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Breast cancer has become the malignant tumor with the highest incidence rate among women, of which human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for about 15%-20%. With the development of anti HER2 targeted drugs, the survival and prognosis of HER2 positive breast cancer has significantly benefited. About 45%-55% of breast cancer patients have low HER2 expression, and these patients usually do not receive anti HER2 treatment. However, there is a significant difference between the biological behavior and prognosis of breast cancer with low HER2 expression and breast cancer with zero HER2 expression. It is helpful to differentiate and adopt corresponding treatment strategies to improve the prognosis of patients. At present, there have been many advances in targeted therapy of breast cancer with low HER2 expression, which provides a useful reference for precision treatment of breast cancer with low HER2 expression.
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<p><b>OBJECTIVE</b>To explore the feasibility and clinical significance of precision low inferior mesenteric artery (IMA) ligation with the left colonic artery (LCA) preservation and root lymph node dissection in laparoscopic radical resection for rectal cancer, according to the inferior mesenteric artery (IMA) types.</p><p><b>METHODS</b>One Hundred and fore cases of rectal cancer patients who underwent laparoscopic resection in The Sixth Affiliated Hospital of Sun Yat-sen University from October 2015 to June 2016 were selected and divided into study group and control group according to different surgical methods. The study group (52 cases) accepted precision low IMA ligation with the LCA preservation and root lymph node (No.253) dissection, according to the IMA types and length examined by preoperative computed tomography angiography (CTA) reconstruction. The control group (52 cases) accepted the traditional high IMA ligation. The perioperative efficacy indexes and postoperative recovery situation of the two groups were compared.</p><p><b>RESULTS</b>The IMA types, IMA length and preoperative clinical stages were not significantly different between the two groups (all P>0.05). The surgery was completed smoothly for patients in both groups, with no conversion to open surgery. But two patients in the study group underwent left colonic artery ligation for intra-operative need. There were no significant differences in the operative time, intra-operative blood lose, the rate of protective ileostomy and post-operative pathological stages between the two groups (all P>0.05). More total lymph nodes [(24.9±5.7) vs. (16.9±4.2), P=0.001] and No.253 lymph nodes [(2.4±1.1) vs. (1.5±0.8), P=0.001] were harvested in study group as compared to control group. However, the positive rate of total harvested lymph nodes and No.253 lymph nodes between the two groups were not significantly different (P>0.05). There were no significant differences between the two groups in postoperative first anal exhaust time, postoperative hospital stay, total volume of postoperative intraperitoneal drainage, postoperative abdominal drainage tube retention time, postoperative anal drainage tube retention time and postoperative catheter retention time (All P>0.05). There were 2 cases of postoperative dysuria and 1 case of anastomotic bleeding in study group. There were 3 cases of postoperative dysuria and 2 cases of anastomotic leak in control group. Less postoperative complications (5.8% vs. 9.6%, P<0.05) in study group as compared to control group. There was no rehospitalization or death case in two groups within 30 days after operation.</p><p><b>CONCLUSIONS</b>In the laparoscopic radical resection of rectal cancer, preserving LCA and cleaning the root lymph nodes according to IMA types, which could increase the number of harvested lymph nodes and reduce the postoperative complications was safe and effective.</p>
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Liver metastasis is the most common cause of death for patients with colorectal cancer.Surgical resection is the first choice for colorectal cancer liver metastasis (CRLMs),but only 10％-25％ of them are resectable.Patients with unresectable CRLMs are usually treated with systemic chemotherapy and/or local ablative therapies as alternative options.The safety and efficiency of thermal ablation therapies have been improved in recent years.The 5-year survival rate of patients underwent thermal ablation is higher than that of patients underwent chemotherapy for treating CRLMs.A consensus for thermal ablation of colorectal liver metastasis was provided by international experts panel on 2013.The recommendations and indications of thermal ablation for CRLMs were considered and documented according to the literature review based on radiofrequency ablation with long-term follow-up.The main content of the consensus from international experts for thermal ablation of colorectal liver metastasis were reviewed in this article.
