for wound infection, obesity has no significant impact on surgical procedures. The underlying mechanisms linking obesity to CRC are still a matter of debate, but metabolic syndrome, insulin resistance and modifications in levels of adipocytokines seem to be of great importance. Other biological factors such as the gut microbita or bile acids are emerging. Many questions still remain unanswered: should preventive strategies specifically target obese patients? Is the risk of cancer great enough to propose prophylactic bariatric surgery in certain patients with obesity?

https://gut.bmj.com/content/gutjnl/62/6/933.full.pdf

Obesity and colorectal cancer

BACKGROUND & AIMS
A cascade of precursor lesions (eg, atrophic gastritis, intestinal metaplasia, and dysplasia) precedes most gastric adenocarcinomas. Quantification of gastric cancer risk in patients with premalignant gastric lesions is unclear, however. Consequently, endoscopic surveillance is controversial, especially in Western populations.


METHODS
To analyze current surveillance practice and gastric cancer risk in patients with premalignant gastric lesions, all patients with a first diagnosis between 1991 and 2004 were identified in the Dutch nationwide histopathology registry (PALGA); follow-up data were evaluated until December 2005.


RESULTS
In total, 22,365 (24%) patients were diagnosed with atrophic gastritis, 61,707 (67%) with intestinal metaplasia, 7616 (8%) with mild-to-moderate dysplasia, and 562 (0.6%) with severe dysplasia. Patients with a diagnosis of atrophic gastritis, intestinal metaplasia, or mild-to-moderate dysplasia received re-evaluation in 26%, 28%, and 38% of cases, respectively, compared with 61% after a diagnosis of severe dysplasia (P < .001). The annual incidence of gastric cancer was 0.1% for patients with atrophic gastritis, 0.25% for intestinal metaplasia, 0.6% for mild-to-moderate dysplasia, and 6% for severe dysplasia within 5 years after diagnosis. Risk factors for gastric cancer development were increasing severity of premalignant gastric lesions at initial diagnosis (eg, severe dysplasia, hazard ratio 40.14, 95% confidence interval 32.2-50.1), increased age (eg, 75-84 years, hazard ratio 3.75, 95% confidence interval 2.8-5.1), and male gender (hazard ratio 1.50, 95% CI 1.3-1.7).


CONCLUSIONS
Patients with premalignant gastric lesions are at considerable risk of gastric cancer. As current surveillance of these patients is inconsistent with their cancer risk, development of guidelines is indicated.

Gastric cancer risk in patients with premalignant gastric lesions

This review summarizes studies on the epidemiology and public health implications of Helicobacter pylori published in peer-reviewed journals from April 2010 through March 2011. Prevalence rates vary widely between different geographical regions and ethnic groups. An interesting study from the USA identified the degree of African ancestry as an independent predictor of H. pylori infection. Two studies have demonstrated early childhood as the period of transmission of infection and identified an infected sibling as an important risk factor. An oral–oral route of spread has been substantiated with several studies showing the presence of H. pylori in the oral cavity. Studies have shown the presence of H. pylori in drinking water and the role of poor living conditions and sanitation in H. pylori infection, supporting an oral–fecal route of spread. Screening for H. pylori as a gastric cancer pre-screening strategy has been described in Japan, and the importance of H. pylori eradication as a gastric cancer–prevention strategy has now been further emphasized in Japanese guidelines. Two studies have shown a decrease in the burden of dyspepsia and peptic ulcer disease with H. pylori eradication.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1523-5378.2011.00874.x

