The ypT may better predict the efficacy of neoadjuvant chemoradiotherapy than tumor regression grade in locally advanced rectal cancer patients diagnosed ypT1-4N0.

PURPOSE: This study aimed to assess the impact of ypT stage and tumor regression grade (TRG) on the long-term prognosis of patients with locally advanced rectal cancer (LARC) stage ypT1-4N0 after neoadjuvant chemoradiotherapy (NCRT). METHODS: We retrospectively analyzed 585 patients with histologically diagnosed middle-low LARC (cT3-4 or cN + by pelvic MRI) from 2014 to 2019. All patients underwent NCRT, followed by total mesorectal excision. Disease-free survival (DFS) rates were compared among patients with different ypT stages and TRGs by Kaplan-Meier survival analysis. The chi-square test was used to analyze the relationship between clinicopathological or therapeutic factors and ypT stage. RESULTS: The median follow-up was 35.8 months (range 2.8-71.8 months). The 3-year DFS was 79.5%. A better 3-year DFS was achieved in patients with a pathologic complete response (94.0% vs. 74.3%, p < 0.001) and those in the ypT0-2 (86.5% vs. 66.6%, p < 0.001), ypN0 (85.0% vs. 60.2%, p < 0.001), and TRG0 + 1 (83.1% vs. 73.0%, p = 0.004) subgroups. A total of 309 patients (52.8%) achieved stage ypT1-4N0 after surgery. Among these patients, the ypT1-2N0 subgroup achieved a significantly higher 3-year DFS than the ypT3-4N0 subgroup (85.4% vs. 72.8%, p = 0.018); in contrast, the 3-year DFS did not significantly differ between the TRG1 and TRG2 + 3 subgroups (79.9% vs. 81.1%, p = 0.833). In the ypT1-2N0 or ypT3-4N0 subgroup, different TRG had no significant effect on failure patterns. CONCLUSIONS: For LARC patients with a ypT1-4N0 status after NCRT, ypT stage may be a more effective predictor of long-term prognosis than TRG.

Impact of neoadjuvant chemotherapy on surgical and pathological results of gastric cancer patients: A case-control study.

BACKGROUND AND OBJECTIVE: Neoadjuvant chemotherapy (NACT) followed by radical surgery represents a treatment option for patients with advanced gastric cancer (GC). This case-control study aimed to evaluate the clinicopathological characteristics and surgical outcomes of GC patients who received NACT, and its impact on survival. METHODS: We retrospectively reviewed all patients with GC who underwent gastrectomy. A total of 45 cases with NACT were matched with consecutive 45 patients who underwent upfront gastrectomy for the following characteristics: gender, age, gastrectomy type, lymphadenectomy extent, American Society of Anesthesiologists class, histological type, cT and cN. RESULTS: NACT group had smaller tumors (4.9 vs 6.8 cm P = .006), lower lymphatic invasion rate (40% vs 73.3%, P = .001), lower venous invasion rate (18% vs 46.7%, P = .003) and lower perineural invasion rate (35% vs 77.8%, P < .0001). The ypTNM stage was lower in patients treated with NACT (P < .001). The major postoperative complication (POC) rate was lower in NACT patients (6.7% vs 24.4%, P = .02), as was hospital length of stay (10.8 vs 17 days, P = .005). CONCLUSIONS: NACT allowed nodal and tumor downstaging. In addition, patients who underwent NACT had fewer POC and shorter length of hospital stay.

Lymph node regression after neoadjuvant chemotherapy: A predictor of survival in gastric cancer.