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<p><b>OBJECTIVE</b>To study the impact of neoadjuvant radiochemotherapy on erectile and urinary functions in mid-low rectal cancer patients.</p><p><b>METHODS</b>Seventy mid-low rectal cancer patients from January 2012 to May 2013 in The Sixth Affiliated Hospital, Sun Yat-sen University were prospectively enrolled. According to tumor staging and patient decision, patients received neoadjuvant radiochemotherapy(50 Grays administered over a six-week period and four cycles of concomitant mFOLFOX6 chemotherapy followed by operation (study group) or surgery alone(control group). Dropouts, loss to follow up and relapse during follow-up were removed from the analysis. A total of 30 patients stayed in study group and 29 patients in control group. To assess erectile and urination functions, the five-item version of the international index of erectile function (IIEF-5) and the international prostate symptom score (IPSS) questionnaires were used before therapy and 12 months after surgery.</p><p><b>RESULTS</b>In both study and control groups, total IIEF-5 score was decreased significantly at postoperative 12-month compared to initial assessment(P<0.01). Compared with control group, IIEF-5 score change was significantly higher in study group (9.6 ± 6.1 vs. 5.3 ± 5.3; P<0.01). Total IPSS score in both groups was increased significantly at postoperative 12-month compared to initial assessment(P<0.05). No significant difference was found in IPSS score change between the two groups (3.0 ± 3.4 vs. 1.5 ± 3.0, P>0.05). Univariate analysis on study group showed that age, tumor location and maximal diameter were associated with erectile dysfunction. Age was associated with urination dysfunction (all P<0.05).</p><p><b>CONCLUSION</b>Neoadjuvant radiochemotherapy has significant impact on erectile dysfunction after surgery in mid-low rectal cancer patients.</p>
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Humans , Male , Chemoradiotherapy , Erectile Dysfunction , Neoadjuvant Therapy , Neoplasm Staging , Prospective Studies , Rectal Neoplasms , Surveys and Questionnaires , Urinary IncontinenceABSTRACT
<p><b>OBJECTIVE</b>To evaluate the influences of inferior mesenteric artery (IMA) types and Riolan artery arcade absence on the incidence of anastomotic leakage(AL) after laparoscopic resection of rectal cancer.</p><p><b>METHODS</b>Clinical data of 116 local advanced rectal cancer patients who underwent laparoscopic resection in The Sixth Affiliated Hospital of Sun Yat-sen University from January 2012 to December 2014 were analyzed retrospectively. IMA and Riolan artery arcade were examined by preoperative computed tomography angiography (CTA) reconstruction. The influences of IMA type, Riolan artery arcade absence and ligation site (high or low) on AL were analyzed by Logistic regression.</p><p><b>RESULTS</b>The proportion of IMA types(I(-IIII() was 57.8%(67/116), 10.3%(12/116), 31.0%(36/116) and 0.9%(1/116), respectively. Riolan artery arcade absence was found in 60.3%(70/116). Eight (6.9%) patients suffered from AL. IMA type III( had significantly higher AL incidence as compared to other IMA types [19.4%(7/36) vs. 1.2%(1/80), P=0.001]. Meanwhile, patients with Riolan artery arcade absence also had significantly higher AL incidence[11.4%(8/70) vs. 0.0%(0/46), P=0.030]. However, the difference in AL incidence between high and Low IMA ligation was not statistically significant [8.0%(7/87) vs. 3.4%(1/29), P=0.531]. Seven of these 8 AL patients were found in IMA type III( with Riolan artery arcade absence and high ligation. Multivariate analysis showed that IMA type III( (P=0.001) and Riolan artery arcade absence (P=0.002) were independent risk factors of AL.</p><p><b>CONCLUSIONS</b>IMA type III( with Riolan artery arcade absence increases AL incidence significantly in laparoscopic resection of rectal cancer. IMA type and Riolan aretry arcade absence or not contribute to the selection of IMA ligation site in the operation. For the colorectal cancer patients with IMA type III( and Riolan artery arcade absence, selective low IMA ligation with root lymph node dissection should be recommended.</p>
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Adult , Female , Humans , Male , Middle Aged , Anastomotic Leak , Arteries , Colorectal Neoplasms , General Surgery , Incidence , Laparoscopy , Ligation , Lymph Node Excision , Lymphatic Metastasis , Mesenteric Artery, Inferior , Rectal Neoplasms , General Surgery , Retrospective StudiesABSTRACT
