Three-Dimensional Conformal Radiotherapy for Rectal Cancer and the Changes in Cancer Multi-biomarkers

OBJECTIVE To investigate the clinical efficacy of three-dimensional conformal radiotherapy(3D-CRT)for local y advanced or postoperatively relapsed rectal cancer,and to examine the changes in cancer multi-biomarkers. METHODS Sixty patients with locally advanced or postoperatively relapsed rectal cancer were randomly divided into two groups after 40 Gy external radiation,namely a late-course 3D-CRT group and a conventional radiotherapy group that served as the control.There were 30 patients in each group.For patients in the 3D-CRT group,multi-biomarkers were measured before and after radiotherapy and after relapse. RESULTS Response rates in the 3D-CRT and the control groups were 86.7%(26/30)and 70%(21/30)respectively,without a significant difference (P>0.05).The 1-,2-and 3-year survival rates were 80%,53.3%and 36.7% in the 3D-CRT group;in the control group the rates were 56.7%,40%and 13.3%respectively,with a significant difference(P=0.0213).CEA,CA19-9, CA242 and FER decreased after radiotherapy in the 3D-CRT group,P<0.01, indicating a significant difference.The values after relapse were higher than those without relapse,P<0.01,indicating a significant difference. CONCLUSION Conventional radiotherapy with a 3D-CRT boost gives better therapeutic effect to patients with locally advanced or postoperatively local y relapsed rectal cancer.A multi-biomarker protein chip diagnosis system can be utilized as an effective tool to determine the therapeutic effect and prognosis.     

Muir-Torre Syndrome: expanding the genotype and phenotype—a further family with a MSH6 mutation

Muir-Torre Syndrome (MTS) is a phenotypic variant of HNPCC traditionally associated with mutations in the mismatch repair genes MLH1 and MSH2. We draw attention to recent reports of MTS found in association with a constitutional MSH6 mutation and describe a further MTS family with a MSH6 mutation, in whom a preponderance of extra-colonic tumours was found.     

Is the Management of Rectal Cancer Using a Watch and Wait Approach Feasible,Safe and Effective in a Publicly Funded General Hospital?

AimsAlthough there is emerging evidence to suggest equivalent oncological outcomes using a watch and wait approach compared with primary total mesorectal excision surgery, there is a paucity of evidence about the safety and efficacy of this approach in routine clinical practice. Here we report the long-term outcomes and quality of life from patients managed with watch and wait following a clinical complete response (cCR) to neoadjuvant therapy.Materials and methodsPatients with adenocarcinoma of the rectum with cCR following neoadjuvant therapy managed using watch and wait were retrospectively identified. Demographic data, performance status, pretreatment staging information, oncological and surgical outcomes were obtained from routinely collected clinical data. Quality of life was measured by trained clinicians during telephone interviews.ResultsOver a 7-year period, 506 patients were treated for rectal cancer, 276 had neoadjuvant therapy and 72 had a cCR (26.1%). Sixty-three were managed with watch and wait. Thirteen patients had mucosal regrowth. There was no significant difference in the incidence of metastatic disease between the surgical and watch and wait cohorts (P = 0.38). The 13 patients with mucosal regrowth underwent salvage surgery. Eleven of the patients who underwent surgical resection had R0 resections. There was also a statistically and clinically significant improvement in the Functional Assessment of Cancer Therapy – Colorectal (FACT-C) trial outcome index (P = 0.022).ConclusionThis study shows that watch and wait is safe and effective outside of tertiary referral centres. It suggests that an opportunistic cCR is durable and when mucosal regrowth occurs it can be salvaged. Finally, we have shown that quality of life is probably improved if a watch and wait approach is adopted.     

Can We Reliably Predict a Clinical Complete Response in Rectal Cancer? Current Trends and Future Strategies

Purpose of Review

Prediction of clinical complete response is pivotal in the management of patients with rectal cancer. The ability to determine tumor response to neoadjuvant therapy in rectal cancer might guide subsequent treatment modalities. We review the current literature on predictors of complete response after neoadjuvant for rectal cancer with an emphasis of clinical complete response rather than pathological complete response.

Recent Findings

Clinical and radiological findings have been used to predict response, as well as a myriad of biomarkers. There is limited evidence validating most of these strategies. The role of imaging in defining tumor response has been assessed retrospectively. The TRIGGER trial is a randomized trial that will evaluate stratified management of rectal cancer based on their tumor regression grade.

