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1.

Background

Lynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families.

Methods

Data were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population.

Results

A total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations.

Conclusion

Lynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types.
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2.

Background

Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system.

Methods

We compiled data from publications and hereditary cancer registries to characterize the Lynch syndrome mutation spectrum in South America. In total, data from 267 families that fulfilled the Amsterdam criteria and/or the Bethesda guidelines from Argentina, Brazil, Chile, Colombia and Uruguay were included.

Results

Disease-predisposing mutations were identified in 37% of the families and affected MLH1 in 60% and MSH2 in 40%. Half of the mutations have not previously been reported and potential founder effects were identified in Brazil and in Colombia.

Conclusion

The South American Lynch syndrome mutation spectrum includes multiple new mutations, identifies potential founder effects and is useful for future development of genetic testing in this continent.
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3.

Background

Colorectal carcinomas with high-frequency microsatellite instability (MSI-H) account for 15% of all colorectal cancers, including 12% of sporadic cases and 3% of cancers associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome, HNPCC). Lynch syndrome is an autosomal dominant hereditary cancer syndrome, caused by germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2.

Methods

Published articles from peer-reviewed journals were obtained from PubMed, Google Scholar and Clinicaltrials.gov. Based on the recent research data, we provide an update on the MSI testing, along with the evolving role of MSI in diagnosis, prognosis and treatment of colorectal cancers.

Results

Studies have led to significant advances in the molecular pathogenesis and clinicopathological characteristics of MSI-H colorectal cancers. Emerging evidence suggests that colorectal cancers with MSI-H show different outcome and treatment response from those with microsatellite stable (MSS) tumors. Therefore, MSI testing is essential not only in the genetic context, but it may also have important prognostic and predictive value of response to chemotherapy and immunotherapy.

Conclusions

Many experts and professional authorities have recommended a universal MSI testing in all individuals newly diagnosed with colorectal cancers.
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4.

Purpose of Review

This review will discuss the genetic basis and epidemiology of Lynch syndrome, review Lynch Syndrome colorectal cancer screening guidelines, and summarize the screening guidelines pertaining to other cancers that are associated with Lynch syndrome.

Recent Findings

All colorectal tumors should be universally tested for microsatellite instability (MSI) changes regardless of the age of the patient. Genetic testing of family members of patients with Lynch syndrome has significant cost effectiveness implications. Polyethylene glycol bowel preparation and chromocolonoscopy improve screening exams. Aspirin use is associated with decreased colorectal cancer risk. Phosphodiesterase-1 (PD-1) inhibitor immunotherapy is effective treatment in mismatch repair (MMR) deficiency tumors.

Summary

Lynch syndrome should be suspected if patients with malignancies exhibit diagnostic criteria and these tumors should be tested for MMR deficiencies. Colonoscopy is used for surveillance of colorectal cancers in Lynch syndrome, and bowel preparation quality and colonoscopy techniques are important factors contributing to efficacy. Clinicians should be aware of screening modalities for extracolonic cancers including upper endoscopy, regular transvaginal ultrasound with endometrial sampling, and urinalysis.
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5.
6.

Background

Women with breast cancer are at increased risk of developing skin cancer. Little is known about how tamoxifen affects this risk. We aimed to investigate whether tamoxifen treatment following breast cancer is associated with skin cancer.

Methods

A cohort consisting of 44,589 women diagnosed with breast cancer during 1977–2007 from the nationwide clinical database of the Danish Breast Cancer Cooperative Group, was followed for a primary skin cancer [basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or melanoma] in the Danish Cancer Registry supplemented by data on BCC and SCC from the Danish Pathology Register. We investigated incidence of skin cancer among 16,214 women treated with tamoxifen compared to 28,375 women not treated with tamoxifen by calculating incidence rate ratios (IRRs) in Cox regression models.

Results

Tamoxifen users were followed for a median of 2.9 years. The median duration of tamoxifen treatment increased from around 1 year among women diagnosed before 1999 to nearly 2.5 years among women diagnosed in 1999 or later. Women treated with tamoxifen had an IRR 1.06 (95 % CI 0.72–1.55) for SCC and an IRR 1.40 (95 % CI 0.95–2.08) for melanoma when compared to non-users. The observed number of these types of cancer (37 SCCs and 38 melanomas among users) did not allow stratification on calendar-period. The overall IRR for BCC was 0.96 (95 % CI 0.84–1.09), but the IRR differed by menopausal status and calendar-period at diagnosis of breast cancer.

