Limited Liver or Lung Colorectal Cancer Metastases. Systemic Treatment, Surgery, Ablation or SBRT.

The prognosis for oligometastatic colorectal cancer has improved in recent years, mostly because of recent advances in new techniques and approaches to the treatment of oligometastases, including new surgical procedures, better systemic treatments, percutaneous ablation, and stereotactic body radiation therapy (SBRT). There are several factors to consider when deciding on the better approach for each patient: tumor factors (metachronous or synchronous metastases, RAS mutation, BRAF mutation, disease-free interval, size and number of metastases), patient factors (age, frailty, comorbidities, patient preferences), and physicians' factors (local expertise). These advances have presented major challenges and opportunities for oncologic multidisciplinary teams to treat patients with limited liver and lung metastases from colorectal cancer with a curative intention. In this review, we describe the different treatment options in patients with limited liver and lung metastases from colorectal cancer, and the possible combination of three approaches: systemic treatment, surgery, and local ablative treatments.

Description of the genetic variants identified in a cohort of patients diagnosed with localized anal squamous cell carcinoma and treated with panitumumab.

Squamous cell carcinoma is the most frequent histologic type of anal carcinoma. The standard of care since the 1970s has been a combination of 5-fluorouracil, mitomycin C, and radiotherapy. This treatment is very effective in T1/T2 tumors (achieving complete regression in 80-90% of tumors). However, in T3/T4 tumors, the 3-year relapse free survival rate is only 50%. The VITAL trial aimed to assess the efficacy and safety of panitumumab in combination with this standard treatment. In this study, 27 paraffin-embedded samples from the VITAL trial and 18 samples from patients from daily clinical practice were analyzed by whole-exome sequencing and the influence of the presence of genetic variants in the response to panitumumab was studied. Having a moderate- or high-impact genetic variant in PIK3CA seemed to be related to the response to panitumumab. Furthermore, copy number variants in FGFR3, GRB2 and JAK1 were also related to the response to panitumumab. These genetic alterations have also been studied in the cohort of patients from daily clinical practice (not treated with panitumumab) and they did not have a predictive value. Therefore, in this study, a collection of genetic alterations related to the response with panitumumab was described. These results could be useful for patient stratification in new anti-EGFR clinical trials.

Comprehensive Characterization of the Mutational Landscape in Localized Anal Squamous Cell Carcinoma.

Anal squamous cell carcinoma (ASCC) is a rare neoplasm. Chemoradiotherapy is the standard of care, with no therapeutic advances achieved over the past three decades. Thus, a deeper molecular characterization of this disease is still necessary. We analyzed 46 paraffin-embedded tumor samples from patients diagnosed with primary ASCC by exome sequencing. A bioinformatics approach focused in the identification of high-impact genetic variants, which may act as drivers of oncogenesis, was performed. The relation between genetics variants and prognosis was also studied. The list of high-impact genetic variants was unique for each patient. However, the pathways in which these genes are involved are well-known hallmarks of cancer, such as angiogenesis or immune pathways. Additionally, we determined that genetic variants in BRCA2, ZNF750, FAM208B, ZNF599, and ZC3H13 genes are related with poor disease-free survival in ASCC. This may help to stratify the patient's prognosis and open new avenues for potential therapeutic intervention. In conclusion, sequencing of ASCC clinical samples appears an encouraging tool for the molecular portrait of this disease.

Genetic Profile and Functional Proteomics of Anal Squamous Cell Carcinoma: Proposal for a Molecular Classification.

Anal squamous cell carcinoma is a rare tumor. Chemo-radiotherapy yields a 50% 3-year relapse-free survival rate in advanced anal cancer, so improved predictive markers and therapeutic options are needed. High-throughput proteomics and whole-exome sequencing were performed in 46 paraffin samples from anal squamous cell carcinoma patients. Hierarchical clustering was used to establish groups de novo Then, probabilistic graphical models were used to study the differences between groups of patients at the biological process level. A molecular classification into two groups of patients was established, one group with increased expression of proteins related to adhesion, T lymphocytes and glycolysis; and the other group with increased expression of proteins related to translation and ribosomes. The functional analysis by the probabilistic graphical model showed that these two groups presented differences in metabolism, mitochondria, translation, splicing and adhesion processes. Additionally, these groups showed different frequencies of genetic variants in some genes, such as ATM, SLFN11 and DST Finally, genetic and proteomic characteristics of these groups suggested the use of some possible targeted therapies, such as PARP inhibitors or immunotherapy.

