Zero-Time Kidney Histology Predicts Early Graft Function

Our purposes are to determine the impact of histological factors observed in zero-time biopsies on early post transplant kidney allograft function. We specifically want to compare the semi-quantitative Banff Classification of zero time biopsies with quantification of % cortical area fibrosis. Sixty three zero-time deceased donor allograft biopsies were retrospectively semiquantitatively scored using Banff classification. By adding the individual chronic parameters a Banff Chronic Sum (BCS) Score was generated. Percentage of cortical area Picro Sirius Red (%PSR) staining was assessed and calculated with a computer program. A negative linear regression between %PSR/ GFR at 3 year post-transplantation was established (Y=62.08 +-4.6412X; p=0.022). A significant negative correlation between arteriolar hyalinosis (rho=-0.375; p=0.005), chronic interstitial (rho=0.296; p=0.02) , chronic tubular ( rho=0.276; p=0.04) , chronic vascular (rho= -0.360;P=0.007), BCS (rho=-0.413; p=0.002) and GFR at 3 years were found. However, no correlation was found between % PSR, Ci, Ct or BCS. In multivariate linear regression the negative predictive factors of 3 years GFR were: BCS in histological model; donor kidney age, recipient age and black race in clinical model. The BCS seems a good and easy to perform tool, available to every pathologist, with significant predictive short-term value. The %PSR predicts short term kidney function in univariate study and involves extra-routine and expensive-time work. We think that %PSR must be regarded as a research instrument.

Clinical and Pathological Findings in Women with Fabry Disease

Introduction. Fabry disease is a rare metabolic disorder caused by the genetic deficiency of the lysosomal hydrolase alpha-galactosidase A, located on chromosome X. Females with the defective gene are more than carriers and can develop a wide range of symptoms. Nevertheless, disease symptoms generally occur later and are less severe in women than in men. The enzyme deficiency manifests as a glycosphingolipidosis with progressive accumulation of glycosphingolipids and deposit of inclusion bodies in lysosomes giving a myelinlike appearance. Patients and Methods. Records of renal biopsies performed on adults from 1st January 2008 to 31st August 2011, were retrospectively examined at the Renal Pathology Laboratory. We retrieved biopsies diagnosed with Fabry disease and reviewed clinical and laboratory data and pathology findings. Results. Four female patients with a mean age of 49.3±4.5 (44-55) years were identified. The mean proteinuria was 0.75±0.3 g/24h (0.4-1.2) and estimated glomerular filtration rate (CKD EPI equation) was 71±15.7 ml/min/1.73m2 (48-83). Three patients experienced extra-renal organ involvement (cerebrovascular, cardiac, dermatologic, ophthalmologic and thyroid) with distinct severity degrees. Leukocyte α-GAL A activity was below normal range in the four cases but plasma and urinary enzymatic activity was normal. Light microscopy showed predominant vacuolisation of the podocyte cytoplasm and darkly staining granular inclusions on paraffin and plastic-embedded semi-thin sections. Electron microscopy showed in three patients the characteristic myelin-like inclusions in the podocyte cytoplasm and also focal podocyte foot process effacement. In one case the inclusions were also present in parietal glomerular cells, endothelial cells of peritubular capillary and arterioles. Conclusion. Clinical signs and symptoms are varied and can be severe among heterozygous females with Fabry disease. Intracellular accumulation of glycosphingolipids is a characteristic histologic finding of Fabry nephropathy. Since this disease is a potentially treatable condition, its early identification is imperative. We should consider it in the differential diagnosis of any patient presenting with proteinuria and/or chronic kidney disease, especially if there is a family history of kidney disease.

Neuroendocrine Tumours of the Female Genital Tract: a Case-Based Imaging Review with Pathological Correlation