Summary

The management of locally advanced rectal cancer is evolving. The ability to predict clinical complete response in patients that have undergone neoadjuvant chemoradiation will allow us to select potential patients that can benefit from a “watch and wait” strategy. Identifying patients that will have a complete response will result in decreased surgical overtreatment, favoring organ-sparing strategies. Treatment individualization will require further research. Emphasis should be made in validating prediction markers; these should be cost-effective and of minimally invasive retrieval. Surveillance protocols to assess for tumor regrowth are yet to be determined.

     

Optimal Interval to Surgery After Neoadjuvant Chemoradiotherapy in Rectal Cancer: A Systematic Review and Meta-analysis

This study aimed to evaluate the influence of a waiting interval of ≥ 8 weeks between the end of preoperative neoadjuvant chemoradiotherapy (nCRT) and surgery on the outcomes of patients with locally advanced rectal cancer. We conducted a comprehensive literature review of retrospective and prospective studies from PubMed, Embase, and Cochrane Library databases to investigate the length of the preoperative nCRT–surgery waiting interval and outcomes in patients with locally advanced rectal cancer. The primary outcome measure was pathologic complete response (pCR) rate. Secondary outcome measures included overall survival, disease-free survival, operative time, and the incidence of local recurrence, postoperative complications, anastomotic leakage, and sphincter-preserving surgery. Standardized mean differences and risk ratios were calculated. Thirteen studies involving 19,652 patients were included. The meta-analysis demonstrated that pCR was significantly increased in patients with locally advanced rectal cancer and a waiting interval of ≥ 8 weeks between preoperative nCRT and surgery compared to a waiting interval of < 8 weeks, or a waiting interval of > 8 weeks compared to ≤ 8 weeks (risk ratio = 1.25; 95% confidence interval, 1.16-1.35; P < .0001). There were no significant differences in overall survival, disease-free survival, operative time, or incidence of local recurrence, postoperative complications, or sphincter-preserving surgery. This study revealed that performing surgery after a waiting interval of ≥ 8 weeks after the end of preoperative nCRT is safe and efficacious for patients with locally advanced rectal cancer, significantly improving pCR without increasing operative time or incidence of postoperative complications, compared to a waiting interval of ≤ 8 weeks.     

Investigation of β-catenin and E-cadherin Expression in Dukes B2 Stage Colorectal Cancer with Tissue Microarray Method. Is It a Marker of Metastatic Potential in Rectal Cancer?

β-catenin and E cadherin are both membrane-associated proteins which are essential regulators and providers of cellular adhesion. In the metastatic cascade of malignant tumours, detachment of tumour cells from each other is a very important step. It has been shown in several tumour types, that reduced expression of these proteins is important. The aim of our study was to clarify the expression profile of these proteins, and correlate the findings with the metastasizing potential of early stage colon and rectal cancers. Formalin fixed and paraffin embedded samples from 79 Dukes B2 stage colorectal cancer were examined using a tissue microarray approach. The expression of β-catenin and E-cadherin proteins was determined immunohistochemically. Our findings indicated that there is a tendency for metastatic spread in cases when membranous expression of β-catenin is lost (p = 0.062). Similarly metastases in negative cases developed more rapidly, than in positive ones (p = 0.05). Survival rate was worse in the negative cases. The risk of metastasis in rectal cancer was significantly higher in the β-catenin membranously negative than positive groups (p = 0.024) and in case of β-catenin nuclear expression the risk was also higher (p = 0.047). Reduced E-cadherin expression also correlated with development of metastatic disease, but this association was statistically not significant. The immunohistochemical analysis of 79 cases shows that in Dukes B2 stage colorectal tumours clarification of β-catenin and E-cadherin expression patterns is reliable for predicting the metastatic potential of early stage rectal cancer and hence the method may have relevant implications in the therapeutic management of these cancers.     

