Fighting Global Disparities in Cancer Care: A Surgical Oncology View.

Cancer is the second leading cause of death globally after cardiovascular disease. Long-term cancer survival has improved in the Western world due to early detection and the use of effective combined treatment modalities, as well as the development of effective immunotherapy and drug-targeted therapy. Surgery is still the mainstay for most solid tumors; however, low- and middle-income countries are facing an increasing lack of primary surgical care for easily treatable conditions, including breast, colon, and head and neck cancers. In this paper, a surgical oncology view is presented to elaborate how the Western surgical oncologist can take part in the 'surgical fight' against global disparities in cancer care, and a plea is made to strive for structural solutions, such as a partnership in surgical oncology training. The pros and cons of the use of eHealth and mHealth technologies and education programs for schools and the community are discussed as these create an opportunity to reach a large portion of the population in these countries, at low cost and with high impact.

Immunohistochemical analysis of steroid hormone receptors in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory follicular skin disease. In women and men, the condition starts after puberty, has a peak in the third decade, and is rare after the menopause in women. This age distribution suggests a hormonal influence in the pathogenesis of the disease. We therefore hypothesized that apocrine glands in HS patients have a different expression of androgen receptor (AR) and estrogen receptor (ER) compared with healthy skin. METHODS: Axillary, inguinal, and perianal skin biopsies from female and male patients with HS were immunohistochemically stained for AR and ER activities. Expression of both receptors in apocrine glands of HS patients was compared with expression in apocrine glands in normal axillary or inguinal skin of a control group of women. RESULTS: Twenty-two patients with HS were included (16 women), with 10 women in the control group. In the HS group, apocrine glands were present in 11 out of 22 skin biopsies and in the control group in 4 out of 10 biopsies. Expression of ER in the apocrine gland was weak and observed in 2 out of 4 patients in the control group and in none of the HS patients. Expression of the AR was strong and observed in all apocrine glands in both groups. CONCLUSIONS: We could not demonstrate a significant difference in the expression of ER and AR in apocrine glands in skin biopsies of patients with HS, compared with healthy skin biopsies. The exact relation between sex hormones and occurrence of HS therefore remains unclear.

Implementation of the physician assistant in Dutch health care organizations: primary motives and outcomes.

Physician assistants (PAs) are trained to perform medical procedures that were traditionally performed by medical physicians. Physician assistants seem to be deployed not only to increase efficiency but also to ensure the quality of care. What is not known is the primary motive for employing PAs within Dutch health care and whether the employment of the PAs fulfills the perceived need for them. Supervising medical specialists who used PAs in their practices were interviewed about their primary motives and outcomes. The interviews were semistructured. Two scientists coded the findings with respect to motives and outcomes. In total, 55 specialists were interviewed about their motives for employing a PA, and 15 were interviewed about the outcomes of employing a PA. With respect to the primary motives for employing a PA, the most frequent motive was to increase continuity and quality of care, followed by relieving the specialist's workload, increasing efficiency of care, and substituting for medical residents. The outcomes were found to be consistent with the motives. In conclusion, the primary motive for employing a PA in Dutch health care is to increase continuity and quality of care.

Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk.

Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC; rs9257809) and closely to the Forkhead-F1 (FOXF1; rs9936833) coding gene. An interesting issue is whether polymorphisms associated with Barrett's esophagus, are also implicated in esophageal carcinoma (EC), and more specifically EAC genesis. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from surveillance programs. Our hypothesis: Barrett associated MHC and FOXF1 variants modify EC risk in Caucasians. In a Dutch case-control study, 431 patients with EC and 605 healthy controls were included. Polymorphisms at chromosomes 6p21 (MHC) and 16q24 (FOXF1) were determined by means of real-time polymerase chain reaction (RT-PCR). Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals. The FOXF1 rs9936833 variant C allele was associated with an increased EAC susceptibility; OR, [95% CI]; 1.21, [0.99-1.47]. A sex-stratified analysis revealed a similar association in males; 1.24 [1.00-1.55]. The variant MHC rs9257809 G allele as well as the MHC heterozygous AG genotype significantly increased ESCC risk; 1.76 [1.16-2.66] and 1.74 [1.08-2.80], respectively. Sex-stratification showed that the variant G allele was especially present in female patients; 2.32 [1.04-5.20]. In conclusion, this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett's esophagus, also increase ESCC and EAC susceptibility in Caucasians. FOX proteins are transcription factors involved in organogenesis of the GI tract, while MHC haplotypes are strongly associated with smoking behavior, a crucial risk factor for ESCC. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from (Barrett) surveillance programs.