<p><b>OBJECTIVE</b>To compare two different routes of totally implantable venous access ports (TIVPs) from the upper arm vein and the subclavian vein in terms of complications for patients with gastrointestinal malignancy.</p><p><b>METHODS</b>Patients who underwent implantations of TIVPs from September 2013 to January 2015 were retrospectively evaluated. The outcome measurements were rates and types of postprocedural early-stage and long-term complications.</p><p><b>RESULTS</b>A total of 208 patients(upper arm vein group, 86; subclavian vein group, 122) were included in this study. All TIVPs were implanted successfully. The rate of catheter displacement was higher in upper arm vein group(14.0% vs 5.7%, P=0.04), while other postprocedural early-stage complications had no significant difference between the two groups. The occurrence of transfusion obstacle and rates of overall postprocedural long-term complications were significantly lower in upper arm vein group than that in subclavian vein group(1.2% vs. 9.8%, P=0.02; 7.0% vs. 27.0%, P=0.01, respectively).</p><p><b>CONCLUSION</b>Compared with subclavian vein group, upper arm vein group has lower postprocedural long-term complication rates and is recommended as a safe and comfortable choice for port implantation.</p>
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Objective To investigate the expression of astrocyte elevated gene 1(AEG-1) in non-small cell lung cancer(NSCLC) and its clinicalpathological significance .Methods The expression of AEG-1 in NSCLC tissues and adjacent normal lung tissues was detected by RT-PCR and Western blot .The expression of AEG-1 in 87 NSCLC samples and 54 non-cancerous lung tissues was ex-amined with immunohistochemistry .Results RT-PCR and Western blot indicated that AEG-1 was more expressed in NSCLC tis-sues compared with adjacent normal lung tissues .The positive rate of AEG-1 in NSCLC tissues was 52 .9% ,which was significantly higher than that in non-cancerous lung tissues .The difference between the two groups was significant (P=0 .007) .Relevance was analyzed between the expression of AEG-1 and clinicalpathological characteristic .The expression of AEG-1 was positively correlated with T stage and N stage(P<0 .05) .Conclusion AEG-1 was specifically up-regulated in NSCLC tissues compared with non-can-cerous lung tissues ,suggesting that AEG-1 may play an important role in tumor development and progression ,and could be identi-fied as a biomarker for diagnosis of NSCLC .
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<p><b>OBJECTIVE</b>To evaluate the erectile function of male patients treated by neoadjuvant radiochemotherapy and neoadjuvant chemotherapy alone for mid-low rectal cancer.</p><p><b>METHODS</b>The clinical data of 66 patients with rectal cancer from March 2011 to March 2013 were prospectively analyzed. Of all the patients, 56 cases were finally included in the study and were randomly allocated to two groups. Thirty patients were treated by neoadjuvant radiochemotherapy followed by surgery (RCS group), and 26 were treated by neoadjuvant chemotherapy followed by surgery (NCS group). The five-item version of the international index of erectile function (IIEF-5) questionnaire were used to determine erectile function before therapy and at least 12 months after surgery. The impacts of age, location, size of tumor, and body mass index on erectile function were analyzed.</p><p><b>RESULTS</b>Total score was decreased significantly at follow-up compared to initial assessment in both RCS and NCS groups (23.4 ± 1.30 vs. 11.7 ± 5.8, t = 10.748, P < 0.01; 23.1 ± 1.3 vs. 15.2 ± 6.7, t = 5.910, P < 0.01, respectively). Score difference was statistically higher in RCS group compared with NCS group (11.7 ± 5.6 vs. 8.0 ± 6.0, t = 2.394, P = 0.020). In terms of tumor location for RCS group, difference was statistically higher in the patients with low rectal cancer compared with those with middle rectal cancer (14.5 ± 3.5 vs. 9.5 ± 6.0, t = 2.894, P = 0.008).</p><p><b>CONCLUSIONS</b>The erectile functions of patients treated by neoadjuvant radiochemotherapy followed by surgery are more affected than that of patients treated by neoadjuvant chemotherapy followed by surgery in mid-low rectal cancer. Also low rectal cancer are significantly associated with erectile dysfunction in the patients treated by neoadjuvant radiochemotherapy followed by surgery.</p>
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Humans , Male , Chemoradiotherapy , Follow-Up Studies , Neoadjuvant Therapy , Penile Erection , Physiology , Prospective Studies , Rectal Neoplasms , General Surgery , Therapeutics , Treatment OutcomeABSTRACT
ObjectiveTo observe the clinical efficacy of plasmapheresis plus acupoint injection in treating severe hepatitis. MethodSixty patients with severe hepatitis were randomized into a treatment group of 31 cases and a control group of29 cases. The two groups both received plasmapheresis in addition to the comprehensive internal medicine treatment, while thetreatment group simultaneously received acupoint injection withHuang Qi(Radix Astragali) at Zusanli (ST 36). After the intervention, the symptoms, signs, liver function, blood coagulation, and blood ammonia were observed in the two groups.ResultAfter the intervention, the symptoms, signs, and biochemical indexes were significantly improved,and theindexes in the treatment group were significantly different from that in the control group (P<0.05,P<0.01), and the total effective rate of the treatment group was markedly higher than that of the control group (P<0.05).ConclusionPlasmapheresis plus acupoint injection can effectively improve the short-term condition of the patients, enhance therapeutic efficacy, with fewer adverse reactions.