Epidemiology of Helicobacter Pylori Infection and Public Health Implications

Blood metabolites can be detected as low-mass ions (LMIs) by mass spectrometry (MS). These LMIs may reflect the pathological changes in metabolism that occur as part of a disease state, such as cancer. We constructed a LMI discriminant equation (LOME) to investigate whether systematic LMI profiling might be applied to cancer screening. LMI information including m/z and mass peak intensity was obtained by five independent MALDI-MS analyses, using 1,127 sera collected from healthy individuals and cancer patients with colorectal cancer (CRC), breast cancer (BRC), gastric cancer (GC) and other types of cancer. Using a two-stage principal component analysis to determine weighting factors for individual LMIs and a two-stage LMI selection procedure, we selected a total of 104 and 23 major LMIs by the LOME algorithms for separating CRC from control and rest of cancer samples, respectively. CRC LOME demonstrated excellent discriminating power in a validation set (sensitivity/specificity: 93.21%/96.47%). Furthermore, in a fecal occult blood test (FOBT) of available validation samples, the discriminating power of CRC LOME was much stronger (sensitivity/specificity: 94.79%/97.96%) than that of the FOBT (sensitivity/specificity: 50.00%/100.0%), which is the standard CRC screening tool. The robust discriminating power of the LOME scheme was reconfirmed in screens for BRC (sensitivity/specificity: 92.45%/96.57%) and GC (sensitivity/specificity: 93.18%/98.85%). Our study demonstrates that LOMEs might be powerful noninvasive diagnostic tools with high sensitivity/specificity in cancer screening. The use of LOMEs could potentially enable screening for multiple diseases (including different types of cancer) from a single sampling of LMI information.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.28517

Low‐mass‐ion discriminant equation: A new concept for colorectal cancer screening

AIMS AND BACKGROUND The pretreatment serum carcinoembryonic antigen (CEA) level is an independent prognostic factor in colorectal cancer. We aimed to investigate the significance of CEA as a prognostic or predictive factor in rectal cancer patients receiving preoperative chemoradiotherapy (CRT). METHODS AND STUDY DESIGN In total, 609 patients with locally advanced (cStage II-III) mid to distal rectal cancer who underwent preoperative CRT and radical surgery between 2001 and 2008 were analyzed retrospectively. Predictive factors for pathologic CRT response were determined using multivariate logistic regression. A prognostic factor analysis was performed using the log-rank test and Cox proportional hazards regression. RESULTS Elevated CEA levels (>5 ng/mL) were observed in 201 (33.0%) patients at diagnosis. Following preoperative CRT, downstaging (ypStage 0-I) occurred in 255 (41.9%) patients, of whom 88 had pathologic complete tumor regression. Pretreatment CEA was significantly associated with pathologic CRT response in terms of downstaging and tumor regression grade, and was the most relevant predictive factor. After a median follow-up period of 60 months, the 5-year disease-free and overall survival rates were 76.2% and 84.6%, respectively. Prognostic factors independently associated with recurrence or survival included ypStage, circumferential resection margin, and histologic grade. CONCLUSIONS In patients with rectal cancer who received preoperative CRT, the pretreatment CEA level was a significant and independent predictor of pathologic CRT response. However, it may not be able to predict long-term outcomes independently of ypStage.

/pdf/reappraisal-of-pretreatment-carcinoembryonic-antigen-in-1amtac8g1u.pdf

Reappraisal of pretreatment carcinoembryonic antigen in patients with rectal cancer receiving preoperative chemoradiotherapy.

Three-drug combination of fluoropyrimidine, irinotecan and oxaliplatin has shown survival benefits in patients with metastatic colorectal cancer (mCRC). Recently we performed a phase II study of a new 3-drug regimen, TIROX (S-1 plus irinotecan and oxaliplatin) to evaluate efficacy and safety in refractory mCRC patients. Patients with refractory to all of 3 drugs, age ≥18 years, PS 0–2, ≥1 measurable lesion(s) and adequate organ functions were eligible. S-1 was given 40 mg/m2 twice a day on D1–14, oxaliplatin 85 mg/m2 and irinotecan 150 mg/m2 on D1 every 3 weeks. The primary endpoint was overall response rate (ORR). Between Mar 2007 and Nov 2007, 19 patients (of 18 planned) were enrolled; median age 50 years; M/F 12/7; PS 0/1/2 5/13/1; colon/rectum 11/8. By intent-to-treat analysis, ORR was 21.1% (95% CI, 8.7–43.7) and disease control rate was 52.6% (95% CI 31.5–72.8) with four PRs and six SDs. Median duration of disease control was 4.3 months (95% CI 1.7–6.9). Median PFS was 2.6 months (95% CI 2.2–2.9) and median OS was 9.8 months (95% CI 5.3–14.4) after median F/U of 15.4 months. G3/4 toxicities per pt included neutropenia (five, 26.3%), febrile neutropenia (two, 10.5%), thrombocytopenia (one, 5.3%), diarrhea (two, 10.5%) and fatigue (two, 10.5%). TIROX seemed to be feasible and efficacious for refractory mCRC patients, and could be an alternative for patients with good PS but no further treatment options.