PPARγ and Colon and Rectal Cancer: Associations with Specific Tumor Mutations, Aspirin, Ibuprofen and Insulin-Related Genes (United States)

We hypothesize that the peroxisome proliferator-activated receptor-γ (PPARγ) is associated with colorectal cancer given its association with insulin, diabetes, obesity, and inflammation. In this study, we evaluated the association between colorectal cancer and specific tumor mutations and the Pro12Ala (P12A) PPARγ polymorphism. We also evaluated interactions between the PPARγ gene and other insulin-related genes and use of aspirin and non-steroidal anti-inflammatory drug use. Data were available from 1,577 cases of colon cancer that were matched to 1,971 population-based controls and 794 cases of rectal cancer that were matched to 1,001 population-based controls. Colon tumors from the case subjects were evaluated for p53 and Ki-ras mutations and microsatellite instability (MSI). Insulin-related genes evaluated were the Bsm1, polyA, and Fok1 polymorphisms of the VDR gene; the G972R IRS1 polymorphism; the G1057D IRS2 polymorphism; the 19CA repeat polymorphism of the IGF1 gene; and the –200A>C IGFBP3 polymorphism. The odds ratio (OR) between the PA/AA genotypes and proximal tumors was 0.83 (95% CI: 0.69–1.01); for distal tumors was 1.00 (95% CI: 0.83–1.21); and for rectal tumors was 1.04 (95% CI: 0.86–1.25). Evaluation of specific types of tumor mutations showed that colon cancer cases with the PA or AA genotypes were less likely to have p53 tumor mutations (OR 0.78; 95% CI: 0.62–0.99), specifically transition mutations (OR 0.74; 95% CI: 0.56–0.97). Colon cancer cases also were less likely to have a tumor with MSI if they had the PA or AA PPARγ genotype (OR 0.68; 95% CI: 0.47–0.98); differences in Ki-ras mutations were not seen in colon tumors by PPARγ genotype. Those who did not take ibuprofen-type drugs and had the PA or AA genotypes were at a significantly greater risk of rectal cancer (OR 2.11; 95% CI: 1.52–2.92; p interaction 0.03) than people with the PP genotype regardless of ibuprofen-type drug use. There was a significant interaction between the −200A>C IGFBP3 polymorphism and the Pro12Ala PPARγ polymorphism and risk of colon cancer (p for interaction = 0.02) with individuals being at significantly lower risk if they had both the CC IGFBP3 genotype and the PA/AA PPARγ genotype. For rectal cancer there was a significant interaction between the Bsm1/polyA polymorphisms (p = 0.001) of the VDR gene and the PA/AA Pro12Ala PPARγ polymorphism with the highest risk group being those with both the PA/AA Pro12Ala PPARγ and the BB/SS VDR genotypes. These data suggest that PPARγ may be associated with many aspects of colorectal cancer including insulin- and inflammation-related mechanisms.     

The Role of Contact X-Ray Brachytherapy in Early Rectal Cancer – Who,when and How?

The National Institute for Health and Care Excellence (NICE) has recommended the use of contact X-ray brachytherapy (CXB) for rectal cancer patients who are not suitable for surgery. At present, patients with early rectal cancer who wish to avoid major surgery and a stoma are not usually offered CXB as an alternative treatment option to surgery. The main reason for this has been a lack of large, randomised trial evidence, hence NICE encouraged provision of this evidence in their recommendation. In 2015, the OPERA (Organ Preservation in Early rectal Adenocarcinoma) trial was set up and the 3-year organ-preservation results were presented at the American Society of Clinical Oncology (ASCO) meeting in Chicago on 4 June 2022. We are now awaiting full publication of the OPERA results. Most rectal cancer patients who are not suitable for surgery are currently offered external beam radiotherapy (EBRT) with or without chemotherapy after the multidisciplinary discussions. Clinical complete response (cCR) rates vary between 20 and 50% after EBRT. Those who achieve cCR usually adopt a ‘watch and wait’ policy, but patients who have residual disease are often not offered any additional treatment. We hypothesised that dose escalation with a CXB boost could achieve a higher cCR and therefore lead to improved organ-preservation rates. This was the rationale behind the OPERA trial, which randomised patients between standard of care [EBRT with chemotherapy (EBCRT)] followed by an EBRT boost against EBCRT with a CXB boost to evaluate the role of CXB in dose escalation. In 1993, the first CXB centre was established in the UK at Clatterbridge Cancer Centre. There are now four centres offering CXB in the UK and 10 centres in Europe. Patients should be provided with full information during the consent discussion and offered all the treatment options that are available, so that they can share in decision making and be empowered to make treatment decisions of their choice after proper fully informed consent. Randomised trial evidence of the role of dose escalation with CXB from the OPERA trial, when published, will help in consenting patients who are keen to avoid surgery. We hope this review will help to provide some information about who should be offered CXB, when this modality should be offered and how this is delivered.     