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Objective To investigate the influence of plasma exchange with acupuncture point injection therapy on liver fibrosis indexes in patients with severe hepatitis. Methods Sixty patients with severe hepatitis were randomly divided into group A with 29 cases receiving plasma replacement and group B of 31 cases receiving astragalus injection at Zusanli point in addition to plasma replacement. Changes of liver fibrosis indexes including serum hyaluronic acid (HA), laminin (LN), collagenⅣ(Ⅳ-C), typeⅢpre-collagen (PCⅢ) were observed, which were compared with those from group C with 30 healthy subjects. Results Before treatment, there was no statistical significance in comparison of liver fibrosis index in group A and B (P>0.05), but all the indexes were higher than those in group C (P0.05). Conclusion Plasma exchange with astragalus injection at Zusanli point can effectively improve liver fibrosis indexes in patients with severe hepatitis and then improve the prognosis of patients.
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[Objective] To investigate the association between -31C/G polymorphism in the promoter of survivin gene and the susceptibility to sporadic colorectal cancer in southern Chinese population. [Methods] Survivin-31C/G genotypes were determined by polymerase chain reaction-restriction fragment length polymorpbism (PCR-RFLP) in 711 healthy controls and 702 CRC cases. [Results] The number of CRC patients carrying with CC genotype was much higher than those of controls (36.5 % vs. 26.12%, X~2=17.89, P<0.001). Compared with CC genotypes, CG, GG genotypes and G allele carriers had a significantly decreased risk of CRC, with the decrease being 0.61-fold (95% CI=0.46-0.81, P<0.001), 0.52-fold (95% CI=0.38-0.71, P<0.001) and 0.58-fold (95% CI=0.45-0.74, P<0.001), respectively. [Conclusion] Survivin gene -31C/G polymorphism is associated with sporadic CRC risk, the G variant genotypo is the independent protective factors against sporadic CRC in soutbem Chinese population.
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Objective To study cancer metastasis in mesorectum and ischiorectal loss in cases of ultra-low rectal cancer and evaluate the rationale of Miles procedure. Methods Whole-mount slice and tissue mieroarray technique were used to study the dissected specimen from 23 cases of uhra-low rectal cancer for metastatic lymph nodes. Result 415 lymph nodes were harvested in 23 mesorectum specimen, 169 and 59 lymph nodes were metastasic and micrometastasie respectively. 12 eases were diagnosed with metastasis, 4 cases were found to have micrometastasis. Metastatic lymph nodes in the lateral and anterior mesorectum were 29.0% (49/169) and 17.2% (29/169) respectively. There were 2 patients with metastasis and 1 with micrometsstssis in ischiorectal fossa lymph nodes, accounting for 13% patients. Conclusion Regional metastasis exists in ultra-low rectal cancer and its incidence varies in different location of mesorectum and ischiorectal fessa. The value of Miles procedure as the standard therapy for ultra-low rectal cancer should undergo an evaluation.