BACKGROUND: Both primary and secondary gynaecological neuroendocrine (NE) tumours are uncommon, and the literature is scarce concerning their imaging features. METHODS: This article reviews the epidemiological, clinical and imaging features with pathological correlation of gynaecological NE tumours. RESULTS: The clinical features of gynaecological NE tumours are non-specific and depend on the organ of origin and on the extension and aggressiveness of the disease. The imaging approach to these tumours is similar to that for other histological types and the Revised International Federation of Gynecology and Obstetrics (FIGO) Staging System also applies to NE tumours. Neuroendocrine tumours were recently divided into two groups: poorly differentiated neuroendocrine carcinomas (NECs) and well-differentiated neuroendocrine tumours (NETs). NECs include small cell carcinoma and large cell neuroendocrine carcinoma, while NETs account for typical and atypical carcinoids. Cervical small cell carcinoma and ovarian carcinoid are the most common gynaecological NE tumours. The former typically behaves aggressively; the latter usually behaves in a benign fashion and tends to be confined to the organ. CONCLUSION: While dealing with ovarian carcinoids, extra-ovarian extension, bilaterality and multinodularity raise the suspicion of metastatic disease. NE tumours of the endometrium and other gynaecological locations are very rare. TEACHING POINTS: • Primary or secondary neurondocrine (NE) tumours of the female genital tract are rare. • Cervical small cell carcinoma and ovarian carcinoids are the most common gynaecological NE tumours. • Cervical small cell carcinomas usually behave aggressively. • Ovarian carcinoids tend to behave in a benign fashion. • The imaging approach to gynaecological NE tumours and other histological types is similar.

Disruption of Urate Transport in Familial Renal Glucosuria and Report on SGLT2 Expression in Normal and Pathological Kidney

Familial renal glucosuria (FRG) is a rare co -dominantly inherited benign phenotype characterized by the presence of glucose in the urine. It is caused by mutations in the SLC5A2 gene that encodes SGLT2, a Na+ -glucose co -transporter. The purpose of our current work was twofold: to characterize the molecular and phenotype findings of an FRG cohort and, in addition, to detail the SGLT2 expression in the adult human kidney. The phenotype of FRG pedigrees was evaluated using direct sequencing for the identification of sequence variations in the SLC5A2 gene. The expression of SGLT2 in the adult human kidney was studied by immunofluorescence on kidney biopsy specimens. In the absence of renal biopsies from FRG individuals, and in order to evaluate the potential disruption of SGLT2 expression in a glucosuric nephropathy, we have selected cases of nucleoside analogues induced proximal tubular toxicity. We identified six novel SLC5A2 mutations in six FRG pedigrees and described the occurrence of hyperuricosuria associated with hypouricaemia in the two probands with the most severe phenotypes. Histopathological studies proved that SGLT2 is localized to the brush -border of the proximal tubular epithelia cell and that this normal pattern was found to be disrupted in cases of nucleoside analogues induced tubulopathy. We present six novel SLC5A2 mutations, further contributing to the allelic heterogeneity in FRG, and identified hyperuricosuria and hypouricaemia as part of the FRG phenotype. SGLT2 is localized to the brush -border of the proximal tubule in the adult human normal kidney, and aberrant expression of the co -transporter may underlie the glucosuria seen with the use of nucleoside analogues.

Psychosocial Morbidity and its Correlates in Cancer Patients of the Mediterranean Area: Findings from the Southern European Psycho-Oncology Study

BACKGROUND: A few and partial data are available on psychosocial morbidity among cancer patients in Mediterranean countries. As a part of a more general investigation (Southern European Psycho-Oncology Study-SEPOS), the rate of psychosocial morbidity and its correlation with clinical and cultural variables were examined in cancer patients in Italy, Portugal and Spain. METHODS: A convenience sample of cancer outpatients with good performance status and no cognitive impairment were approached. The Hospital Anxiety-Depression scale (HAD-S), the Mini-Mental Adjustment to Cancer scale (Mini-MAC), and the Cancer Worries Inventory (CWI) were used to measure psychological morbidity, coping strategies and concerns about illness. RESULTS: Of 277 patients, 34% had pathological scores ("borderline cases" plus "true cases") on HAD-S Anxiety and 24.9% on HAD-S Depression. Total psychiatric "caseness" was 28.5% and 16.6%, according to different HAD cut-offs (14 and 19, respectively). Significant relationships of HAD-S Anxiety, HAD-S Depression, HAD-S Total score, with Mini-MAC Hopeless and Anxious Preoccupation, and CWI score were found. No differences emerged between countries on psychosocial morbidity, while some differences emerged between the countries on coping mechanisms. Furthermore, Fatalism, Avoidance and marginally Hopeless were higher compared to studies carried out in English-speaking countries. LIMITATIONS: The relatively small sample size and the good performance status prevent us to generalize data on patients with different cancer sites and advanced phase of illness. CONCLUSIONS: One-third of the patients presented anxiety and depressive morbidity, with significant differences in characteristics of coping in Mediterranean countries in comparison with English-speaking countries.