A Germline Mutation in the BRCA1 3’UTR Variant Predicts Susceptibility to Breast Cancer in a Saudi Arabian Population

Purpose: The impact of the BRCA1-3’UTR-variant on BRCA1 gene expression and altered responses to externalstimuli was previously tested in vitro using a luciferase reporter assay. Its ability to predict breast cancer risk in womenwas also assessed but the conclusions were inconsistent. The present study concerns the relationship between theBRCA1-3’UTR germline variant rs8176318G>T and susceptibility to Breast cancer in an ethnic population of SaudiArabia. Methodology: The study included 100 breast cancer patients and 100 sex matched healthy controls fromthe northwestern region (Tabuk) and Dammam of Saudi Arabia were investigated for the BRCA1-3’UTR germlinevariant rs8176318G>T using an allele specific PCR technique. Genotype distributions were then compared. Results:The frequencies of the three genotypes GG, TT and GT in our Saudi Arabian patients were 26%, 8% and 66% andin healthy controls were 45%, 5% and 50%, respectively (p=0.03). Risk of developing breast cancer was found to besignificantly associated with the GT variant (OR 2.28, 1.24-4.191; RR 1.47, 1.11-1.93; P=0.007), GT+TT (OR, 2.32,1.28-4.22; RR 1.48, 1.13-1.94; P=0.005) and the T allele (OR 1.62 , 1.072- 2.45; RR 1.28, 1.02-1.60: P=0.020). Therewere 2.76 and 2.28 fold increase risks of developing breast cancer associated with the TT and GT genotypes in ourcases. A significant correlation was also found between the BRCA1 3’UTR variants with the stage of the disease anddistant metastasis but not with age, grade, and ER, PR and her2/neu status. Conclusion : The rs8176318G/T in the3’untranslated region (UTR) of the BRCA1 gene was found to be associatedwith increased susceptibility to breastcancer in our study population, increased risk being noted with the GT and TT genotypes. Further association studiesare needed to confirm this finding in other regions of Saudi Arabia.     

ERCC1, MLH1, MSH2, MSH6, and βIII-Tubulin: Resistance Proteins Associated With Response and Outcome to Platinum-based Chemotherapy in Malignant Pleural Mesothelioma

IntroductionPlatinum-based chemotherapy is besides the standard antifolate therapy with pemetrexed, the cornerstone for treatment of patients with malignant pleural mesothelioma (MPM), and its efficacy depends on several DNA repair enzymes. Therefore, these enzymes could be biomarkers for “tailoring” chemotherapy. This study evaluated enzymes involved in repair of platinum-caused DNA damage, potentially resulting in a biomarker panel associated with patient response and outcome to platinum-based chemotherapy.Material and MethodsPre- or posttreatment specimens from a total of 103 patients with MPM who were undergoing first-line chemotherapy were tested separately. Immunohistochemistry for ERCC1 (endonuclease excision repair cross-complementing 1), MLH1 (MutL homologue 1), MutS homologue (MSH) 2, MSH6, and βIII-tubulin protein expression, and pyrosequencing for ERCC1 codon 118 and C8092A polymorphisms were performed, and their results were correlated to clinicopathologic data.ResultsERCC1, MLH1, MSH2, MSH6, and βIII-tubulin were expressed in human MPM specimens at different intensities. When considering only pretreatment specimens, MSH6 protein levels were correlated to progression during chemotherapy (P = .0281). MLH1 protein levels (P = .0205), and ERCC1 codon 118 polymorphisms (P ≤ .0001) were significantly associated with progression-free survival. A significant association between ERCC1 protein levels and overall survival was noted (P = .032). Analyses of posttreatment specimens revealed significant associations between βIII-tubulin protein levels and progression-free survival (P = .0066). ERCC1 C8092A polymorphisms were significantly associated with progression-free survival and overall survival (P = .0463 and P = .0080, respectively) in this group.ConclusionsEnzymes involved in DNA repair mechanisms are associated with patient response and outcome to platinum-based chemotherapy. Their assessment may be a helpful tool to tailor platinum-based chemotherapy of MPM patients who might expect the largest clinical benefit. Prospective validation of this biomarker panel is warranted.     

A ‘Nonsense’ Mutation Leads to Aberrant Splicing of hMLH1 in a German Hereditary Non-polyposis Colorectal Cancer Family

Hereditary Non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by germline mutations in at least four genes encoding integral components of the cellular DNA mismatch repair (MMR) system. The spectrum of genetic alterations encompasses missense- and nonsense mutations, intronic mutations affecting splice donor or acceptor sites as well as small-scale deletions and insertions. We have identified a ‘nonsense’ mutation that activates a cryptic splice site generating an in frame deletion of the last 17 codons of exon1 of the hMLH1 gene causing HNPCC in a German family. We present a comprehensive genetic analysis of this family that demonstrates important aspects of HNPCC pathogenesis.     