VITAL phase 2 study: Upfront 5-fluorouracil, mitomycin-C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09-02).

AIM: VITAL, a phase II single-arm study, aimed to evaluate efficacy and safety of panitumumab addition to 5-fluorouracil (5-FU), mitomycin-C (MMC) and radiotherapy (RT) in patients with localized squamous cell carcinoma of the anal canal (SCCAC). METHODS: Adult, treatment-naïve SCCAC patients (Stage T2-T4, any N, M0) and ECOG-PS ≤2, received panitumumab (6 mg/kg, day 1 and Q2W; 8 weeks), 5-FU (1000 mg/m2 /d, days 1-4 and 29-32), MMC (10 mg/m2 , days 1 and 29) and RT 45 Gy (1.8 Gy/fraction) to the primary tumor and mesorectal, iliac and inguinal lymph nodes, plus 10-15 Gy boost dose to the primary tumor and affected lymph nodes. The primary objective was disease free survival rate (DFS) at 3-years (expected 3-year DFS rate: 73.7 ± 12%). RESULTS: Fifty-eight patients (31 women; median age: 59 years; ECOG-PS 0-1:98%; TNM II [29%] (T2 or T3/N0/M0)/IIIA (T1-T3/N1/M0 or T4/N0/M0) [21%]/IIIB (T4/N1/M0 or any T/N2 or N3/M0) [47%]/nonevaluable [4%]) were included. The median follow-up was 45 months. The 3-year DFS rate was 61.1% (95% CI: 47.1, 72.4). The 3-year overall survival rate was 78.4% (95% CI: 65.1, 87.1). Eighteen patients (31.0%) required a colostomy within 2 years posttreatment. Grade 3-4 toxicities were experienced by 53 (91%) patients. Most common grade 3-4 treatment-related events were radiation skin injury (40%) and neutropenia (24%). No toxic deaths occurred. Improved efficacy in colostomy-free survival and complete response rate was observed in human papilloma virus positive patients. CONCLUSIONS: Panitumumab addition to MMC-5FU regimen in SCCAC patients increases toxicity and does not improve patients' outcomes. RT plus MMC-5FU remains the standard of care for localized SCCAC patients.

Outcomes after neoadjuvant treatment with gemcitabine and erlotinib followed by gemcitabine-erlotinib and radiotherapy for resectable pancreatic cancer (GEMCAD 10-03 trial).

BACKGROUND: Neoadjuvant therapy (NAT) for pancreatic adenocarcinoma (PDAC) patients has shown promising results in non-randomized trials. This is a multi-institutional phase II trial of NAT in resectable PDAC patients. METHODS: Patients with confirmed resectable PDAC after agreement by two expert radiologists were eligible. Patients received three cycles of GEM (1000 mg/m2/week) plus daily erlotinib (ERL) (100 mg/day). After re-staging, patients without progressive disease underwent 5 weeks of therapy with GEM (300 mg/m2/week), ERL 100 mg/day and concomitant radiotherapy (45 Gy). Efficacy was assessed using tumor regression grade (TRG) and resection margin status. Using a single-arm Simon's design, considering the therapy not useful if R0 < 40% and useful if the R0 > 70% (alpha 5%, beta 10%), 24 patients needed to be recruited. This trial was registered at ClinicalTrials.gov, number NCT01389440. RESULTS: Twenty-five patients were enrolled. Adverse effects of NAT were mainly mild gastrointestinal disorders. Resectability rate was 76%, with a R0 rate of 63.1% among the resected patients. Median overall survival (OS) and disease-free survival (DFS) were 23.8 (95% CI 11.4-36.2) and 12.8 months (95% CI 8.6-17.1), respectively. R0 resection patients had better median OS, compared with patients with R1 resection or not resected (65.5 months vs. 15.5 months, p = 0.01). N0 rate among the resected patients was 63.1%, and showed a longer median OS (65.5 vs. 15.2 months, p = 0.009). CONCLUSION: The results of this study confirm promising oncologic results with NAT for patients with resectable PDAC. Therefore, the present trial supports the development of phase II randomized trials comparing NAT vs. upfront surgery in resectable pancreatic cancer.