Appendiceal Mucocele – Unexpected Diagnosis in a Gynecology Department

Appendiceal mucocele is a rare entity, occuring in < 1% among appendicectomies, with a female predominance 4/1 (F/M) and a mean age of more than 50 years. The preoperative diagnosis is difficult; in most cases, it´s an intraoperative finding. In such work, we describe the two clinical cases occurring in last 10 years in our Department. Case 1 - 56 years old, posmenopausal, referred to our Department (02/2004) because an asymptomatic right adnexal septated cystic image, 53x48mm, with hipovascularized septa and a vascularised capsule with low flow resistance (IR 0,57). CA 125 elevated (71,3 U/mL).Exploratory laparotomy: an ovary increased, with a gelatanious consistency and an appendicular enlargement. Extemporaneous examination: a pseudomixoma peritonei, associated with a mucinous appendicular and an ovary tumor. It was performed a radical surgery. The histo-pathological analysis showed a mucinous cystadenoma of the appendix with peritoneal mucinous dissemination involving the ovary. Expectant attitude since the surgery, without clinical and imaging signs of recurrence. Case 2- 62 years old posmenopausal and asymptomatic woman, with a large adnexal mass detected on routine pelvic ultrasound: heterogeneous, 94x84mm without vascularisation signs in its interior. CEA was elevated (41,47U/ml). Exploratory laparotomy (02/2010): enlarged appendix and macroscopically normal pelvic organs. An appendicectomy was performed. The histo-pathological analysis showed a 10cm mucinous cystadenoma of the appendix and signs of localized (visceral peritoneal surface) pseudomyxoma peritonei. Currently she’s clinically well, in an expectant attitude. Despite mucoceles of the appendix are rare, they should be considered in women presenting with abnormal quadrant masses.

Clinical Dilemma in the Treatment of a Patient with Microangiopathic Haemolytic Anaemia, Thrombocytopaenia and Severe Hypertension

While haemolytic uraemic syndrome in children is predominantly associated with Shiga toxin -producing Escherichia coli (typically 0157:H7), some cases occur without associated diarrhoea, or as the manifestation of an underlying disorder other than infection. Haemolytic uraemic syndrome is characterised by microangiopathic anaemia, thrombocytopaenia and renal failure, on occasion accompanied by severe hypertension. Malignant hypertension is a syndrome that sometimes exhibits the same laboratory abnormalities as haemolytic uraemic syndrome as it may share the same pathological findings: thrombotic microangiopathy. As clinical features of both entities overlap, the distinction between them can be very difficult. However, differentiation is essential for the treatment decision, since early plasma exchange dramatically reduces mortality in haemolytic uraemic syndrome not associated with diarrhoea. An increasing number of genetic causes of this pathology have been described and may be very useful in differentiating it from thrombotic microangiopathy due to other aetiologies. Despite advances in the understanding of the pathophysiology of haemolytic uraemic syndrome not associated with diarrhoea, the management often remains empirical. We describe a patient with simultaneous microangiopathic haemolytic anaemia, thrombocytopaenia and severe hypertension managed in the acute period of illness with plasma exchange.

Gravidez após Colocação de Banda Gástrica para Tratamento da Obesidade Mórbida

Obesity is known to have a negative impact on pregnancy outcome, as it is associated with an increase in the incidence of gestational diabetes, hypertension, preeclampsia, neural tube defects, macrosomia, and late fetal death. Gastric banding is considered an appropriate intervention for morbid obesity when other weight-loss measures are unsuccessful, and this treatment has been shown to be effective in causing a sustainable weight loss. Some women will become pregnant after bariatric surgery, and the nutritional and metabolic challenges brought by gastric banding may have a profound impact on maternal health and pregnancy outcome. The authors report the case of a 27 year old pregnant woman, with a past medical history of gastric banding surgery for morbid obesity. At 18 weeks of gestation, the patient started complaining of severe nausea and vomiting, The situation deteriorated three weeks later when she rapidly developed severe desnutrition, dehydration and early signs of liver and renal failure. Migration of the gastric band was diagnosed, and laparoscopy conducted to remove it. In the day following surgery the patient complained of absent fetal movements, and an intrauterine demise was diagnosed on ultrasound. Pathological examination of the fetus and placenta failed to reveal the cause of death, but no growth restriction was documented, suggesting the occurrence of an acute event.