BACKGROUND AND OBJECTIVE: Neoadjuvant chemotherapy (nCMT) has been increasingly used in advanced gastric cancer (GC). However, the prognostic impact of tumor response remains unclear. This study aimed to evaluate if tumor response at the primary site and lymph nodes (LN) correlate with survival in GC patients after nCMT. METHODS: Patients with gastric adenocarcinoma treated with nCMT followed by gastrectomy were evaluated. Residual tumor was graded from 0% to 100%, defining two groups: poor (PR) and major response (MR). LN regression rate (LNRR) was determined based on tumor/fibrosis examination at each LN and a cutoff value established by receiver operating characteristic curve. RESULTS: Among 62 cases, 20 (32.2%) had MR and 42 (67.7%) PR. Smaller size, diffuse histology, lower ypT status and less advanced stage were associated with the MR group. Based on cutoff value of 57, 45.6% and 54.4% patients were classified as low-LNRR and high-LNRR. High-LNRR correlated with absence of venous, lymphatic and perineural invasion, and less advanced stage. Survival was equivalent between MR and PR (P = .956). High-LNRR had better disease-free survival (DFS) than low-LNRR (P < .001). In multivariate analysis, only LNRR associated with DFS. CONCLUSION: High-LNRR associates with DFS in GC treated with nCMT. Response at the primary site does not correlate with survival.

The association among HER2, MET and FOXP3 expression and tumor regression grading in gastric adenocarcinoma.

Although the introduction of the perioperative chemotherapy on the management of gastric cancer has improved patients survival, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Thus, this study evaluated the tumor regression grading (TRG) in a series of post-treatment gastric tumors and its associations with HER2, MET, and FOXP3 expression. Material of 54 gastric cancer samples was available for TRG evaluation and immunohistochemistry. We found that total and subtotal pathologic response were significantly associated to the intestinal subtype (p = 0.04) and that well-differentiated tumors were significantly correlated with total or partial response (p = 0.019). Although not associated with the TRG, FOXP3 expression in gastric tumors was associated to poorly differentiated tumors (p = 0.03), to the diffuse and mixed subtypes together (p = 0.04) and to the presence of vascular infiltration (p = 0.04), while HER2 overexpression was associated to better differentiated cases (p = 0.04) and to the absence of vascular infiltration (p = 0.02). MET expression, however, showed no association with the analyzed clinicopathological factors. This study highlights the role of tissue differentiation on pathological response to neoadjuvant chemotherapy in gastric cancer and shows no impact between FOXP3, HER2 and MET expression in terms of TRG.

Nanographene oxide-methylene blue as phototherapies platform for breast tumor ablation and metastasis prevention in a syngeneic orthotopic murine model.

BACKGROUND: In the photodynamic therapy (PDT), the photosensitizer absorbs light and transfers the energy of the excited state to the oxygen in the cell environment producing reactive oxygen species (ROS), that in its turn, may cause cell damage. In the photothermal therapy (PTT), light also is responsible for activating the photothermal agent, which converts the absorbed energy in heat. Graphene oxide is a carbon-based material that presents photothermal activity. Its physical properties allow the association with the photosensitizer methylene blue and consequently the production of ROS when submitted to light irradiation. Therefore, the association between nanographene oxide and methylene blue could represent a strategy to enhance therapeutic actions. In this work, we report the nanographene oxide-methylene blue platform (NanoGO-MB) used to promote tumor ablation in combination with photodynamic and photothermal therapies against a syngeneic orthotopic murine breast cancer model. RESULTS: In vitro, NanoGO-MB presented 50% of the reactive oxygen species production compared to the free MB after LED light irradiation, and a temperature increase of ~ 40 °C followed by laser irradiation. On cells, the ROS production by the nanoplatform displayed higher values in tumor than normal cells. In vivo assays demonstrated a synergistic effect obtained by the combined PDT/PTT therapies using NanoGO-MB, which promoted complete tumor ablation in 5/5 animals. Up to 30 days after the last treatment, there was no tumor regrowth compared with only PDT or PTT groups, which displayed tumoral bioluminescence 63-fold higher than the combined treatment group. Histological studies confirmed that the combined therapies were able to prevent tumor regrowth and liver, lung and spleen metastasis. In addition, low systemic toxicity was observed in pathologic examinations of liver, spleen, lungs, and kidneys. CONCLUSIONS: The treatment with combined PDT/PTT therapies using NanoGO-MB induced more toxicity on breast carcinoma cells than on normal cells. In vivo, the combined therapies promoted complete tumor ablation and metastasis prevention while only PDT or PTT were unable to stop tumor development. The results show the potential of NanoGO-MB in combination with the phototherapies in the treatment of the breast cancer and metastasis prevention.