Polymorphisms in alcohol-metabolizing enzymes and esophageal carcinoma susceptibility: a Dutch Caucasian case-control study.

Esophageal cancer (EC), mainly consisting of squamous cell carcinoma (ESCC) in the Eastern world and adenocarcinoma (EAC) in the Western world, is strongly associated with dietary factors such as alcohol use. We aimed to clarify the modifying role in EC etiology in Caucasians of functional genotypes in alcohol-metabolizing enzymes. In all, 351 Caucasian patients with EC and 430 matched controls were included and polymorphisms in CYP2E1, ADH and near ALDH2 genes were determined. In contrast to the results on ESCC in mainly Asian studies, we found that functional genotypes of alcohol-metabolizing enzymes were not significantly associated with EAC or ESCC in an European population.

No role for glutathione S-transferase genotypes in Caucasian esophageal squamous cell or adenocarcinoma etiology: an European case-control study.

BACKGROUND: Identifying and monitoring high-risk patients can aid the prevention of esophageal cancer (EC). The interaction of environmental risk factor exposure and genetic susceptibility may contribute to the etiology of EC. Biotransformation enzymes such as Glutathione S-Transferases (GSTs ) detoxify mutagenic and genotoxic compounds and therefore control the rate of detoxification of carcinogens. Functional polymorphisms in the genes coding for GSTs alter their enzyme activity in vitro, and were reported to modify EC risk in Asians. We hypothesized that altered enzyme activity GST genotypes influence the susceptibility for esophageal adeno- (EAC) and squamous cell carcinoma (ESCC) in Caucasians. METHODS: We performed a case-control study including 440 Caucasian patients with EC and 592 healthy Caucasian controls matched for age and sex. Functional polymorphisms were selected and genotypes were determined in GST classes Alpha, Mu, Theta and Pi by means of polymerase chain reaction. Genotypes were classified into predicted high, intermediate and low enzyme activity categories based on in vitro activity data. The distribution of the activity genotypes were compared between patients with EAC or ESCC, and controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by logistic regression analyses. Gene-gene interactions were tested and for comparison purposes, the predicted low and intermediate activity genotypes were combined. Genotypes with similar risks for EAC or ESCC were combined and analyzed for multiplicative effects. RESULTS: Our analyses includes 327 patients with EAC and 106 patients with ESCC. Low or intermediate activity enzyme genotypes for GSTM1, GSTA1, GSTP1 I105V and A114V as well as for GSTT1, did not significantly modify the risk for ESCC or EAC in our Dutch population. CONCLUSION: Functional genotypes in GST genes are not involved in EAC or ESCC susceptibility in Caucasians, in contrast to results on ESCC from Asia or Africa.

Metalloproteinases and their regulators in colorectal cancer.

Metalloproteinases (MPs) such as the matrix metalloproteinases (MMPs) and adamalysins (ADAMs and ADAMTS) are expressed in various stages of colorectal cancer (CRC), and some correlate with survival and prognosis. The MPs are regulated by various factors including EMMPRIN, TIMPs, and RECK. In addition, micro-RNAs are found to be relevant for both MP expression levels and CRC prognostication. Both MPs and their regulators could be potential targets for intervention and therapy in CRC.

Magnetic resonance imaging in size assessment of invasive breast carcinoma with an extensive intraductal component.