Genomic analysis and clinical management of adolescent cutaneous melanoma.

Melanoma in young children is rare; however, its incidence in adolescents and young adults is rising. We describe the clinical course of a 15-year-old female diagnosed with AJCC stage IB non-ulcerated primary melanoma, who died from metastatic disease 4 years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas and 275 adult cutaneous melanomas. A somatic BRAFV600E mutation and a high mutational load equivalent to that found in adult melanoma and composed primarily of C>T mutations were observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma-predisposing genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood and their clinical course can, as with adults, be unpredictable.

Performance of diagnostic tests in an intensive follow-up protocol for patients with American Joint Committee on Cancer (AJCC) stage IIB, IIC, and III localized primary melanoma: A prospective cohort study.

BACKGROUND: There is no international consensus on optimal follow-up schedules and which supplementary tests should be used after resection of a primary melanoma. OBJECTIVE: We sought to analyze the performance of the follow-up components and identify procedures that detect melanoma metastasis earlier. METHODS: This was a prospective cohort from 290 consecutive patients given a diagnosis of stage IIB, IIC, and III melanoma. Patients were followed up with an intensive protocol based on imaging studies (computed tomography of the chest, abdomen, and pelvis, and brain magnetic resonance imaging), periodic laboratory tests, regular physical examinations, and patient self-examinations. RESULTS: A total of 2382 clinical examinations and 3069 imaging tests were performed. The patients completed 899.8 person-years of follow-up, with a median of 2.5 years. In all, 115 recurrences in 290 patients were recorded, of which computed tomography detected 48.3%; brain magnetic resonance imaging, 7.6%; laboratory test, 2.5%; physician, 23.7%; and patient, 17.8%. LIMITATIONS: Patients with stage III melanoma were not systematically classified into subgroups and overall survival was not evaluated. CONCLUSION: We observed that this intensive monitoring is appropriate for early detection of recurrence in stage IIB, IIC, and III melanoma. Prompt diagnosis of metastasis and the recent development of new therapeutic targets may improve overall survival.

Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation.

AIM: To evaluate the long-term results of conventional chemoradiotherapy and laparoscopic mesorectal excision in rectal adenocarcinoma patients without adjuvant therapy. METHODS: Patients with biopsy-proven adenocarcinoma of the rectum staged cT3-T4 by endoscopic ultrasound or magnetic resonance imaging received neoadjuvant continuous infusion of 5-fluorouracil for five weeks and concomitant radiotherapy. Laparoscopic surgery was planned after 5-8 wk. Patients diagnosed with ypT0N0 stage cancer were not treated with adjuvant therapy according to the protocol. Patients with ypT1-2N0 or ypT3-4 or N+ were offered 5-fluorouracil-based adjuvant treatment on an individual basis. An external cohort was used as a reference for the findings. RESULTS: One hundred and seventy six patients were treated with induction chemoradiotherapy and 170 underwent total mesorectal excision. Cancer staging of ypT0N0 was achieved in 26/170 (15.3%) patients. After a median follow-up of 58.3 mo, patients with ypT0N0 had five-year disease-free and overall survival rates of 96% (95%CI: 77-99) and 100%, respectively. We provide evidence about the natural history of patients with localized rectal cancer achieving a complete response after preoperative chemoradiation. The inherent good prognosis of these patients will have implications for clinical trial design and care of patients. CONCLUSION: Withholding adjuvant chemotherapy after complete response following standard neoadjuvant chemoradiotherapy and laparoscopic mesorectal excision might be safe within an experienced multidisciplinary team.

CA 19-9 in pancreatic cancer: retrospective evaluation of patients with suspicion of pancreatic cancer.