Juvenile Xanthogranuloma Presenting as a Solitary Tracheal Mass in a Child： A Case Report and Literature Review

Juvenile xanthogranuloma （JXG） is an uncommon benign disease, which usually occurs on the skin of head and neck region, as a single or multiple nodular lesions. Tracheal involvement of JXG is extremely rare, and only few cases have been reported in literature. Herein we presented an additional new case and discussed the optimal management of this uncommon disease.     

A Near-Complete Response to Treatment with Gemcitabine plus nab?-Paclitaxel in a Patient with Metastatic Pancreatic Cancer and Poor Performance Status: A Case Report

Patients with metastatic pancreatic adenocarcinoma and poor performance status (PS) are typically excluded from clinical trials of new systemic treatments. Due to concerns that such patients cannot tolerate the greater toxicity sometimes associated with combination chemotherapy regimens, the recommended treatment for pancreatic cancer patients with poor PS is gemcitabine monotherapy. We report the case of a 79-year-old female with pancreatic adenocarcinoma metastatic to the lungs, with multiple comorbidities and an Eastern Cooperative Oncology Group PS of 3, who achieved a rapid and prolonged objective response to gemcitabine plus nab^®-paclitaxel. The patient received a total of 11 cycles of treatment. Although her disease was well controlled with gemcitabine plus nab-paclitaxel, she died just over 11 months after diagnosis as a result of her comorbid conditions compounded by treatment-related hematologic toxicity. This case suggests that patients with metastatic pancreatic adenocarcinoma and poor PS may benefit from first-line combination therapy with gemcitabine plus nab-paclitaxel. Further study of this regimen in such patients is warranted.Key words: Gemcitabine, Metastatic, nab^®-Paclitaxel, Pancreatic cancer, Poor performance status     

Quality of Life and Influencing Factors in Patients with a Gynaecologic Cancer Diagnosis at Gazi University,Turkey

Negative impacts of gynecologic cancers on women’s health are multi-dimensional. The aim of this study wasto determine the quality of life (QOL) of affected patients in comparison with a control group diagnosed withgynecological problems other than cancer, and to investigate demographic and socio-cultural factors potentiallyaffecting QOL. The study, performed between June-December 2008, covered 120 inpatients diagnosed withgynecological cancer at the Gynecologic Oncology Department of Gazi University Medical School and 123educational level and age matched outpatients without cancer, of the Department of Obstetrics and GynecologyOutpatient Unit. Data were collected through a face to face questionnaire form including basic socio-culturaland demographic characteristics and a quality of life scale (Short Form-36, SF-36). Data entry and analysiswere performed with the SPSS v11.5 package program and comparisons were conducted according to sociodemographicand disease-related characteristics of participants. Averages of total scores and all componentsof the SF-36 Scale of the case group were significantly lower in the cancer group. It is essential to ensuremultidisciplinary approaches for living areas determined to be affected by gynecological cancer and also tomake efforts to enhance quality of life; therefore, some suggestions were made regarding these issues peculiarlyconsidering early diagnosis of gynecological cancer.     

The Relationship of PSA, PSAD and Clinicopathological Stage in Patients with Prostate Cancer

OBJECTIVE To investigate the relationship between the clinicopatho- logical stage and serum prostate specific antigen(PSA)concentration and PSAdensity(PSAD)in patients with prostate cancer. METHODS The clinicopathological stage was determined on the basis of a pathological examination and clinical data in 65 prostate cancer patients treated by radical prostatectomy.PSA and PSAD were measured before the operation.The Spearman rank correlation was applied to evaluate the relationship between the clinicopathological stage,serum PSAconcentration and PSAD. RESULTS Patients with higher PSA and PSAD were significantly more likely to have higher clinical stages,a higher Gleason score,positive surgical margins,capsular penetration,and seminal vesicle invasion(each P<0.05). But there was no significant association between PSA and lymph node metastasis(P=0.053).The levels of serum PSA concentration and PSAD were significantly correlated with the clinical stage(P<0.05)in the prostate cancer patients. CONCLUSION The level of both PSA and PSAD were significantly correlated with the clinical stage(P<0.05)in the prostate cancer patients.But PSAD may be a more powerful predictor of clinical stage and prognosis than PSA.