BACKGROUND: Breast-conserving treatment of invasive breast carcinoma with an extensive intraductal component (EIC) is associated with DCIS-involved surgical margins and therefore it has an increased recurrence rate. EIC is a non-palpable lesion of which the size is frequently underestimated on mammography. This study was undertaken to evaluate the accuracy of MRI in size assessment of breast cancer with EIC. METHODS: 23 patients were identified and the mammographic (n = 21) and MR (n = 23) images were re-reviewed by a senior radiologist. Size on MR images was compared with histopathological tumour extent. RESULTS: The correlation of radiological size with histopathological size was r = 0.20 in mammography (p = 0.39) compared to r = 0.65 in MRI (p < 0.01). Mammography underestimated histopathological tumour size in 62%. MR images over- or underestimated tumour size in 22% and 30% of the cases, respectively. In poorly differentiated EIC, MRI adequately estimated the extent more often compared to moderately differentiated EIC (60% versus 25%, respectively). CONCLUSION: Size assessment of MRI imaging was more accurate compared to mammography. This was predominantly true for poorly differentiated EIC.

Metastatic dormancy imposed by the primary tumor: does it exist in humans?

BACKGROUND: In cancer patients, occult micrometastases may become apparent shortly after removal of the primary tumor. Animal experiments have shown that metastatic dormancy is maintained by apoptosis, and that primary tumor removal induces a flare-up of angiogenesis, leading to metastatic outgrowth. This phenomenon has led to the hypothesis that the primary tumor generates certain factors that inhibit angiogenesis at distant sites. It is still unknown whether such a phenomenon is operative in human cancer as well. Should it occur, it might have important therapeutic consequences. MATERIALS AND METHODS: Evidence for such a mechanism may be obtained from studies that analyze a series of tissue samples of metastases, taken before or after surgical removal of the primary lesion. RESULTS: Data from our laboratory on colorectal cancer have shown that, in the absence of the primary tumor, vascular density in the metastases is increased as well as their metabolic activity, as measured by (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Mitotic activity is increased mildly, while levels of apoptosis are collapsed. CONCLUSION: These data indicate that a mechanism of primary-tumor-induced inhibition of angiogenesis exists, maintaining metastatic dormancy. We now suggest that this mechanism may be exploited to avoid the use of exogenous, potentially harmful angiogenesis inhibitors such as bevacizumab in a neoadjuvant setting. Treatment of patients with the primary tumor still in situ could thus be restricted to chemotherapy, since the synergistic effect of an angiogenesis inhibitor would be generated by the primary tumor itself. In the present paper the clinical relevance and possible consequences of our findings and suggestions are discussed.

Surgical treatment of hidradenitis suppurativa with gentamicin sulfate: a prospective randomized study.

BACKGROUND AND METHOD: This article describes and discusses a prospective randomized study with gentamicin sulfate in the surgical treatment of hidradenitis suppurativa. The purpose of the study was to investigate whether enclosure of antibiotics after primary excision and closure reduces the number of postoperative infections. Therefore, the hidradenitis lesions were excised and closed with or without enclosure of a gentamicin-collagen sponge (GC). RESULTS: A total of 200 patients were included in the study. Seventy-six patients underwent surgical excision with primary closure (PC), and 124 PCs over a GC. After 1 week there were significantly fewer complications (infection, dehiscence, etc.) in the GC group, 35% versus 52%; after 3 months the complications in both groups were comparable, 12% versus 19% (Table 2). The mean period of wound healing was 21 days in the first group and 24 days in the second group. The recurrence rate after 3 months was comparable in both groups, 40% versus 42%. CONCLUSION: This study shows that enclosure of gentamicin after primary excision of hidradenitis suppurativa reduces the number of complications 1 week postoperatively. Furthermore, in 65% of the patients treated with gentamicin, the wound was completely healed within 2 months. There is no effect on the long term recurrence rate, as expected.

Local recurrences after different treatment strategies for ductal carcinoma in situ of the breast: a population-based study in the East Netherlands.