Histopathological regression of gastric adenocarcinoma after neoadjuvant therapy: a critical review.

As the perioperative chemotherapy has been widely implemented on the management of gastric cancer patients, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Tumor histological response to preoperative therapy has been graded by various systems in order to categorize the amount of regressive changes induced by chemotherapy in relation to residual tumor. In this context, tumor regression grading (TRG) systems might provide important prognostic information as the variety of tumor response may imply on different clinical outcomes with impact in survival rates. Moreover, gastric cancer behavior varies enormously upon individual factors such as histological classification and tumor anatomic site of involvement that have been shown to affect the TRG interpretation. On the other hand, some studies have assessed the role of molecular markers as a predictor of tumor response to neoadjuvant chemotherapy in terms of TRG. Thus, the aim of this review is to evaluate how TRG has been interpreted in gastric cancer, discuss their clinical and prognostic relevance and also address the molecular markers involved in this process.

Can tumor regression grade influence survival outcome in ypT3 rectal cancer?

PURPOSE: Locally advanced rectal cancer (LARC) patients achieving ypT3 status following neoadjuvant chemoradiation are considered to have poor response with minimal downstaging. However, residual cancer cell amounts vary in the subserosa/perirectal fat. Tumor regression grading (TRG) is an evaluation method based on the proportion of fibrosis and residual cancer cells. The aim of this study is to assess the influence of TRG in ypT3 rectal cancer patients who received neoadjuvant chemoradiation. METHODS: We retrospectively reviewed 325 LARC patients who received neoadjuvant chemoradiation and surgery. TRG scores were recorded by two independent pathologists. Among these patients, 143 were staged as ypT3. We analyzed TRG and other clinicopathological factors and their relationship with survival outcome including overall survival (OS) and disease-free survival (DFS). RESULTS: Among 143 ypT3 patients, 44 (30.8 %) were TRG1, 84 (58.7 %) were TRG2 and 15 (10.5 %) were TRG3. Seventy-nine (55.3 %) of these patients had metastatic lymph nodes. In univariate analysis, TRG was not associated with DFS (TRG2 vs TRG1, P = 0.852; TRG3 vs TRG1, P = 0.593) or OS (TRG2 vs TRG1, P = 0.977; TRG3 vs TRG1, P = 0.665). Palliative surgery (HR 3.845; 95 % CI 1.670-8.857; P = 0.002) and metastatic lymph nodes after surgery (HR 5.894; 95 % CI 1.142-3.48; P = 0.015) were significantly associated with decreased DFS, while palliative surgery was the only factor associated with worse OS (HR 6.011; 95 % CI 2.150-16.810; P = 0.001). Palliative surgery (HR 3.923; 95 % CI 1.696-9.073; P = 0.001) and metastatic lymph nodes (HR 2.011; 95 % CI 1.152-3.512; P = 0.014) also showed prognostic significance for DFS in multivariate analysis. CONCLUSIONS: Residual cancer cells evaluated by TRG score after neoadjuvant chemoradiation do not influence survival outcome in ypT3 rectal cancer patients. However, lymph node status is a significant prognostic factor in ypT3 patients.