Argyria. Case Report

A 70-year-old male rural worker was referred to our clinic with widespread grey pigmentation of the skin and nails. The condition had been asymptomatic for its entire duration (5 years). He reported past intranasal application of 10% Silver Vitellinate. A skin biopsy was performed and histology corroborated the clinical diagnosis of Argyria. This case represents a currently rare dermatological curiosity. Although silver colloids and salts have been withdrawn and/or banned by some drug surveillance agencies, they continue to be freely sold and unregulated as food supplements and as ingredients in alternative medicines, thereby risking the emergence of new cases of silver poisoning.

Carcinoma Oculto da Mama com Metástases Axilares. A Propósito de Dois Casos Clínicos

INTRODUÇÃO: O carcinoma oculto é uma entidade pouco frequente, que se define como a presença de metástases com tumor primário indetetável na altura da apresentação. O prognóstico da maioria dos casos de tumor oculto é reservado, no entanto, o desenvolvimento de técnicas imunohistoquímicas que permitem a caracterização do tumor, tornaram alguns subgrupos de tumor oculto potencialmente curáveis. A presença de adenopatias axilares é a forma de apresentação do cancro da mama em 0,3-1% das mulheres, sendo a origem mais provável a mama ipsilateral. CASO CLÍNICO: Os autores relatam dois casos clínicos de tumor oculto da mama: Caso 1: Doente de 57 anos, com antecedentes familiares de primeiro e segundo grau de cancro da mama, com estudo genético negativo. Recorreu à consulta por adenopatia axilar direita.Exame objetivo (EO), mamografia + ecografia mamária normais. Microbiópsia (MB) ganglionar:metástase de carcinoma compatível com origem na mama, recetores de estrogénios (RE) +, HER2 +, CK7 +, Ca125 +, CK20 (-). RMN mamária e PET não identificaram tumor primário. Procedeu-se a dissecção axilar: 10 gânglios sem metástases. Realizou terapêutica adjuvante com quimioterapia (QT) e imunoterapia (IT). Manteve follow-up regular com EO, RMN e mamografia alternadas até aos 4 anos sem alterações. Aos 4,5 anos detetou-se ao E.O. nódulo palpável na mama direita e nódulo axilar. Mamografia + ecografia: lesão sólida suspeita (R5) cuja caracterização histológicademonstrouCDIG3, recetores hormonais (-) (RH), HER2 3+, Ki67 >30%. A TC TAP e a cintigrafia óssea não revelaram alterações. Em reunião multidisciplinar de decisão terapêutica (RMDT) decidiu-serealizar mastectomia total direita + mastectomia profilática contralateral com reconstrução. Exame histológico:CDI G3 com 22mm,confirmando-se a caracterização imunohistoquímica, com invasão vascular e presença de 3 gânglios com metástase e extensão extracapsular (T2 N2). Realizou terapêutica adjuvante com QT + IT+ Radioterapia (RT) da parede torácica e ganglionar. Um ano após a mastectomia, a doente mantém-se em follow-up sem sinais de recidiva. Caso 2: Doente de 50 anos, com antecedentes familiares de primeiro grau de cancro da mama. Recorreu à consulta por nódulo da axila esquerda e nódulo da mama direita com 2 meses de evolução. EO: nódulo palpável da mama direita e duas adenopatias axilares à esquerda. Mamografia + eco: microcalcificações atípicas da mama esquerda (R5) ealterações benignas da mama direita (R2). Realizaram-se microbiópsia por estereotaxia e biópsia assistida por vácuo da mama esquerda e citologia aspirativa de agulha fina (CAAF) de nódulo da mama direita:sem alterações neoplásicas. A biópsia de adenopatia axilar revelou metástase ganglionar de carcinoma compatível com origem na mama, RH (-), GCDFP15 (-),HER2 3+ e CK7 +.A RM mamária revelou apenas lesões benignas. TC TAP, ecografia abdominal e cintigrafia óssea normais. PET: lesão localizada na axila esquerda, nos três níveis axilares. Por recusa da doente em realizar microbiópsias adicionais ou mastectomia radical modificada, optou-se por realizar dissecção axilar esquerda. Exame histológico: 7 em 14 gânglios com metástases, morfologia e estudo imunohistoquímico concordantes com o anterior. Em RMDT foi decidida terapêuticaadjuvante com RT, QT e IT que a doente se encontra no momento a realizar. DIAGNÓSTICOS DIFERENCIAIS/ DISCUSSÃO A presença de adenopatias axilares relaciona-se na maioria dos casos com processos benignos, mas naqueles em que se diagnostica uma neoplasia maligna, mais de 50% correspondem a carcinoma da mama. Outras neoplasias que se podem apresentar com metástases axilares são: linfoma, melanoma, sarcoma, tiróide, pulmão, estômago, ovário, útero. A avaliação diagnóstica deve incluir além do exame físico, a biópsia ganglionar (para exame histológico e caracterização imunohistoquímica), mamografia, ecografia mamária e ressonância magnética mamária, eventual TC toraco-abdominal, cintigrafia óssea nas mulheres sintomáticas, existindo controvérsia sobre autilidade da PET. CONCLUSÕES O tumor oculto representa um problema diagnóstico e um desafio terapêutico. O carcinoma da mama apresentando-se sob a forma de metástase axilar sem tumor primário identificável e sem doença à distância, considera-se um dos casos potencialmente curáveis, se for tratado de acordo com as guidelines para o estadio II do cancro da mama. A abordagem recomendada inclui dissecção axilar, de importância crucial pela informação prognóstica que guiará o restante tratamento e por ajudar no controlo local da doença. A terapêutica adequada da mama ipsilateral é controversa, e pode passar pela mastectomia radical modificada ou RT. Não existem até à data estudos randomizados comparando a mastectomia versus RT mamária e os estudos retrospetivos disponíveis não apresentam resultados consensuais. A decisão de RT da parede torácica pós-mastectomia e de terapêutica adjuvante deverá ser tomada tendo em conta as guidelines publicadas. BIBLIOGRAFIA 1- www.uptodate.com; Kaklamani, V., et al; “Axillary node metastases with occult primary breast cancer”; Mar 2012 2- Wang, J., et al; “Occult breast cancer presenting as metastatic adenocarcinoma of unknown primary: clinical presentation, immunohistochemistry, and molecular analysis”; Case Rep Oncol 2012;5:9-16 3- Takabatake, D.; “Two cases of occult breast cancer in which PET-CT was helpful in identifying primary tumors”; Breast Cancer (2008) 15:181-184 4- Kinoshita, S., et al.; “Metachronous secondary primary occult breast cancer initially presenting with metastases to the contralateral axillary lymph nodes: report of a case”; Breast Cancer (2010) 17:71-74 5- Bresser, J., et al; “Breast MRI in clinically and mammographically occult breast cancer presenting with an axillary metastasis: a systematic review”; EJSO 36 (2010) 114-119 6- Sharon, W., et al.; “Benefit of ultrasonography in the detection of clinically and mammographically occult breast cancer”; World J Surg (2008) 32:2593-2598 7- Masinghe, S.P., et al.; “Breast radiotherapy for occult breast cancer with axillary nodal metastases – does it reduce the local recurrence rate and increase overall survival?”; Clinical Oncology 23 (2011) 95-100 8- Altan, E., et al.; “Clinical and pathological characteristics of occult breast cancer and review of the literature”; J Buon 2011 Jul-Sep;16(3):434-6