PURPOSE: Outcomes after different treatment strategies for ductal carcinoma in situ (DCIS) of the breast were analyzed for a geographically defined population in the East Netherlands. METHODS AND MATERIALS: A total of 798 patients with a first diagnosis of DCIS between January 1989 and December 2003 were included and their medical records were reviewed. Survival rates for ipsilateral recurrences were calculated by the Kaplan-Meier method and a multivariate Cox proportional hazards regression model was used to evaluate the prognostic significance of different variables. RESULTS: The 5-year recurrence-free survival was 75% for breast conserving surgery (BCS) alone (237 patients) compared with 91% for BCS followed by radiation therapy (RT; 153 patients) and 99% for mastectomy (408 patients, p < 0.01). Independent risk factors for local recurrences were treatment strategy, symptomatically detected DCIS, and presence of comedo necrosis. Margin status reached statistical significance only for patients treated by BCS (hazard ratio, 2.0; 95% confidence interval, 1.1-4.0) whereas significance of other prognostic variables did not change. CONCLUSIONS: In a defined population outside a trial setting, RT after BCS for DCIS lowered recurrence rates. Besides the use of RT, a microscopically complete excision of DCIS is essential. This is especially true for patients with symptomatically detected DCIS and with tumors that contain comedo necrosis, as these groups are at particular high risk for recurrent disease.

The efficacy of physiotherapy upon shoulder function following axillary dissection in breast cancer, a randomized controlled study.

BACKGROUND: Many patients suffer from severe shoulder complaints after breast cancer surgery and axillary lymph node dissection. Physiotherapy has been clinically observed to improve treatment of these patients. However, it is not a standard treatment regime. The purpose of this study is to investigate the efficacy of physiotherapy treatment of shoulder function, pain and quality of life in patients who have undergone breast cancer surgery and axillary lymph node dissection. METHODS: Thirty patients following breast cancer surgery and axillary lymph node dissection were included in a randomised controlled study. Assessments were made at baseline and after three and six months. The treatment group received standardised physiotherapy treatment of advice and exercises for the arm and shoulder for three months; the control group received a leaflet containing advice and exercises. If necessary soft tissue massage to the surgical scar was applied. Primary outcome variables were amount of pain in the shoulder/arm recorded on the Visual Analogue Scale, and shoulder mobility (flexion, abduction) measured using a digital inclinometer under standardized conditions. Secondary outcome measures were shoulder disabilities during daily activities, edema, grip strength of both hands and quality of life. The researcher was blinded to treatment allocation. RESULTS: All thirty patients completed the trial. After three and six months the treatment group showed a significant improvement in shoulder mobility and had significantly less pain than the control group. Quality of life improved significantly, however, handgrip strength and arm volume did not alter significantly. CONCLUSION: Physiotherapy reduces pain and improves shoulder function and quality of life following axillary dissection after breast cancer.

Correlation of reversion-inducing cysteine-rich protein with kazal motifs (RECK) and extracellular matrix metalloproteinase inducer (EMMPRIN), with MMP-2, MMP-9, and survival in colorectal cancer.

mRNA, and latent and active levels MMP-2 and -9 were higher in tumor tissue compared to normal tissue from 63 patients with colorectal cancer, whereas RECK and EMMPRIN levels were lower. Correlations between mRNA, latent, and active MMP were particular high for MMP-2 in tumor tissue (R(s)=0.6-0.8, P<0.001). For active MMP-2, but not for MMP-9, a significant negative partial correlation (R(p)=-0.440, P<0.001) for RECK was found in tumor tissue, which was confirmed by linear regression analysis. In exploratory survival analyses we found that in patients with localized disease the RECK level in normal or tumor tissue had a significant (P=0.017) association with overall survival.

The value of magnetic resonance imaging in diagnosis and size assessment of in situ and small invasive breast carcinoma.

