Dimensão ética da alimentação e hidratação artificiais no doente terminal / Ethics, artificial nutrition, and hydration in terminal patients / Dimensión ética de la nutrición e hidratación artificial en los pacientes terminales

Resumo Dada a insuficiente evidência científica, decisões relativas à utilização de nutrição e hidratação artificiais em pacientes terminais configuram um importante dilema ético. Identifica-se um conflito entre as perspetivas de "tratar" e "cuidar", com variação quanto a sua utilização conforme o contexto legal e cultural de diferentes países. O intuito deste estudo é esclarecer se essa prática constitui uma medida de cuidado básico ou um tratamento fútil e desproporcionado. Procede-se a uma revisão das diretrizes e dos códigos deontológicos de diferentes países europeus. Em Portugal, na Itália e na Polônia, tal prática é vista como uma medida de cuidado básico; já em países como França, Inglaterra, Noruega, Irlanda, Alemanha, Finlândia, Holanda, Bélgica e Suíça, é considerada um tratamento fútil. Na Romênia, na Croácia e na Hungria, verifica-se um enquadramento ético e legal insuficiente. As diferenças de abordagem a doentes terminais podem ser reflexo das diferentes perspetivas culturais.

Abstract Given the lack of scientific evidence, decisions regarding the administration of artificial nutrition and hydration in terminally ill patients constitute an important ethical dilemma due to the conflict between "treat" and "care" perspectives and the varying usage depending on the legal and cultural background across countries. This study aims to explain whether this practice configures a basic care intervention or a futile medical treatment. Therefore, we review the national guidelines and codes of ethics from several European countries. Countries such as Portugal, Italy, and Poland view it as a basic care intervention, whereas France, England, Norway, Ireland, Germany, Finland, Netherlands, Belgium, and Switzerland, as a medical treatment. Moreover, countries such as Romania, Croatia, and Hungary lack such legal framework. The different approaches regarding the care of terminally ill patients can reflect differences on cultural perspectives.

Resumen Dada la insuficiente evidencia científica, las decisiones sobre el uso de la nutrición e hidratación artificiales en los pacientes terminales constituyen un importante dilema ético. Se identifica un conflicto entre las perspectivas de "tratar" y "cuidar", con variaciones en su uso según el contexto legal y cultural de los diferentes países. El objetivo de este estudio es dilucidar si esta práctica constituye una medida de atención básica o un tratamiento fútil y desproporcionado. Se realiza una revisión de las directrices y códigos deontológicos de diferentes países europeos. En Portugal, Italia y Polonia, se considera esta práctica como una medida de atención básica; mientras que en países como Francia, Inglaterra, Noruega, Irlanda, Alemania, Finlandia, Holanda, Bélgica y Suiza, se considera un tratamiento fútil. En Rumanía, Croacia y Hungría, el marco ético y jurídico es insuficiente. Las diferencias en el tratamiento de los pacientes terminales pueden reflejar diferentes perspectivas culturales.

Distribution and Clinical Significance of HPV16 Variants in Head and Neck Squamous Cell Carcinomas: Data from a Portuguese Cohort and Systematic Review.

INTRODUCTION: Genomic variants of the human papillomavirus type 16 (HPV16) are thought to play differential roles in the susceptibility to head and neck squamous cell carcinomas (HNSCC) and its biological behaviour. This study aimed to establish the prevalence of HPV16 variants in an HNSCC cohort and associate them with clinical pathological characteristics and patient survival. METHODS: We retrieved samples and clinical data from 68 HNSCC patients. DNA samples were available from tumour biopsy at the time of the primary diagnosis. Targeted next-generation sequencing was used to obtain whole-genome sequences, and variants were established based on phylogenetic classification. RESULTS: 74% of samples clustered in lineage A, 5.7% in lineage B, 2.9% in lineage C, and 17.1% in lineage D. Comparative genome analysis revealed 243 single nucleotide variations. Of these, one hundred were previously reported, according to our systematic review. No significant associations with clinical pathological variables or patient survival were observed. The E6 amino acid variations E31G, L83V, and D25E and E7 N29S, associated with cervical cancer, were not observed, except for N29S in a single patient. CONCLUSION: These results provide a comprehensive genomic map of HPV16 in HSNCC, highlighting tissue-specific characteristics which will help design tailored therapies for cancer patients.