Conclusions

Our overall results indicate that tamoxifen is not associated with skin cancer. However, the inconsistency of results from stratifications prevents a firm conclusion.
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7.

Purpose

Patients with Lynch syndrome (LS) have a significantly elevated lifetime risk of developing biliary tract cancers (BTCs) compared to the general population. However, few studies have characterized the clinical characteristics, genetic features, or long-term outcomes of mismatch-repair deficient (dMMR) cholangiocarcinomas associated with LS.

Methods

A retrospective review of a prospectively maintained Familial High-Risk GI Cancer Clinic database identified all patients with BTCs evaluated from 2006 to 2016 who carried germline mutations in MLH1, MSH2, MSH6, or PMS2.

Results

Eleven patients with BTCs were identified: four perihilar, four intrahepatic, one extrahepatic, one gallbladder, and one ampulla of Vater. All patients had underlying germline mutations and a personal history of a LS-associated malignancy, most commonly (63.3%) colorectal cancer. Ten (90.9%) patients were surgically explored, and margin negative resection was possible in seven (63.3%). Chemotherapy (90.9%) and/or chemoradiation (45.5%) was administered to most patients. Among the seven patients presenting with non-metastatic disease who underwent surgical resection with curative intent, the 5-year overall survival rate was 53.3%. The median overall survival for the four patients not treated with curative intent was 17.2 months.

Conclusions

dMMR biliary tract cancers associated with LS are rare but long-term outcomes may be more favorable than contemporaneous cohorts of non-Lynch-associated cholangiocarcinomas. Given the emerging promise of immunotherapy for patients with dMMR malignancies, tumor testing for dMMR followed by confirmatory germline testing should be considered in patients with BTC and a personal history of other LS cancers.
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8.

Background

The role of Merkel cell polyomavirus (MCV) infection in the etiology of non-melanoma skin cancers, other than Merkel cell carcinoma, is unclear. Previously, we reported a significant association between seropositivity to MCV capsid antigen and MCV DNA-positive cutaneous squamous cell carcinoma (SCC). Here we present associations between SCC and seroreactivity to MCV T-antigen (T-Ag) oncoprotein, as well as MCV DNA detected in eyebrow hairs.

Findings

A clinic-based case–control study, including 171 SCC cases and 300 controls without skin cancer, was conducted at Moffitt Cancer Center in Tampa, Florida. Multiplex assays were used to measure serum antibodies against MCV small and large T-Ag and MCV DNA in both eyebrow hairs and SCC tumors (n?=?144). Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated using logistic regression to evaluate the associations between MCV and SCC. No significant association was observed between seroreactivity to MCV full-length large or small T-Ag and SCC, overall [ORlarge T-Ag?=?0.99 (0.48-2.08), ORsmall T-Ag?=?0.31 (0.06–1.62)] or when comparing tumor MCV DNA-positive cases to controls [ORlarge T-Ag?=?1.06 (0.38–2.93)]. Only presence of MCV DNA in eyebrow hairs was significantly associated with MCV DNA-positive SCC [OR?=?4.05 (2.01–8.18)].

Conclusion

MCV infection is unlikely to play a direct role in SCC.
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9.
10.

Background

Squamous cell carcinoma (SCC) of the breast is a rare and generally aggressive disease that accounts for less than 0.1% of all breast carcinomas. Although SCCs have distinct morphological features, their origin and cytogenetic profile are not well understood.

Methods

Five patients with SCC were studied. The tumor area that was predominantly composed of SCC components was macrodissected and DNA was extracted. In three cases, an invasive or noninvasive ductal carcinoma of no special type (NST) component was also present. NST-component DNA was also extracted. The tumor DNA was used for array comparative genomic hybridization analysis using a high-density oligonucleotide microarray. The cytogenetic profile of the SCC components was compared with each other and with the paired NST component in three of the five cases.

Results

The cytogenetic profile of the SCC components indicated large intertumoral heterogeneity. There were between 2 and 160 copy number alterations per case, and no common copy number alterations were identified. The cytogenetic profiles of the paired SCC and NST components were similar but not identical. Although, in one case, a larger number of copy number aberrant regions were detected in the SCC component than the NST component. In this case, all the NST component aberrations were present in the SCC component. This implies that the SCC component originated from the NST component. There were no common SCC component-specific aberrations in the three NST-component cases.

Conclusion

Our results demonstrate the cytogenetic inter- and intratumoral heterogeneity of SCC of the breast. Our comparison of cytogenetic profiles indicated that the SCC component originated from the NST component in one case.
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11.