Ambulatory Hysteroscopy Results Post-Menopause: Comparative Study Between Patients With and Without Metrorrhagia

Our objective was to compare the results of ambulatory hysteroscopy in postmenopausal women with and without uterine bleeding. A retrospective descriptive study was carried out on 236 women who were at least 2 years into the menopause, who were not undergoing hormone treatment and who had had abnormal pelvic ultrasound results. Of these women, 150 were asymptomatic and 86 reported haemorrhage. Diagnostic and operative outpatient hysteroscopy was performed between January 2002 and December 2003. There was no difference between the two groups regarding age of patients, age of menopause and presence of at least one of the risk factors for endometrial carcinoma evaluated, although obesity was more frequent in the symptomatic group. Abnormal ultrasound results for these women corresponded in the majority of cases to intracavitary disease, and the absence of organic endometrial pathology was 9.3% vs 11.3% in each group. The more frequent pathology was benign endometrial polyps (64% in bleeding patients and 84.7% in asymptomatic ones). Endometrial carcinoma was diagnosed in 23.3% of women with metrorrhagia and in 1.3% of asymptomatic women. We diagnosed 2.6% of malignancy inside polyps. Hysteroscopy results were confirmed by histology in 90.3% of cases. See and treat in one session was achieved in 91% of benign endometrial polyps. Ambulatory hysteroscopy has high sensitivity and specificity for intracavitary pathology and high tolerability and safety. See and treat in one session can be achieved in the majority of lesions with indication for excision. These results make us advise our menopausal patients with abnormal uterine bleeding to undergo diagnostic hysteroscopy complemented with biopsy.