CA 19.9 serum levels were prospectively determined in 573 patients admitted to hospital for suspicion of pancreatic cancer. The final diagnosis was 77 patients with no malignancy, 389 patients with pancreatic cancer, 37 neuroendocrine pancreatic cancer, 28 cholangiocarcinomas, 4 gallbladder cancer, 27 ampullary carcinomas, and 11 periampullary carcinomas. CA 19.9 was determined using a commercial assay from Roche Diagnostics, and 37 U/ml was considered as the upper limit of normality. Abnormal CA 19.9 serum levels were found in 27%, 81.5%, 85.7%, 59.3%, 63.6%, and 18.9% of patients with benign diseases, pancreatic cancer, cholangiocarcinomas, and ampullary, periampullary, or neuroendocrine tumors. Significantly higher concentrations of CA 19.9 were found in patients with than in those without malignancy or with neuroendocrine tumors. CA 19.9 serum levels were higher in pancreatic cancer or cholangiocarcinoma than in other malignancies (p < 0.0001). CA 19.9 serum levels were also correlated with tumor stage, treatment (significantly lower concentrations in resectable tumors), and tumor location (the highest in those located in the body, the lowest in those in the tail or uncinate) and site of metastases (highest in liver metastases). A trend to higher CA 19.9 serum concentrations was found in patients with jaundice, but only with statistical significance in the early stages. Using 50 or 100 U/ml in patients with jaundice, CA 19.9 was useful as an aid in the diagnosis of pancreatic cancer (sensitivity 77.9%, specificity 95.9%) as well as tumor resectability in pancreatic cancer with different cutoffs according to tumor location and bilirubin serum levels with specificities ranging from 90% to 100%. CA 19.9 is the tumor marker of choice in pancreatic adenocarcinomas, with a clear relationship with tumor location, stage, and resectability.

Comparison of positron emission tomography (PET) and computed tomography (CT) for better target volume definition in radiation therapy planning.

BACKGROUND: In cancer patients, positron emission tomography/ computed tomography (PET/CT) fused images present less variability in target contouring, respect to use only CT images, respectively. However, the gold standard has not yet been clearly established between radiation oncologists with regard to PET images and the methodology of contouring targets with confidence using PET/CT fused images. The aim of this study was to determine whether integrated PET/CT fused images provide advantages in virtual simulation compared with morphological contouring only with CT. MATERIAL AND METHODS: Thirty cancer patients were evaluated in an adapted PET/CT hybrid in radiotherapy (RT) setup position, with 20 of them being suitable for RT: 17 were suitable for curative intent, which was the group of interest in this study. All image series were sent to the RT work station (WS) where CT and PET series were automatically fused by Digital Imaging and Communications in Medicine (DICOM) in each case. PET series were threshold and were subjected to source-to-background contrast algorithms to fi nally redefine the original tumour description. Three different radiotherapy plans (RTP) for each patient were compared after targets were contoured: [1] planning over metabolic (PET) contoured targets, [2] planning over only morphologic (CT) targets, and [3] planning over targets obtained for treatment based on fused PET/CT images. RESULTS: PET/CT findings altered initial-stage planning in four patients (23.5%) because they had been undergoing chemotherapy. Gross target volume (GTV) and planning target volume (PTV) based only on PET showed more homogeneity to obtain mean doses (p = 0.025) with respect to those based on PET/CT, respectively. However, no percentage differences were observed in median PTV doses between the planning methods, although there was higher variability in PET/CT planning. Morphological (CT) and PET/ CT target volumes were more voluminous than metabolic (PET) volumes. On the other hand, 20% of metabolic (PET) PTV were out of those defined by PET/CT. Thoracic RT plans based on PET preserved better bilateral lung [percentage volume of lung irradiated with a dose of 20 Gy (V20); significance, R(2) = 0.559, p = 0.006]. CONCLUSIONS: For our physicians, PET/CT fused images allowed better contouring of primary tumours in 40% of head and neck cancers and 34% of thoracic cancers. PET/CT provides useful information for virtual simulation therapy. Image treatment and planning in an RT workstation is mandatory.

[Changes in the incidence of falls in an intermediate and long-term care center]. / Evolución de la incidencia de caídas en un centro hospitalario de media y larga estancia.