Purpose

We sought to evaluate prevalence, age-adjusted distribution, and impact of single and multiple high- and low-risk human papillomavirus (HPV) subtypes and their associations with cervical lesions.

Methods

Data were extracted from 11,224 women who underwent routine screening of HPV genotyping and liquid-based cytology co-testing. Fifteen high-risk (HR) and six low-risk (LR) HPV types were genotyped.

Results

Overall HPV prevalence was 10.7 %, and young women (under 21 years old) harbored highest HPV infection rate (40.38 %). The rate declined in old women 9.49 % (age 30–49) and 6.89 % (age 50 and above). Normal cytology had lowest HPV (5.66 %) compared to low-grade (60.49 %), high-grade (71.96 %) squamous intraepithelial lesions (LSIL and HSIL) and squamous cell carcinoma SCC (86.9 %). LR HPV subtypes were absent in SCC and were consistently lower than HR HPV in LSIL (6.74 vs. 33.54 %) and HSIL (2.12 vs. 51.32 %). Multiple HPV infection was more frequent in young women under 30 years old (10 %) than older women (2 %) and in LSIL (20.2 %), HSIL (18.5 %) than SCC (4.4 %). HR HPV 52, 16, 18, and 58 were the most frequent subtypes in normal, LSIL, and HSIL. Greater or equal proportion of HPV 16, 18, 45, and 52 was found in SCC compared to normal cytology (SCC/normal ratios 4.8, 1.2, 1.6, and 1.7). While important in LSIL and HSIL, HPV58 was not detected in SCC.

Conclusion

Taken together, identification of these HPV types, especially HPV 16, 18, 45, and 52, and their associated cervical lesions may improve cervical cancer preventive strategies in Indonesia.
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12.

Introduction

The aim of the study is to evaluate the incidence and phenotype - genotype characteristics of hereditary colorectal cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by these syndromes.

Materials and methods

From 02/1999-09/2002 in several hospitals in Latvia cancer family histories were collected from 865 patients with CRC. In families suspected of having a history consistent with a hereditary colorectal cancer syndrome, DNA testing for MLH1, MSH2 and MSH6 genes was performed. In addition immunohistochemical (IH) examination of the normal and cancer tissue from large bowel tumors for MSH2 and MSH6 protein expression was performed prior to DNA analysis.

Results

From the 865 CRC cases only 3 (0.35%) pedigrees fulfilled the Amsterdam II criteria of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) and 15 cases (1.73%) were suspected of HNPCC. In 69 cases (8%) with a cancer family aggregation (CFA) were identified. Thus far 27 IH analyses have been performed and in 3 cancers homogenous lack of MSH2 or MSH6 protein expression was found. In one of these cases a mutation in MSH6 was identified. In 18 patients suspected of HNPCC or of matching the Amsterdam II criteria, denaturing high performance liquid chromatography (DHPLC) followed by DNA sequencing of any heteroduplexes of the 35 exons comprising both MLH1 and MSH2 was performed revealing 3 mutations.For all of kindreds diagnosed definitively or with a high probability of being an HNPCC family appropriate recommendations concerning prophylactic measures, surveillance and treatment were provided in written form.

Conclusions

Existing pedigree/clinical data suggest that in Latvia the frequency of HNPCC is around 2% of consecutive colorectal cancer patients. It is crucial that genetic counseling is an integral part of cancer family syndrome management.
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13.

Objective

We assessed whether the functional V16A polymorphism in the MnSOD gene is associated with skin cancer risk.

Methods

We conducted a nested case–control study (219 melanoma, 286 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 873 matched controls) within the Nurses’ Health Study. Genotyping was performed by the 5′ nuclease assay (TaqMan®). We used logistic regression to model the association between the genotype and skin cancer risk.

Results and conclusions

Overall, there was no significant association between this polymorphism and the risk of each type of skin cancer. No significant interaction was observed between this polymorphism and sunburn history and constitutional susceptibility on skin cancer risk. For interactions between intakes of α-carotene and β-carotene and the MnSOD polymorphism on SCC, the inverse association of intake of either carotene with SCC risk was limited to the Val carriers, whereas no association was observed among women with the AA genotype. We observed an interaction between total vitamin C intake and the MnSOD polymorphism on melanoma risk. No interaction was observed for the intakes of other carotenoids, vitamin E, and vitamin A. Further research is needed to confirm these possible associations.
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14.