PIK3CA Gene Mutations in HNSCC: Systematic Review and Correlations with HPV Status and Patient Survival.

PIK3CA mutations are believed to contribute to the pathogenesis of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC). This study aims to establish the frequency of PIK3CA mutations in a Portuguese HNSCC cohort and to determine their association with the HPV status and patient survival. A meta-analysis of scientific literature also revealed widely different mutation rates in cohorts from different world regions and a trend towards improved prognosis among patients with PIK3CA mutations. DNA samples were available from 95 patients diagnosed with HNSCC at the Portuguese Institute of Oncology in Lisbon between 2010 and 2019. HPV status was established based on viral DNA detected using real-time PCR. The evaluation of PIK3CA gene mutations was performed by real-time PCR for four mutations (H1047L; E542K, E545K, and E545D). Thirty-seven cases were found to harbour PIK3CA mutations (39%), with the E545D mutation (73%) more frequently detected. There were no significant associations between the mutational status and HPV status (74% WT and 68% MUT were HPV (+); p = 0.489) or overall survival (OS) (3-year OS: WT 54% and MUT 65%; p = 0.090). HPV status was the only factor significantly associated with both OS and disease-free survival (DFS), with HPV (+) patients having consistently better outcomes (3-year OS: HPV (+) 65% and HPV (-) 36%; p = 0.007; DFS HPV (+) 83% and HPV (-) 43%; p = 0.001). There was a statistically significant interaction effect between HPV status and PIK3CA mutation regarding DFS (Interaction test: p = 0.026). In HPV (+) patients, PIK3CA wild-type is associated with a significant 4.64 times increase in the hazard of recurrence or death (HR = 4.64; 95% CI 1.02-20.99; p = 0.047). Overall, PIK3CA gene mutations are present in a large number of patients and may help define patient subsets who can benefit from therapies targeting the PI3K pathway. The systematic assessment of PIK3CA gene mutations in HNSCC patients will require further methodological standardisation.

Paragangliomas da Cabeça e Pescoço: A Experiência de um Centro Oncológico do Sul da Europa.

INTRODUCTION: Paragangliomas are usually benign slow-growing tumors, but they are locally invasive and can cause significant morbidity. The aim of this study was to characterize the presenting symptoms, secretory status, genetics, imaging features, treatment modalities, post-treatment complications and survival of patients with head and neck paragangliomas treated at a single institution. MATERIAL AND METHODS: We retrospectively reviewed the clinical records of patients managed at our center between 1997 and 2020. RESULTS: Seventy-three patients were included in the study, encompassing 89 head and neck paragangliomas. Forty-eight patients (65.8%) were female and 15 (20.5%) had multiple tumor sites (including 10 patients with multicentric benign paragangliomas and five with disseminated malignant disease). Regarding location, our series encompassed 40 temporal bone paragangliomas (44.9%), 24 carotid body paragangliomas (27%), 22 vagal paragangliomas (24.7%), two laryngeal paragangliomas (2.2%) and one sinonasal paraganglioma (1.1%). Excessive catecholamine secretion was detected in 11 patients (15.1%). Sixty-four patients (87.7%) underwent genetic testing. Of those, 24 (37.5%) exhibited pathogenic succinate dehydrogenase complex germline mutations. Regarding patients who presented with untreated disease, 45 patients (66.2%), encompassing 55 tumors, underwent surgery as primary treatment modality, 20 (29.4%; 23 tumors) were initially treated with radiotherapy and three patients (4.4%, encompassing three solitary tumors) were kept solely under watchful waiting. Five-year overall survival was 94.9% and disease-free survival was 31.9%. CONCLUSION: Head and neck paragangliomas are rare, slow-growing but locally aggressive tumors resulting in high morbidity but low mortality rates.