INTRODUCTION: The characteristics of falls in older patients admitted to an institution in 2 different periods. MATERIAL AND METHODS: We performed a prospective study of falls among inpatients admitted to an intermediate and long-term care center. Age, sex, Barthel index, main diagnoses, medication at the time of the fall, place, the shift when the fall occurred, lighting, characteristics of the floor, the use of walking aids and/or restraints, the kind of shoes worn, and activity at the moment of the fall were registered. During the first 2-year study period (period A), there were 332 beds (intermediate care and rehabilitation unit, long-term care unit, palliative care unit, psychogeriatric unit and assisted residential home). During the second 2-year period (period B), the palliative and intermediate care units were moved to another center (255 beds remaining). RESULTS: Period A: there were 647 falls in 227 patients; the total number of patients admitted was 1387 (accumulated incidence of falls: 46.6%). Period B: there were 539 falls in 191 patients; the total number of patients admitted was 908 (accumulated incidence of falls: 59.3%). Significant differences between the two periods were found in age (79.8+/-10.6 versus 81.3 10.2) (p<0.02), the percentage of women (55.2% versus 66.4%) (p<0.001), neurological diagnoses (26.7% versus 36.1%) (p< 0.001), antidepressants (12.6% versus 16.4%), neuroleptics (10.3% versus 15.2%) (p<0.001), falls in the bedroom (39.7% versus 41.6%) (p<0.001), falls when moving from bed to chair (41.3% versus 30.8%) (p<0.001), and the use of walking aids (65.8% versus 40.5%) (p<0.001). CONCLUSIONS: a) the incidence of falls increased in the second period of the study; b) in period A, risk factors for falls related to rehabilitation (moving from bed to chair, use of walking aids) were more frequent. In period B, risk factors related to the characteristics of psychogeriatric patients were predominant (neurological illness, use of psychotropic drugs, and c) the difference in the incidence of falls between the two study periods may be related to the distinct characteristics of the patients (case mix).

[Prediction of prognosis of patients with pancreatic adenocarcinoma with curative intent resection by means of histologic grade and pathologic N stage]. / Predicción del pronóstico de los pacientes con adenocarcinoma pancreático resecado con intención curativa mediante el grado histológico y el estadio N patológico.

BACKGROUND AND OBJECTIVE: Pancreatic cancer has the poorest prognosis of any common gastrointestinal malignancy, with a 5-year overall survival of less than 5%. A better knowledge of prognostic factors related to this neoplasia might help improve the survival of these patients. We evaluated the prognostic significance of different factors in both overall survival and tumor recurrence in patients with pancreatic adenocarcinoma who had undergone pancreatic resection with curative intent. PATIENTS AND METHOD: All patients with pancreatic adenocarcinoma submitted to surgical resection in our unit from January 1995 to February 2005 were evaluated. Twenty-three pre-surgical, therapeutic, and histopathologic variables were analyzed. Univariate (Kaplan-Meier, log-rank test) and multivariate (Cox regression) analyses were performed to select independent prognostic factors. RESULTS: Ninety-four patients were evaluated. The median age of patients was 63 years and 53% were woman. The probability of overall survival was 63% at 1 year, 18% at 3 years, and 8% at 5 years, with a median survival of 18 months. Univariate analysis identified performance of adjuvant therapy, histologic grade, percentage of involved-resected lymph nodes, pathologic N stage, and pathologic TNM stage as variables associated with overall survival. On the other hand, the probability of tumor recurrence was 52% at 1 year, 83% at 3 years, and 91% at 5 years, with a median time to tumor recurrence of 12 months. Predictive variables of tumor recurrence in the univariate analysis were preoperative N stage, preoperative TNM stage, postoperative CA 19.9 serum concentration, histological grade, percentage of involved-resected lymph nodes, pathologic N stage and pathologic TNM stage. Multivariate analysis identified histological grade and pathologic N stage as independent predictive factors of both overall survival (histologic grade: HR=2.341 [CI 95%, 1.342-4.098; p=0.003]; pathologic N stage: HR=2.242 [1.213-4.149; p=0.01]) and tumor recurrence (histological grade: HR=1.742 [CI 95%, 1.121-3.086; p=0.05]; pathologic N stage: HR=2.096 [1.089-4.032; p=0.027]). CONCLUSIONS: The histological grade and pathologic N stage predict the prognosis of patients with pancreatic adenocarcinoma after surgical resection.