Background

Integrin-extracellular matrix interactions activate signaling cascades such as mitogen activated protein kinases (MAPK). Integrin binding to extracellular matrix increases tyrosine phosphorylation of focal adhesion kinase (FAK). Inhibition of FAK activity by expression of its carboxyl terminus decreases cell motility, and cells from FAK deficient mice also show reduced migration. Paxillin is a focal adhesion protein which is also phosphorylated on tyrosine. FAK recruitment of paxillin to the cell membrane correlates with Shc phosphorylation and activation of MAPK. Decreased FAK expression inhibits papilloma formation in a mouse skin carcinogenesis model. We previously demonstrated that MAPK activation was required for growth factor induced in vitro migration and invasion by human squamous cell carcinoma (SCC) lines.

Methods

Adapter protein recruitment to integrin subunits was examined by co-immunoprecipitation in SCC cells attached to type IV collagen or plastic. Stable clones overexpressing FAK or paxillin were created using the lipofection technique. Modified Boyden chambers were used for invasion assays.

Results

In the present study, we showed that FAK and paxillin but not Shc are recruited to the β1 integrin cytoplasmic domain following attachment of SCC cells to type IV collagen. Overexpression of either FAK or paxillin stimulated cancer cell migration on type IV collagen and invasion through reconstituted basement membrane which was dependent on MAPK activity.

Conclusions

We concluded that recruitment of focal adhesion kinase and paxillin to β1 integrin promoted cancer cell migration via the mitogen activated protein kinase pathway.
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15.

Purpose

Short stature has been reported in pediatric cancer survivors. Data on retinoblastoma survivors are limited. We conducted a cross-sectional study to assess the height in retinoblastoma survivors.

Method

The recorded height was compared with median height for age and sex as per the Indian Academy of Pediatrics. Z-score less than ?2 was considered short statured.

Result

Thirty percent of the survivors were short statured. The mean height was shorter than the mean 50th percentile height (119.7 ± 14.8 vs 128.7 ± 15 cm, p < 0.001). Previous chemotherapy showed a trend toward association (p = 0.09).

Conclusion

Short stature affects a significant number of retinoblastoma survivors.
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16.

Background

The mechanism underlying the malignant transformation of inverted papilloma (IP) has not yet been elucidated.

Methods

To clarify the genes responsible for the malignant transformation, we analyzed 10 cases of IP, 8 of IP with dysplasia, and 11 of squamous cell carcinoma (SCC) by targeted amplicon sequencing.

Results

The number of mutant genes increased in the order of IP?<?dysplasia?<?SCC. Significant differences were observed in the mutation rates of three genes (KRAS, APC and STK11) in particular. TP53 was altered frequently in each group and might be involved in malignant transformation based on to the site of the mutation. A comparison of the genetic variants by region of IP tissue among patients with IP alone, and those with dysplasia or SCC revealed significant differences in the mutation rate of the KRAS gene.

Conclusion

Identification of genetic mutations in KRAS is effective for predicting the malignant transformation of IP.
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17.

Purpose

To determine the histological distribution and trends in incidence of sinonasal malignancies in Jamaica.

Methods

Cases of all sinonasal malignancies diagnosed between 1973 and 2007 were extracted from the archives of the Jamaica Cancer Registry. Data recorded for each case included age at diagnosis, sex, year of diagnosis, topography, and histology. Data were used to calculate frequencies, age-specific incidence rates, and age-standardized incidence rates (ASRs). Linear regression analysis was used to determine significance of trends in incidence rates; p values of ≤0.05 were significant.

Results

Sinonasal malignancies were commoner in males (male: female ratio, 1.1:1), and the median ages were 62 (males) and 66 years (females). Most were located in either the maxillary sinus (61.3%) or nasal cavity (24.3%). The commonest histological types were squamous cell carcinoma (SCC) (55.9%) and non-Hodgkin’s lymphoma (17.1%), which were predominantly of T-cell immunophenotype, in both the nasal cavity and sinuses. There was no documentation in registry data regarding separation into NK/T and peripheral T-subtypes. The ASRs in males and females were consistently less than 1.5 per 100,000 per year. In males, there was a significant decrease in SCC ASR (p = 0.014) over time.

Conclusions

The age, gender, and anatomical and histological distribution patterns of sinonasal malignancies in Jamaica are similar to those reported internationally, and the low ASRs are in keeping with previous global reports. Broader local immunohistochemistry panels are warranted for further delineation of sinonasal T-cell lymphomas. Investigation into factors contributing to the decreasing incidence of sinonasal SCC is also required.
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18.

Background

Esophagectomy following neoadjuvant chemotherapy (NAC) is a standard treatment for resectable advanced esophageal cancer in Japan. However, approximately 10 % of patients with resectable advanced esophageal cancer experience recurrence within 6 months.