Introdução: Os paragangliomas apresentam frequentemente um comportamento benigno e um crescimento indolente. Apesar disso, são localmente invasivos, podendo causar morbilidade significativa. O objetivo deste trabalho foi descrever as manifestações clínicas, atividade secretora, estudos genéticos e imagiológicos, modalidades terapêuticas, complicações e sobrevivência dos doentes com paragangliomas da cabeça e pescoço. Material e Métodos: Estudo retrospetivo dos doentes com paragangliomas da cabeça e pescoço observados num centro hospitalar terciário entre 1997 e 2020. Resultados: Foram incluídos no estudo 73 doentes, englobando 89 paragangliomas. Quarenta e oito doentes (65,8%) eram do sexo feminino e 15 (20,5%) apresentavam múltiplos focos tumorais (10 por multicentricidade e cinco por doença maligna disseminada). Foram incluídos 40 paragangliomas do osso temporal (44,9%), 24 tumores do corpo carotídeo (27%), 22 vagais (24,7%), dois laríngeos (2,2%) e um nasossinusal (1,1%). A secreção excessiva de catecolaminas foi detetada em 11 doentes (15,1%). Sessenta e quatro doentes (87,7%) foram alvo de teste genético. Desses, 24 (37,5%) exibiram mutações patogénicas do complexo succinato desidrogenase. Dos doentes com doença primária, 45 (66,2%; 55 tumores) foram submetidos a tratamento cirúrgico, 20 (29,4%; 23 tumores) a radioterapia e três (4,4%) ficaram sob vigilância. Aos cinco anos, a sobrevida global foi de 94,9% e a sobrevida livre de doença foi de 31,9%. Conclusão: Os paragangliomas da cabeça e pescoço são tumores raros, de crescimento lento, mas localmente agressivos que resultam em elevadas taxas de morbilidade, mas baixas taxas de mortalidade.

Surgery versus radiotherapy: Long term outcomes of T1 glottic cancer.

AIM: The aim of this study was to compare the outcomes, patterns of failure and laryngeal preservation rates in patients with T1N0 glottic cancer treated with surgery or radiotherapy. MATERIALS/METHODS: Retrospective study of T1N0 glottic cancer patients treated in our institution between January 2007 and December 2017. Histologically proven squamous cell carcinoma patients, treated with upfront cordectomy/partial laryngectomy (S group) or radiotherapy (RT group) were included. Elective treatment of the neck was not permitted. Local failure (LF), disease-free survival (DFS), ultimate disease-free survival (UDFS), laryngectomy-free survival (LFS), disease-specific mortality (DSM) and overall survival (OS) were evaluated. RESULTS: Two hundred and one patients were eligible (172 S group, 29 RT group), with a median follow-up of 38.8 months. Overall, 33 (16%) patients had a recurrence, 30 (17%) in the S group and 3 (10%) in the RT group. Local failure was the predominant site of failure (28 S, 2 RT). Overall, of all those that were salvaged, 17 (8%) underwent total laryngectomy (15 S, 2 RT). There was no significant difference in the 5-year cumulative incidence of LF (20.8% S, 8.1% RT, p = 0.138), 5-y LFS (85.0% vs. 91.7%, p = 0.809), 5-y DFS (67.5% vs. 82.1%, p = 0.343), 5-y UDFS (82.5% vs. 90.3%, p = 0.647) and 5-y OS (84.5% vs. 90.3%, p = 0.892). Multivariate analysis showed no correlation between initial treatment and the analyzed outcomes. CONCLUSION: Primary surgery or radiotherapy were similar first line options, since they do not differ in all outcomes. Patients' and physician's preferences must be considered when choosing first treatment.