BACKGROUND: The value of magnetic resonance imaging (MRI) in diagnosis and size assessment of ductal carcinoma-in-situ (DCIS) and DCIS with small (<10 mm) invasive carcinoma was evaluated. METHODS: Fifty-four patients with DCIS and 12 patients with DCIS and small invasive carcinoma were included. Mammographic (N = 64) and MRI (N = 22) images were retrospectively reviewed. Correlation coefficients were calculated to assess differences in size between imaging and histopathologic examination. RESULTS: Mammographic rate of detection for DCIS was 48/52 (92%) and for DCIS with small invasive carcinoma, 10/12 (83%). MRI revealed 1 false negative case and the rate of detection for DCIS was 16/17 (94%). Correlation of mammographic size with histopathologic size was r = .44 (P < .01) and r = 0.49 (P = .03) for MRI. Mammography underestimated lesion size by 5 mm or more in 47%, whereas with MRI size was adequately assessed in 43% and overestimated in 38%. CONCLUSIONS: DCIS can be visualised on MRI with high sensitivity, although tumor size can be overestimated.

Role of epoxide hydrolase, NAD(P)H:quinone oxidoreductase, cytochrome P450 2E1 or alcohol dehydrogenase genotypes in susceptibility to colorectal cancer.

Colorectal cancer (CRC) is one of the most common forms of cancer in Western countries. CRC has been associated with genetic and lifestyle factors. Individual susceptibility to CRC may be due partly to variations in detoxification capacity in the gastrointestinal tract. Genetic polymorphisms in detoxification enzymes may result in variations in detoxification activities, which subsequently might influence the levels of toxic/carcinogenic compounds, and this may influence the risk for CRC. Therefore, we determined whether polymorphisms in the genes coding for microsomal epoxide hydrolase (EPHX1), NAD(P)H:quinone oxidoreductase (NQO1), cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase (ADH3) predispose to the development of CRC. DNA samples were obtained from 371 patients with sporadic CRC and 415 healthy controls. Patients and controls were all of Caucasian origin. All genetic polymorphisms were determined by polymerase chain reaction, eventually followed by restriction-fragment-length-polymorphism analyses, except for the EPHX1 codon 113 polymorphism, which was genotyped by an allele-specific discrimination assay. Calculation of crude Odds Ratios (ORs) revealed an increased risk for CRC associated with variant NQO1 (OR 1.5, 95% CI 1.1-2.0) and CYP2E1 intron 6 genotypes (OR 2.2, 95% CI 1.3-3.8). However, after adjustment for age and gender, logistic regression analyses only showed a statistically significant risk for CRC associated with variant NQO1 genotypes (OR 1.6, 95% CI 1.03-2.4). No associations were found between CRC and the other polymorphic genes as mentioned above. In conclusion, these data suggest that the presence of variant NQO1 genotypes, with expected reduced enzyme activities might enhance susceptibility to CRC.

MRI-guided preoperative wire localization of nonpalpable breast lesions.

With the increasing use of magnetic resonance imaging (MRI), the physician is more frequently confronted with nonpalpable breast lesions that are only visible on MRI. In these cases, it is often difficult to obtain adequate material for pathological examination. One of the methods that may be performed is excisional biopsy after MRI-guided wire localization. This study intends to examine the feasibility and added benefit of this method. It appears to be a reliable and useful tool that is, therefore, of additional benefit to surgical practice.

Physician assistants in medical ward care: a descriptive study of the situation in the Netherlands.