Methods

One hundred twenty-eight patients with resectable advanced esophageal cancer underwent NAC between October 2008 and July 2015 in Kumamoto University Hospital. Among them, 82 patients with esophageal squamous cell carcinoma (SCC), who underwent curative esophagectomy without adjuvant treatment, were eligible. Clinicopathological factors correlated with early recurrence were retrospectively analyzed.

Results

Of 82 patients, 14 (17 %) recurred within 6 months after surgery. The logistic regression analysis suggested that CRP before NAC ≥ 0.5 mg/dl [hazard ratio (HR) 33.8, 95 % confidence interval (CI) 2.767–413.9; p = 0.006), presence of poorly differentiated SCC component (HR 138, 95 % CI 5.339–3576; p = 0.003), and pathological vessel invasion (HR 16.3, 95 % CI 1.960–136.1; p = 0.010) were candidates for independent risk factors of early recurrence. Patients with at least two factors frequently recurred (82 %). Of 14 patients with early recurrence, 13 (93 %) had a distant metastasis.

Conclusions

Patients with resectable advanced esophageal cancer with at least two factors of CRP before NAC ≥ 0.5 mg/dl, presence of poorly differentiated SCC component, and pathological vessel invasion might be at high risk for early recurrence after esophagectomy following NAC. These patients might be considered for additional treatment and should be meticulously followed up after treatment.
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19.

Background

The therapeutic significance of neoadjuvant chemotherapy (NAC) followed by radiation therapy (RT) was negated during the early 1990s. Here, we compared post-NAC RT to surgery for chemo-sensitive cervical squamous cell carcinoma (SCC).

Methods

This study included 79 consecutive patients with cervical SCC who were treated by NAC followed by surgery (n = 49) or by definitive RT (n = 30). We compared characteristics and survival outcomes between the surgery and RT groups by their responses to NAC.

Results

Of the 79 patients, 70 (89%) had stage II–IV disease and 41 (52%) had radiological pelvic lymph node enlargement. The 5-year disease-specific survival (DSS) rate of the entire cohort was 66.4% (median follow-up 54 months). Fifty-five patients (70%) achieved sufficient (complete or partial) responses to NAC. Among patients with insufficient NAC responses, the 5-year DSS rate of the surgery group (55.6%) was significantly higher than the RT group (20.0%; P = 0.044). However, among patients with sufficient responses to NAC, 5-year DSS rates did not significantly differ between the surgery and RT groups (82.3 vs 78.6%; P = 0.79) even though the RT group had many more unfavorable prognostic factors and received fewer subsequent treatments than the surgery group.

Conclusions

Post-NAC survival outcomes among patients with chemo-sensitive cervical SCC who then underwent RT were not inferior to those treated with surgery, and NAC did not detract from the efficacy of subsequent RT. Among selected patients who respond favorably to NAC, RT could be a less invasive substitute for surgery without compromising treatment outcomes.
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20.

Background

Neoadjuvant chemoradiation (NCRT) has been shown to improve survival in patients with locally advanced esophageal squamous cell carcinoma (SCC). The aim of the present study was to evaluate the role of 18-FDG PET-CT in predicting pathological response to NCRT.

Material and Methods

We assessed 70 patients of esophageal SCC who underwent NCRT and were evaluated with baseline and post chemoradiation 18F-FDG PET-CT scan. Receiver operating characteristic (ROC) curve was generated by analyzing the sensitivity and specificity of different cut-off points for defining a positive test and their ability to predict pathological complete response. Univariate and multivariate analysis were performed using log-rank and Cox proportional hazards models, and survival curves were estimated using the Kaplan-Meier method.

Results

Radiological and pathological complete response was achieved in 44.3 % (n = 31) and 34.3 % (n = 24) patients, respectively. Using ROC curves, post-treatment standardized uptake value (SUV) max [3.25, area under curve (AUC) 0.752] and % change in SUVmax cut-off value (72.32 %, AUC 0.705) was used to predict pathological response. Significant associations between pathological response in primary tumor and post chemotherapy/radiotherapy SUVmax values (p = 0.016), % change in SUVmax (p = 0.006), radiological response in primary (p = 0.006), and grade of dysphagia at presentation (p = 0.041) were observed. Mean overall survival and relapse free survival was 83 and 58 %, respectively at 34 months.

Conclusion

18F-FDG PET-CT can be used to predict pathological response to NCRT in locally advanced SCC.
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