Improved long-term results of intensity-modulated radiotherapy for a non-endemic European nasopharyngeal carcinoma cohort: single-center retrospective study.

PURPOSE: Report our matured outcomes of European nasopharyngeal carcinoma (NPC) treatment from a non-endemic region in the IMRT era. METHODS: We reviewed 109 consecutive patients with biopsy proven NPC treated between 2009 and 2013. All received IMRT as per RTOG 0615. Toxicity was scored accordingly to CTCAE 4.03. Platinum-based chemotherapy was delivered following the Intergroup 0099. RESULTS: Median age of 53 years; 97% Caucasian; 74% male; 72% WHO grade III; 43% T1; 14% T2; 18% T3, 25% T4; 17% N0; 17% N1; 39% N2; 27% N3. Compliance to adjuvant chemotherapy was 88%. With a median follow up of 56 months, the 4-year local control was 90.2% (88.6% for T1; 100% for T2; 85% for T3; and 91.7% for T4), the 4-year distant metastases-free survival was 86% and an overall survival rate was 77%. Local control and survival were better in G3 (p < 0.001 and p = 0.032, respectively). Xerostomia was the most frequent late toxicity in 55% (n = 60). Hypothyroidism requiring hormonal reposition occurred in 15.5% (n = 17). From the 36 deaths, 20 were due to distant metastases, 3 grade 5 toxicity, 2 from local progression, 5 non-cancer deaths and unknown cause in the remaining 6. On multivariable analysis, age (p = 0.017), local recurrence and distant metastases were associated with death (p < 0.001, both). CONCLUSION: Our matured data from the IMRT era showed a major improvement from our 3D cohort series reaching excellent local and regional control, even in T4. Local recurrences, despite few, and distant metastases were correlated with the risk of death.

External auditory canal carcinoma: clinical characteristics and long-term treatment outcomes.

PURPOSE: Evidence-based treatment recommendations for external auditory canal (EAC) carcinoma are lacking in available literature. This study aims to evaluate the clinical characteristics and long-term outcomes of EAC carcinoma in a tertiary referral centre in a period of 15 years and identify independent prognostic factors. METHODS: Retrospective observational study enrolling all patients with primary EAC carcinoma who underwent primary surgical treatment at the Portuguese Institute of Oncology (Lisbon) between 2004 and 2018. Epidemiological, clinical, histopathological and surgical data were retrieved from clinical records and analysed. RESULTS: Twenty-seven patients were identified, with a median age of 77 years (range 29-92 years) and a slight female predominance (59.3%). Squamous cell carcinoma (55.6%) was the most common histological type, followed by basal cell carcinoma (40.7%) and ceruminous adenocarcinoma (3.7%). Pittsburgh tumour staging was distributed as early stage in 51.9% (I: 40.7%; II: 11.1%) and advanced stage in 48.1% (III: 29.6%; IV: 18.5%). Median follow-up period was 21 months (interquartile-range: 47). Four patients (14.8%) showed recurrence; recurrence rate was significantly higher in individuals aged < 60 years (p = 0.025) and with lymphovascular invasion (p = 0.049). Median overall survival was 88 months and estimated 2-year and 5-year overall survival rates were both 66%. Survival rates were higher in early stage patients (p = 0.021) and in those without facial palsy (p = 0.032). CONCLUSION: Based on the available evidence in this review, individuals aged < 60, facial nerve impairment, advanced stage lesions, presence of lymphovascular invasion and squamous cell carcinoma histology are all associated with poor outcome and may be considered when discussing optimal treatment strategies in patients with EAC carcinoma.

Diagnostic accuracy and utility of fine-needle aspiration cytology in therapeutic management of parotid gland tumours.