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Objective To explore disease-associated proteins in the serum of patients with inflammatory bowel disease by serum proteomic analysis combined with mixed sampling strategy. Methods The serum proteins from 8 healthy adults and 8 patients with inflammatory bowel disease who had been admitted to the Sixth Affiliated Hospital of Sun Yat-sen University from March 2007 to June 2008 were collected. Two-dimensional differential in-gel electrophoresis (2D-DIGE) was used to define patterns of protein expression after the serum proteins were cross-labeled with cariant CyDye. Proteins that showed differential expressions were analyzed by matrix-assisted laser dcsorption/ionization time of flight mass spectrometry. The 2D-DIGE images were analyzed using DeCyder V6.0 software, and the differences between the groups were analyzed by t-test. Results Maps of 2D-DIGE of patients with inflammatory bowel disease and healthy adults were obtained. Fifty-six spots of proteins with abnormal expression were detected in patients with inflammatory bowel disease, and 30 proteins were identified using mass spectrometry and database retrieval. The 30 proteins included haptoglobin, complement factor B, apelipoprotein A- Ⅱ precursor and GTPase K-ras. Conclusions Serum proteomic analysis combined with mixed sampling strategy can clearly detect the difference in the expression of serum proteins between patients with inflammatory bowel disease and healthy adults. The differentially expressed proteins may provide new biornarkers for investigating the biological behavior of inflammatory bowel disease.
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AIM: To investigate the effect of 5 - fluorouracil ( 5 - FU ) on the expression of the stem cell marker CD133 on colon cancer stem cells. METHODS:CD133 expression on several colon cancer cell lines was detected by flow cytometry. The CD133 positive cells from DLD1 cells were separated by the method of magnetic activated cell separation. Colony assay was used to measure self - renew ability and MTS assay was used to detect the sensitivity to 5 - FU after separation. After 5 - FU treatment, the change of CD133 mRNA level was measured by qPCR. RESULTS: CD133 expression on the surface of colon cacner cell lines DLD1, HT29, SW480, HCT116, Lovo, RKO was 30.20% , 82.00% , 0.34% , 91.80% , 85.30% , 0.28% respectively. DLD1 cells had two obvious populations according to CD133 expression. CD133 positive cells were separated from DLD1 cells, the positive purity was 87.21% ±5.33% and the negative purity was 84.30% ±4.65%. CD133 positive cells formed more colonies with limited dilution colony assay (46.33% ±4.44% vs 31.00% ±2.00% , P <0.05). CD133 positive cells were less sensitive to 5 - FU compared to CD133 negative cells(20% less, P <0.01). 5 - FU at concentration of 1 mg/L upregulated CD133 mRNA expression in both DLD1 and HT29 cells, the relative quantity was increased from 1 to 1.684 ±0.012(P <0.01 )and 30.702 ±0.280 to 49.379 ±0.460(P <0.01) in HT29 and DLD1, respectively. CONCLUSION: Compared to CD133 negative cells, CD133 positive cells show more ability to form colonies in vitro, and are less sensitive to 5 - FU. 5 - FU upregulats the mRNA expression of CD133, resulting in the CD133 colon cancer stem cells enrichment during 5 - FU treatment.
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AIM: To investigate the association between -31C/G polymorphism in the promoter of survivin gene and the susceptibility to sporadic colorectal cancer (CRC) in southern Chinese population. METHODS: survivin -31C/G genotypes were determined by PCR-RFLP in 711 healthy controls and 702 CRC cases. RESULTS: The number of CRC patients carrying with CC genotype was much higher than that of controls (36.5 % vs 26.2%,χ~2 =17.89,P<0.01). Compared to CC genotypes, CG, GG genotypes and G allele carriers had a significantly decreased risk of CRC, with the decrease being 0.61-fold (95% confidence interval=0.46-0.80, P<0.01), 0.52-fold (95% confidence interval=0.38-0.71,P<0.01) and 0.58-fold (95% confidence interval=0.45-0.74, P<0.01), respectively. CONCLUSION: survivin gene -31C/G polymorphism is associated with sporadic CRC risk, the G variant genotype is the independent protective factors against sporadic CRC in southern Chinese population.