RATIONALE, AIMS AND OBJECTIVES: Medical ward care has been increasingly reallocated from medical doctors (MDs) to physician assistants (PAs). Insight into their roles and tasks is limited. This study aims to provide insight into different organizational models of medical ward care, focusing on the position, tasks and responsibilities of the involved PAs and MDs. METHODS: In this cross-sectional descriptive study 34 hospital wards were included. Characteristics of the organizational models were collected from the heads of departments. We documented provider continuity by examination of work schedules. MDs and PAs in charge for medical ward care (n = 179) were asked to complete a questionnaire to measure workload, supervision and tasks performed. RESULTS: We distinguished four different organizational models for ward care: medical specialists in charge of admitted patients (100% MS), medical residents in charge (100% MR), PAs in charge (100% PA), both MRs and PAs in charge (mixed PA/MR). The wards with PAs had the highest provider continuity. PAs spend relatively more time on direct patient care; MDs spend relatively more time on indirect patient care. PAs spend more hours on quality projects (P = 0.000), while MDs spend more time on scientific research (P = 0.030). CONCLUSION: Across different organizational models for medical ward care, we found variations in time per task, time per bed and provider continuity. Further research should focus on the impact of these differences on outcomes and efficiency of medical ward care.

High oxygen radical production in patients with sporadic colorectal cancer.

It is hypothesized that excessive generation of reactive oxygen species (ROS) by phagocytes or leakage from mitochondria may harm key genes or proteins responsible for intestinal cell homeostasis. This may initiate the multistage process of colon cancer development. The present study investigates whether ROS production by whole blood may contribute to the etiology of colorectal cancer (CRC). Whole-blood oxygen radical production was measured by luminol-enhanced chemiluminescence and performed in fourfold with and without the stimuli phorbol 12-myristate 13-acetate (PMA) and serum-treated zymosan (STZ). We evaluated patients (i) with a history of sporadic CRC at least 3 months after surgery, (ii) who were hereditary nonpolyposis colorectal cancer (HNPCC) gene carriers, and (iii) with familial adenomatous polyposis (FAP). For each patient group (n = 20) an age- and gender-matched healthy control group was measured. Unstimulated and PMA-stimulated values for maximal oxygen radical production were significantly higher in patients with sporadic CRC in comparison to controls (p = 0.01, p = 0.04, respectively). Furthermore, trends toward higher unstimulated and PMA-stimulated area under the curve chemiluminescence were seen in CRC patients compared with controls (p = 0.08, p = 0.09, respectively). In patients with HNPCC or FAP, unstimulated or PMA- or STZ-stimulated chemiluminescence did not differ compared to their control groups. In conclusion, whole-blood oxygen radical production was higher in patients with a history of sporadic CRC, in comparison with age- and gender-matched controls, which indicates that ROS may play a role in the etiology of sporadic CRC.

Magnetic resonance-guided biopsies and localizations of the breast: initial experiences using an open breast coil and compatible intervention device.

OBJECTIVE: The objective of this study was to evaluate the performance of a new commercially available open breast coil and compatible intervention device (Machnet) for magnetic resonance image (MRI)-guided breast interventions. MATERIALS AND METHODS: Breast lesions detected on MRI were evaluated using MRI-guided core biopsy (n = 20) and/or preoperative wire localization (n = 23) on histologic outcome and accuracy of localization. Time needed to perform a procedure and occurring problems were recorded. RESULTS: Mean lesion size was <10 mm. Two of 20 lesions could not be biopsied because they were out of range for the device. Biopsies were conclusive in half of the cases; most lesions missed were <10 mm. The average accuracy for needle placement in the localization procedures was less than 2 mm (range, 0-5 mm). The average procedure time was 40 minutes for a biopsy procedure and 33 minutes for an MRI-guided localization. CONCLUSIONS: Preoperative MRI-guided localizations can be performed quickly and accurately. However, in MRI-guided core biopsies, especially in small lesions, the device does not guarantee conclusive histologic evaluation of the lesion targeted.

Decrease in circulating anti-angiogenic factors (angiostatin and endostatin) after surgical removal of primary colorectal carcinoma coincides with increased metabolic activity of liver metastases.

Removal of a primary colorectal tumor resulted in an increase in metabolic activity in its liver metastasis. Concomitantly, levels of angiostatin and endostatin in urine and plasma, respectively, dropped. This finding indicates that the primary tumor suppressed angiogenesis in its distant metastasis, and that removal of the primary lesion caused a flare-up in vessel neoformation and, thus, enhanced metabolic activity in its liver metastasis.