Prognostic implications of protein S-100beta serum levels in the clinical outcome of high-risk melanoma patients.

OBJECTIVE: It was the aim of this study to analyze the clinical value of the determination of serum S-100beta protein in high-risk melanoma patients. PATIENTS AND METHODS: Patients were tested for serum S-100beta protein by luminoimmunometric assay after melanoma surgical excision, before starting interferon-alpha2b and every 3 months thereafter, until treatment was completed. RESULTS: Ninety-seven patients were included in the study. Median follow-up was 62.9 months (range 32.7-87.4). High baseline S-100beta levels were associated with positive lymph node status (p = 0.02). High S-100beta levels (during therapy) showed a relation with positive lymph node status (p = 0.014), number of positive lymph nodes (p = 0.01), macroscopic lymph node involvement (p = 0.002) and second melanoma diagnosis at study entry (p = 0.001). By univariate analysis, high baseline S-100beta levels were associated with disease-free survival (p = 0.004) and overall survival (p = 0.0007). Similarly, high S-100beta levels during therapy were associated with disease-free survival (p < 0.0001) and overall survival (p < 0.0001). In the multivariate analysis, high S-100beta levels during therapy (hazard ratio 1.017, 95% CI 1.008-1.026; p < 0.0001) and high baseline S-100beta levels (hazard ratio 3.31, 95% CI 1.10-9.89; p = 0.032) were independent prognostic factors for overall survival when compared with low levels while on therapy and low baseline S-100beta levels, respectively. CONCLUSIONS: These results provide evidence of the clinical usefulness of serum S-100beta level determination in high-risk melanoma patients. S-100beta serum determination should be considered to be included in clinical trials that test adjuvant therapies in melanoma patients.

Malignant melanoma with metastasis into the capitate.

Metastases to the hand and wrist are rare, with fewer than 200 cases reported in the literature. Phalanges are more commonly involved than metacarpal and wrist. The lung, breast and kidneys are the more common sites of primary lesions than metastasize in the hand. We present an exceptional case of melanoma that metastasized to the capitate. Melanoma can give bone metastases, but we are not aware of reports of this tumour metastatising to the carpal bones. In our knowledge, we have only found a report of metastases in the capitate, a clear-cell sarcoma of the right foot, a tumour close to melanoma with some cytogenetic differences. Hand metastases in a patient who is suffered melanoma should be ruled out if a lytic aggressive lesion appears on x-ray film or positive technetium bone scan is demonstrated.

Treatment of patients with progressive unresectable metastatic melanoma with a heterologous polyvalent melanoma whole cell vaccine.

Unresectable metastatic melanoma has no elective treatment. Neither chemotherapy, intravenous IL-2 nor biochemotherapy clearly improves the overall survival. Recent assays with therapeutic vaccines have been recently yielded promising results. Here, we describe the application, clinical tolerance and antitumoural activity of a heterologous polyvalent melanoma whole cell vaccine in patients with metastatic melanoma. Twenty-eight AJCC stage III/IV melanoma patients with progressive unresectable metastatic disease were treated with our heterologous polyvalent melanoma whole cell vaccine between July 1, 1998 and July 1, 2002. All patients had already been unsuccessfully treated with high doses of IFN-alpha2 and/or polychemotherapy and/or biochemotherapy and/or perfusion of extremities, or could not receive other treatments due to their age or underlying illness. Twenty-three were assessable. The vaccine was constituted by 10 melanoma cell lines, derived from primary, lymph node and metastatic melanomas. Prior to intradermal inoculation, the cells were irradiated and mixed with BCG, and 50% were treated with DNFB. After a median follow-up of 19 months, 26% of patients responded: 3 CR (18, 16+, and 26+ months), 2 PR (8 and 22 months) and 1 MR (36+ months). The median survival of the whole group was 20.2 months. None of the 28 patients initially included in the study presented significant toxicity. This vaccination program had specific antitumoural activity in advanced metastatic melanoma patients and was well tolerated. The clinical responses and the median survival of our group of patients, together with the low toxicity of our polyvalent vaccine, suggest that this approach could be applied to earlier metastatic melanoma patients.