Tumor growth characteristics of the Walker 256 AR tumor, a regressive variant of the rat Walker 256 A tumor

The present study aimed at characterizing the subcutaneous development of the Walker 256 (W256) AR tumor, a regressive variant of the rat W256 A tumor. Wistar rats were injected subcutaneously with 4x10(6) W256 A or W256 AR tumor cells. The development of tumors was evaluated daily by percutaneous measurements. None of the W256 A tumors (n=20) regressed, but 62 percent of the W256 AR tumor-bearing rats (n=21) underwent complete tumor regression within 35 days. Continuous growth of AR tumors was characterized by an increase of the tumor growth rate from day 12, which reached values above 1.0 g/day, and were significantly higher (p<0.05) than those of the regressive AR tumors. Immunosuppression by irradiation before subcutaneous injection of AR cells completely abrogated tumor regression and was associated with severe metastatic dissemination. Daily evaluation of the tumor growth rate enabled the discrimination, in advance, between continuously growing tumors and those that regressed later on.

O objetivo neste estudo foi caracterizar o desenvolvimento subcutâneo do tumor de Walker 256 (W256) AR, uma variante regressiva do tumor de W256 A de rato. Ratos Wistar foram injetados com 4x10(6) células tumorais de W256 A ou W256 AR. O desenvolvimento tumoral foi avaliado diariamente. Nenhum dos tumores W256 A (n=20) regrediu, mas 62 por cento dos ratos com tumor W256 AR apresentaram regressão completa dos tumores em até 35 dias. O crescimento contínuo dos tumores AR foi caracterizado pelo aumento da taxa de crescimento tumoral a partir do dia 12, alcançando valores maiores que 1,0g/dia, que foram significativamente superiores (p<0,05) aos valores de taxa de crescimento dos tumores regressivos AR. A imunossupressão por irradiação precedendo a injeção das células tumorais AR eliminou completamente a regressão tumoral e favoreceu disseminação metastática severa. Este estudo caracterizou o desenvolvimento do tumor de W256 AR em condições específicas, documentando a regressão espontânea deste tumor após a injeção subcutânea de altas doses de células tumorais em ratos Wistar. A avaliação diária da taxa de crescimento tumoral permite discriminar precocemente os tumores com crescimento continuo daqueles que são regressivos. A taxa de crescimento tumoral é um parâmetro útil para a avaliação dos animais experimentais, particularmente no período que precede a regressão dos tumores.

Regresión biológica espontánea de gliomas de las vías ópticas: un prototipo de tumores de San Peregrino / Spontaneous biological regression of the visual pathway gliomas: a Saint Pellegrino prototype tumors

San Peregrino Lanziosi es considerado el patrón de los pacientes con cáncer y por extensión, de aquellos con HIV/SIDA. Un episodio revelador tuvo lugar hacia 1325, cuando contaba cerca de sesenta años. Una gangrena dolorosa en su pierna derecha se tornó tan seria que su médico le propuso la amputación. En la noche previa a la cirugía, con gran dificultad Peregrino se arrastró hasta un Cristo crucificado localizado en una pared del cuarto y allí, suplicó a Jesús que le curara. Mientras se encontraba medio dormido vio al Señor tocar su pierna mortificada la cual fue curada instantáneamente y en forma espontánea. Desde la ocurrencia del milagro, aquellos tumores que regresan biológicamente hasta desaparecer, son llamados tumores de San Peregrino. Los gliomas de las vías visuales son tumores multifacéticos. Considerados como gliomas pilocíticos benignos juveniles, en algunos casos pueden mostrar progresión invadiendo estructuras de cercanía y causando pérdida visual. En otros permanecen estables por muchos años, y en una cantidad no determinada, aún exhiben regresión biológica espontánea con mejoría de los síntomas. El fenómeno de la regresión espontánea de tumores benignos y malignos está bien documentada en la literatura y comúnmente se atribuye a la inducción de apoptosis o la activación del sistema inmune. Es de crucial importancia el que este fenómeno sea tomado en consideración siempre que se evalúen los resultados de algún tratamiento (resección quirúrgica, radiación o quimioterapia). Apoyado en una secuencia de neuroimágenes, el autor comunica tres de tales casos, ninguno de ellos era portador de una neurofibromatosis tipo 1 (NF-1)