INTRODUCTION AND OBJECTIVES: The utility of fine-needle aspiration cytology (FNAC) in parotid tumours remains widely debated. This study aims to evaluate the accuracy of FNAC in diagnosing parotid tumours. MATERIALS AND METHODS: We performed a retrospective analysis of patients with tumour disease of the parotid gland treated at a Portuguese Oncology Institute, over a period of 25 years. The preoperative FNAC results were compared with the final histopathological diagnosis. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of FNAC for malignancy. Association between malignancy on histopathology and FNAC results were evaluated with the Chi-square test. RESULTS: The study sample consisted of 155 patients (77 males and 78 females) with a mean age of 56.6±17.0 years. In 27 cases (17.4%), the FNAC result was indeterminate. In this group of patients there was a higher proportion of malignancy on histology (48.1%) (X2; p<0.001). In the group with a conclusive result on FNAC, the sensitivity and specificity of FNAC for malignancy was 66.7% and 99.0%, respectively. PPV was 94.1% and NPV was 92.8%. CONCLUSIONS: A benign result on FNAC should be used with caution, due to its low sensitivity for malignancy. An indeterminate result on FNAC should raise suspicion for a malignant tumour.

Hypocalcemia in cancer patients: An exploratory study.

INTRODUCTION: Calcium has several physiological functions and when it registers abnormal serum levels those functions may be impacted with potentially severe consequences. There is much research on hypercalcemia in cancer patients, but there are no recent studies on the prevalence of hypocalcemia in those patients. However, there has been an evolution in oncology, namely, new drugs that may directly or indirectly result in hypocalcemia. The primary aim was to explore the association of hypocalcemia with the diverse types of cancer. The secondary aim was to study the influence that hypocalcemia might have on survival. METHODS: Review of the records of patients ≥18 years old, with total calcium <2.0 mmol/L measured in 2013 in a cancer center. RESULTS: Eight hundred twenty-nine patients were included. Four hundred thirty-nine (53%) were male. The median age was 63 years. The most frequent cancer diagnoses were hematological 196 (24%) and colorectal 111 (13%). Six hundred thirty-eight patients had measured serum albumin, with a median of 25.5 g/L (14-47). When corrected for albumin level, calcium was in the normal range in 210 (33%) cases. The median survival of patients with corrected calcium lower than normal was 479 days (95% confidence interval [CI]: 309-649) and that of patients with normal corrected calcium was 62 days (95% CI: 33-91), P < .001. In a multivariate analysis, age, primary cancer, and albumin were significantly associated with survival. CONCLUSION: Hypocalcemia is associated with several types of cancer. A low calcium level is not by itself a factor of a poor prognosis since other factors seem to be more important.

Surgery vs. primary radiotherapy in early-stage oropharyngeal cancer.

BACKGROUND: Early-stage oropharyngeal squamous cell carcinoma (OPSCC) can currently be treated by surgical resection or definitive radiotherapy (RT). The aim of this study is to review the outcomes of early-stage OPSCC submitted to surgery or primary RT. Preliminary results have shown similar overall survival (OS) and locoregional recurrence-free survival (LRFS). MATERIAL/METHODS: Retrospective study of patients with cT1-T2 cN0-N1 OPSCC, diagnosed between January 2009 and December 2014, treated with surgery or primary RT. RESULTS: 61 patients with cT1-T2 cN0-N1 OPSCC were included. Forty-two (69%) were submitted to surgical resection, of which 37 (88%) had adjuvant treatment (24 received RT and 13 chemoradiotherapy). Nineteen (31%) were treated with primary RT, and 3 of them had concurrent chemotherapy. RT was given with intensity-modulated radiation therapy (IMRT) (71%) or three-dimensional conformal radiation therapy (3D-CRT) (29%). At a median follow-up of 5.4 years, there were 3 tumor persistences, 5 local failures, 2 regional failures and no distant metastasis. The 3-year and 5-year OS were 77% and 71% in the RT group vs. 71% and 59% in the surgery group, respectively (HR 0.60, 95% CI 0.22-1.61; p = 0.30). The 3-year and 5-year LRFS were 71% and 64% in the RT group vs. 66% and 50% in the surgery group, respectively (HR 0.59, 95% CI 0.24-1.45; p = 0.24). Up to 34% had acute grade 3 toxicity and 11% had grade 4 osteoradionecrosis of the jaw. CONCLUSIONS: Longer follow-up still does not show a significant difference in OS and LRFS between both treatments. Because most patients submitted to surgery required adjuvant RT and since its side-effects were not negligible, further studies are warranted to better suit the first treatment for each patient and to prevent the need for adjuvant treatment and the risk of toxicity.