A phase II study of S-1 plus irinotecan and oxaliplatin in heavily-treated patients with metastatic colorectal cancer.

AIM Current fecal screening tools for colorectal cancer (CRC), such as fecal occult blood tests (FOBT), are limited by their low sensitivity. Calgranulin B (CALB) was previously reported as a candidate fecal marker for CRC. This study investigated whether a combination of the FOBT and fecal CALB has increased sensitivity and specificity for a diagnosis of CRC. MATERIALS AND METHODS Patients with CRC (n = 175), and healthy individuals (controls; n = 151) were enrolled into the development (81 cases and 51 controls) and validation (94 cases and 100 controls) sets. Stool samples were collected before bowel preparation. CALB levels were determined by western blotting. FOBT and fecal CALB results were used to develop a predictive model based on logistic regression analysis. The benefit of adding CALB to a model with only FOBT was evaluated as an increased area under the receiver operating curve (AUC), partial AUC, and reclassification improvement (RI) in cases and controls, and net reclassification improvement (NRI). RESULTS Mean CALB level was significantly higher in CRC patients than in controls (P<0.001). CALB was not associated with tumor stage or cancer site, but positivity on the FOBT was significantly higher in advanced than in earlier tumor stages. At a specificity of 90%, the cross-validated AUC and sensitivity were 89.81% and 82.72%, respectively, in the development set, and 92.74% and 79.79%, respectively, in the validation set. The incremental benefit of adding CALB to the model, as shown by the increase in AUC, had a p-value of 0.0499. RI in cases and controls and NRI all revealed that adding CALB significantly improved the prediction model. CONCLUSION A predictive model using a combination of FOBT and CALB may have greater sensitivity and specificity and AUC for predicting CRC than models using a single marker.

/pdf/a-predictive-model-combining-fecal-calgranulin-b-and-fecal-7r58vgkifk.pdf

A predictive model combining fecal calgranulin B and fecal occult blood tests can improve the diagnosis of colorectal cancer.

Introduction: India ink tattooing is widely used for tumor localization; however, the tattooing procedure is not yet standardized. This study aims to evaluate the efficacy of small-dose tattooing with sterile India ink using a saline test-injection method. Patients and Methods: Between April 2009 and August 2009, 20 patients underwent colonoscopic tattooing with prepackaged sterile India ink before resection of colorectal tumor. We injected 0.5 cc of India ink at three circumferential sites at the distal tumor using a saline test-injection method. Observation and leakage of India ink were evaluated during laparoscopic surgery, and the diameter of tattooing in the specimen was assessed. Results: Tattoos were observed intraoperatively in 18 patients (90%). In 2 patients, tattoos were not observed on the serosal surface but were detected on the mucosal surface. Localized leakage of ink was identified during surgery in 1 patient (5%), without fever or abdominal pain. Mean tattoo diameter was 2.1 cm o...

Byung Chang Kim

Papers

Low‐mass‐ion discriminant equation: A new concept for colorectal cancer screening

Reappraisal of pretreatment carcinoembryonic antigen in patients with rectal cancer receiving preoperative chemoradiotherapy.

A phase II study of S-1 plus irinotecan and oxaliplatin in heavily-treated patients with metastatic colorectal cancer.

A predictive model combining fecal calgranulin B and fecal occult blood tests can improve the diagnosis of colorectal cancer.

Small-dose India ink tattooing for preoperative localization of colorectal tumor.