Saint Pellegrino Lanziosi is considered the patron of patients with cancer, and by extension of those with HIV infection/AIDS. A revealing episode took place around 1325, when he was almost sixty years old. A painful gangrene in his right leg became so serious that the friary physician had to amputate the sore limb. The night before the operation Pellegrino crawled with great difficulty to the large Crucifix located inside his room and there he besought Jesus to heal him. While he was half-asleep, he saw Jesus touching his sore leg and he was instantly and spontaneously healed. Since the occurrence of this miracle, tumors that biologically recede until they disappear are known as Saint Pellegrino tumors. Visual pathway gliomas are multifaceted tumors. Although they are considered as benign juvenile pilocytic gliomas, in some cases they may progress, invading neighboring structures and causing loss of vision. In other cases, they remain stable for years, and may even shrink, showing spontaneous biological regression with improvement of related symptoms. The phenomenon of spontaneous regression of benign and malignant tumors is well documented in the literature and is commonly attributed to the induction of apoptosis or the activation of the immune system. It is crucially important that this phenomenon be taken into consideration whenever the results of therapy (surgical resection, radiation, and chemotherapy) are being evaluated. Supported by a sequence of neuroimages, the author communicates three of these cases. None of them were carriers of neurofibromatosis type 1 (NF-1)

Apoptose no tumor venéreo transmissível canino: características morfológicas e evidenciação bioquímica

Fragments of canine transmissible venereal tumors, from natural cases and genital localization, were obtained from five adult male mongrel dogs. Imprints of the tumors were fixed, stained by Giemsa and submitted to cytological analysis to confirm the diagnosis. Representative samples of the tumoral tissue were fixed, embedded in paraffin and processed routinely for microscopic examination. Sections were stained with hematoxylin - eosin and Shorr. Another set of fragments was packed and maintained in dry ice, until DNA could be extracted for agarose gel electrophoresis. Cytological and histological results confirmed the diagnosis of the neoplasia and showed characteristic cellular and tissular patterns, with well-defined clear vacuoles in the cytoplasm. Shorr stained sections showed several shrunken cells, with cytoplasmic acidophilia, chromatin condensation, besides nuclear and cellular fragmentation, typical of apoptosis. Shorr was better than hematoxylin - eosin to distinguish apoptotic cells. Agarose gel electrophoresis of DNA showed the internucleosomal fragmentation of the genome, which was recognized as the classic "ladder pattern". Apoptosis does occur in the natural evolution of canine transmissible venereal tumor.

Fragmentos de tumor venéreo transmissível canino (TVTC) de ocorrência natural, com localização genital, foram obtidos de cinco animais, machos, adultos, sem raça definida. "Imprints" da superfície de corte em lâmina de microscopia foram fixadas em metanol, coradas pelo Giemsa e submetidas à avaliação citológica. Os fragmentos foram fixados e processados rotineiramente para inclusão em parafina e coloração com HE e Shorr, para confirmação histológica do tumor e identificação da apoptose. Outros fragmentos foram envolvidos com papel alumínio e acondicionados dentro de frascos de vidro em gelo seco, para serem processados no mesmo dia, visando à extração de DNA e eletroforese em gel de agarose. Análises cito e histológica do TVTC mostraram a distribuição e o padrão celular e tecidual característicos dessa neoplasia, sobressaindo-se a presença de vacúolos claros, bem definidos no citoplasma à análise citológica. Pela coloração com Shorr pôde-se identificar células retraídas, com aumento da acidofilia citoplasmática e condensação da cromatina nuclear, às vezes com fragmentação do núcleo e das células, caracterizando apoptose. A coloração pelo Shorr mostrou ser mais eficiente na distinção de células apoptóticas do que a coloração por HE. A eletroforese de DNA em gel de agarose demonstrou a fragmentação internucleossômica do genoma, que pôde ser reconhecida pelo clássico "padrão em escada".