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Objective To study the clinical pathological features,treatment and prognosis of umbilical metastases of intra abdominal malignancies (sister Mary Joseph nodule, SMJN). Methods From January 1980 to July 2003, 17 SMJN cases were admitted. The clinical features were reviewed. Results The diagnosis of SMJN was confirmed by pathology in all cases, including epithelial ovarian carcinoma in 6 cases, gastric adenocarcinoma in 6 cases,colon adenocarcinoma in 2 cases, and endometrial carcinoma, gallbladder carcinoma and undifferentiated adenocarcinoma without identifying primary site in one each. Mean survival、half year、one year and two year survival rate in 10 palliative excision cases was 13 5 months、60%、20% and 10%, which were significantly better than 8 25 months、14 3%、0% and 0% in 7 conservative therapy cases ( P
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Objective To analyze clinicopathological features of synchronous colorectal carcinoma. Methods Data of colorectal cancer patients admitted to our hospital from June 1994 to December 2003 were analyzed retrospectively. Patients were divided into multiple synchronous colorectal carcinoma group ( MCG) and single colorectal cancer group ( SCG). Clinicopathological features and prognosis were compared between the two groups. SPSS 10. 0 was used for data analysis. Results Of all colorectal cancer(CRC) patients,3. 2 % (39/1225) had multiple synchronous CRCs and 939 patients had sporadic single CRC. In MCG, two patients had hereditary nonpolyposis colorectal cancer ( HNPCC) syndrome. No significant differences were found between MCG and SCG with regard to demographic features, Dukes stage and differentiation of index CRC. More patients in MCG had metachronous CRC (x2 = 4. 545, P= 0.033) and colorectal polyps ( x2 = 12. 013, P = 0.001) compared with SCG. Forty-six percent of multiple synchronous CRCs located in right colon in MCG, which was higher than that in SCG ( x2 = 25. 757 ,P = 0. 0001). Malignancy in adenoma was the frequent event accompanying cancer in MCG. Five-year survival rate in MCG was 57% compared with 64% in SCG ( x2 =0.084, P = 0.772 ). Conclusion Patients with right colon cancer seem easily to have multiple synchronous CRCs and malignancy in adenoma is most frequently accompanying the cancer. For patients with multiple synchronous CRCs, the prognosis is equivalent to that of patients with SCG.
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ObjectiveTo evaluate the effect on postoperative urinary and sexual function of radical resection with pelvic autonomic nerve preservation for female rectal cancer patients.MethodsPostoperative sex and urination disorders were compared between groups of pelvic autonomic nerve preservation and conventional procedure in 120 female cases of middle-lower rectal carcinoma undergoing radical resection. ResultsThe venery decline、sexual climax slip、vagina wetness degree slip and the coition pain rate were 12.5%、10.5%、8.33%、4.15% in autonomic nerve preservation group and 54.1%、45.9%、41.7%、37.5% in control group, respectively(all P0.05).ConclusionPelvic autonomic nerve preservation is effective to reduce postoperative sex and urination disorders in female rectal cancer cases undergoing radical resection though it does not seem to benift cases receiving posterior pelvic exenteration.
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Objective To evaluate J-pouch coloanal anastomosis after low anterior resection for the middle and low rectal carcinoma. Methods From January 1998 to July 2002, 120 patients undergoing low anterior radical resection for the middle or low rectal carcinomas were divided into groups of coloanal anastomosis and that of 5 cm colonic J-pouch-anal anastomosis. WT5”HZResults These two groups were well matched for gender, age and histologic stage. There were no significant differences in operative time, hospital stay, complications, postoperative recurrence rate and postoperative survival time between the two groups as founded by an average follow-up of 18 months. The mean distance from the inferior edge of the tumor to the dentate line was (3 6?1 5) cm in the J-pouch group, significantly less than that in coloanal anastomosis group of (5 2?1 9) cm, ( P =0 000). Defecation frequency, urgency and incontinence were significantly improved at 3 months and 12 months after operation in the J-pouch group ( P 0 05). Conclusion J-pouch coloanal anastomosis after low anterior resection for the middle and low rectal carcinoma significantly improves the short-term bowel function after operation.
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Objective To investigate the lymph node metastases in gastric carcinoma and its clinical significance Methods The clinicopathological data of 608 patients with gastric carcinoma were analyzed retrospectively The total metastatic rate was calculated Binary logistic regression analysis was used to analyze the influence index of ten clinicopathological factors on the No 7～9 lymph node metastases Results The metastases rate (44 4%) of No 3 group lymph node was the highest seconded by No 15 group (43 2%) The overall lymph node metastases in No 7～9 group was 37 5% The depth of tumor invasion and the lymph node metastases in No 1～6 group were significantly correlated with lymph node metastases in the No 7～9 group ( P