Case Report of Malignant Endometrial Polyps

The aims of this retrospective review were to determine the frequency of malignant endometrial polyps diagnosed with ambulatory hysteroscopy in the Obstetrics/Gynaecology Department of HDE, Lisbon, between January 2001 and December 2005 and to characterize these cases according to risk factors, sonographic and endoscopic findings tumoral histology, and tumor stage.We found seven cases of malignant endometrial polyps in a total of 1333 polyps initially diagnosed: an incidence rate of 0. 53%. These seven patients had a mean age of 68 years (55–82 years), and all were postmenopausal, with five having one risk factor each for endometrial cancer. Metrorrhagia was present in six of the seven patients(85.7%). Ultrasonography was abnormal in all seven patients, with a mean endometrial thickness of 26 mm(range: 12–44 mm). The hysteroscopy images suggested malignancy in all cases. All except one patient had a single polyp. The polyps had volumes between 1.5 and 3 cm; two were removed completely and five were biopsed. The histological subtype was: mixed endometrioid/serous papillary or clear cell (2), adenocarcinoma with squamous differentiation (2), carcinosarcoma (2), and clear cell carcinoma (1). Malignancy inside polyps is rare, but diagnostic hysteroscopy with visual guided biopsies can identify these cases in the earlier stages. The risk factors are not different from those of other endometrial carcinomas, but the histological subtype seems to point to more aggressive cancers.

The Oncological and Functional Risks of the Organ Preservation Experimental Treatment Approach

We increasingly face conservative surgery for rectal cancer and even the so called ‘wait and see’ approach, as far as 10–20% patients can reach a complete pathological response at the time of surgery. But what can we say to our patients about risks? Standard surgery with mesorectal excision gives a <2% local recurrence with a post operative death rate of 2–8% (may reach 30% at 6 months in those over 85), but low AR has some deterioration in bowel function and in low cancer a permanent stoma may be required. Also a long-term impact on urinary and sexual function is possible. Distant metastasis rate seem to be identical in the standard and conservative approach. It is difficult to evaluate conservative approach because a not clear standardization of surgery for low rectal cancer. Rullier et al tried to clarify, and they found identical results for recurrence (5–9%), disease free survival (70%) at 5y for coloanal anastomosis and intersphinteric resection. Other series have found local recurrence higher than with standard approach and functional results may be worse and, in some situations, salvage therapy is compromised or has more complications. In this context, functional outcomes are very important but most studies are incomplete in measuring bowel function in the context of conservative approach. In 2005 Temple et al made a survey of 122/184 patient after sphinter preserving surgery and found a 96.9% of incomplete evacuation, 94.4% clustering, 93.2% food affecting frequency, 91.8% gas incontinence and proposed a systematic evaluation with a specific questionnaire. In which concerns ‘Wait and see’ approach for complete clinical responders, it was first advocated by Habr Gama for tumors up to 7cm, with a low locoregional failure of 4.6%, 5y overall survival 96%, 72% for disease free survival; one fifth of patients failed in the first year; a Dutch trial had identical results but others had worse recurrence rates; in other series 25% of patients could not be salvaged even with APR; 30% have subsequent metastatic disease what seems equal for ‘wait and see’ and operated patients. In a recent review Glynne Jones considers that all the evaluated ‘wait and see’ studies are heterogeneous in staging, inclusion criteria, design and follow up after chemoradiation and that there is the suggestion that patients who progress while under observation fare worse than those resected. He proposes long-term observational studies with more uniform inclusion criteria. We are now facing a moment where we may be more aggressive in early cancer and neoadjuvant treatment to be more conservative in the subsequent treatment but we need a better stratification of patients, better evaluation of results and more clear prognostic markers.