Immediate Reconstruction of Large Full-Thickness Segmental Anterior Maxillary Defect with Bone Transport.

Maxillary segmental defects are a reconstructive challenge particularly when the anterior arch is involved. Missing bone, mucosa, and teeth should be replaced; fistulae closure should be guaranteed by bone and mucosa continuity; stable functional occlusion should be achieved; and facial aesthetics restored. These defects resulting from tumor excisions, if left untreated, will cause additional problems related to interposed scar and collapse of lip and nose. Immediate reconstruction should avoid these problems and should be considered when safe tumor-free margins are obtained. This study describes the treatment of such a defect resulting from a myxoma excision, with trifocal distraction requiring only one additional surgery. Internal distractors were fixed bilaterally for transport of two segmental discs created by inverted L osteotomies at the same surgical time of tumor excision. A second surgery was performed after central contact between transport discs was achieved, for device removal and creation of a dynamic system to regenerate molding and compression-focus development. This was accomplished by internal fixation of one side and central fixation of a full-open distractor to act as compression device when reversely activated. Central perfect adaptation between transported segments and good-quality attached mucosa lining the alveolar crest were determinant to obtain a stable functional and aesthetic result.

Deprescription in Advanced Cancer Patients Referred to Palliative Care.

In palliative care, drugs are considered futile if they do not have a short-term benefit in symptom control or quality of life. The authors examined pharmacotherapy prescribed for patients referred to palliative care to identify futile drugs. This was a retrospective analysis of patients referred over 6 months, focusing on the prescription of gastric protectants, antidiabetic agents, bisphosphonates, anticoagulants, antidementia drugs, statins, and antihypertensive agents. The sample consisted of 448 patients. Gastric protectants were prescribed futilely in 50% of cases (125/248), statins in 97% (69/71), antihypertensive agents in 27% (42/155), antidiabetic drugs in 1% (1/70), bisphosphonates in 27% (4/15), and antidementia drugs in 100% (9/9). This study reveals that many patients with advanced cancer continue to be treated with inappropriate drugs and points to the need for medical training in palliative care, drawing attention to the need for therapeutic review at each medical visit.

Nasopharyngeal carcinoma: our experience.

The objectives of our study were to characterize nasopharyngeal carcinoma patients in the Portuguese Institute of Oncology Hospital in Lisbon (IPOLFG) and identify the main factors that interfere with patients survival rate. We performed a retrospective study involving 157 patients (65% male and 35% female) between the years 2000 and 2005, and a histological classification according to Health World Organization. We constructed a Kaplan-Meier survival curve for the studied patients and evaluated the significance of the different studied factors with a Pearson correlation study. With an average age of 53 years, most of the carcinomas were type III (58%), followed by type II (30%) and at last type I (8%). Fifty-one of carcinomas were in stage IV at time of diagnosis. Ninety-five patients (60%) had remission. Five-year actuarial survival rate of all patients was 65.1%. There was a significant difference (P = 0.033) in the actuarial survival rate of staged IV patients treated with adjuvant chemotherapy. Undifferentiated nasopharyngeal carcinoma is the most frequent type in our geographic area. Chemotherapy improves survival rate, mainly in late stages.