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Pathologic changes related to CMF primary chemotherapy in breast cancer. Pathological evaluation of response predicts clinical outcome.

The pathologic changes associated to response to primary chemotherapy in a series of 303 operable breast cancers are evaluated and correlated to patients' follow-up (interval free of disease and survival). In our series, the incidence of microscopic changes related to chemotherapy is 43.9%. Tumor replacement by loose fibrosis is the most common pathologic event. In most cases, the intensity of fibrotic change is proportional to the degree of clinical-mammographic reduction of the tumor mass. However, some discrepancies exist in the sense of absence of microscopic changes in cases of well-documented mammographic reduction as well as in cases without clinical reduction but with large areas of chemotherapy-related fibrosis. The presence of pathologic response is significantly associated with better survival rate.

Adult↗

A combination of spastic paraparesis, polyneuropathy and adrenocortical insufficiency-a childhood form of adrenomyeloneuropathy.

This report describes a combination of spastic paraparesis and symmetrical sensory motor polyneuropathy with a pathological response to the ACTH test in the case of a 16 year-old boy and a borderline response to the ACTH test in the case of his 8-year-old sister. Another sister, aged 14, showed only a pathological response to ACTH testing, the neurological status being unremarkable. The EEG was normal in all three children examined. Visually evoked potentials were borderline in the case of the boy and normal in the case of the clinically involved sister. Although on examination by light microscopy the sural nerve proved to be normal, the clinical diagnosis of adrenomyeloneuropathy (AMN) in its juvenile form may be assumed, in view of the clinical symptoms and the evidence of adrenocortical insufficiency revealed by the ACTH test.

Adolescent↗

[Prospective phase II study of neoadjuvant radiochemotherapy in advanced operable carcinoma of the mouth cavity. 3-year outcome].

PURPOSE: The purpose of simultaneous chemoradiotherapy is to increase local-regional control and to decrease the incidence of distant metastases. Regimens containing cisplatin/5-FU chemotherapy are widely accepted as standard treatment in advanced head and neck cancer. Most studies reported promising response and survival data, but also severe mucosal toxicity. In recent years the newly developed drug Taxol demonstrated interesting activity in head and neck cancer as a single agent as well as in combination drug regimens. In the present outpatient phase II trial, we investigated the combination of Taxol/carboplatin with 40 Gy radiotherapy in a neoadjuvant setting of operable stage III/IV squamous cell carcinoma of the oral cavity and oropharynx. PATIENTS AND METHODS: Fifty-three patients were enrolled in this trial during the period from May 1998 to October 2000 and received five cycles weekly of Taxol (40 mg/m2) and carboplatin (AUC 1.5) with conventional radiotherapy (40 Gy). Within 3-4 weeks after chemoradiotherapy resection of the primary tumor and the regional neck nodes was performed. RESULTS: Fifty-two patients were evaluable for toxicity and response. Complete response was observed in 31 of 52 patients (CR 60%), and partial remission was seen in 21 of 52 patients (PR 40%). In 30 of 52 patients complete pathologic response (pCR 58%) was documented in the resection specimens. The 1-, 2-, and 3-year overall survival rate was calculated as 84%. CONCLUSION: Our present results demonstrated impressive clinical and pathological response rates of concurrent Taxol/carboplatin and radiotherapy as a preoperative treatment modality in advanced oral and oropharyngeal cancer.

Adult↗

Response-adapted surgical de-escalation following neoadjuvant immunotherapy in resectable mucosal HNSCC A systematic review and meta-analysis.

INTRODUCTION: Recent encouraging outcomes with neoadjuvant immune checkpoint inhibitors (ICIs) in mucosal head and neck squamous cell carcinoma (HNSCC) have generated interest in surgical de-escalation. However, the oncologic safety of response-adapted surgery (RAS) and its ability to achieve survival outcomes comparable to baseline-planned surgery (BPS) remain uncertain. METHODS: A systematic search of the PubMed, EMBASE, Cochrane Library, and the Clinical Trials Registry for studies of neoadjuvant ICIs, with or without chemotherapy, in resectable mucosal HNSCC, that explicitly report surgical extent, between 2020-2025 was performed. Two independent reviewers extracted data following PRISMA guidelines. Main outcomes included major pathologic response (MPR), pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS). Study-level proportions were pooled by random effects models. Heterogeneity was assessed by the I2 statistic. RESULTS: The comparative analysis consisted of 4 RAS studies (involving 202 patients) and 11 BPS studies (403 patients). The pooled overall EFS was 83.3% (76.9-88.2) for the former and 82% (75.2-87.2) for the latter (P=.751), and the respective pooled OS was 92.3% (87.5-95.3) and 91.4% (80.3-96.5) (P=.839). The pooled pCR rate was 41.7% (95% CI 5.4-48.4; I2=.0) for RAS and 19.8% (95%CI 13.3-29.6; I2=.62) for BPS (P=.001), while the MPR was not significantly different (59.6%, versus 48.5%, P=.245). RAS was associated with greater organ preservation and reduced need for mandibulectomy and free-flap reconstruction. CONCLUSIONS: RAS following neoadjuvant ICIs in mucosal HNSCC may enable surgical de-escalation with preserved oncologic outcomes and improved function in selected patients. Larger prospective studies are warranted.

Humans↗

Primary respiratory syncytial virus infection: pathology, immune response, and evaluation of vaccine challenge strains in a new mouse model.

Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract illness in young children. Vaccine development has been hampered by the experience of the formalin-inactivated vaccine tested in the 1960's. Currently, several vaccine candidates are under development and immune response to these candidate vaccines must be evaluated closely. We introduce a novel low-dose murine model of RSV infection and a new pathologic scoring system for the resultant pulmonary disease. We have also developed new sensitive methods for measuring cytokine expression. We then used this new model to test vaccine challenge strains of RSV in order to determine their pathogenicity.

Animals↗

Peri-implant tissue response to pathological insults.

With the increased use of osseointegrated implants and with many implants functioning for long periods of time, the soft tissue barrier around implants has become more important. This paper reviews the soft tissue response around implants under healthy and diseased conditions and presents the etiology of peri-implant tissue breakdown. Diagnostic techniques such as probing pocket depth, radiographic evidence, and microbial sampling have been analyzed and modified from the periodontal field and used during the maintenance phase of the dental implant. The long-term goal of implant maintenance is to prevent or to arrest the progression of disease, and to achieve a maintainable implant site. Recent reports indicate that peri-implant tissues can be treated with either non-surgical or surgical techniques.

Dental Implantation, Endosseous↗

Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial.

PURPOSE: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.

Adult↗

Locally advanced non-metastatic breast cancer: analysis of prognostic factors in 125 patients homogeneously treated with a combined modality approach.

125 stage III breast cancer patients, including 51 cases of inflammatory carcinoma, were treated with the following combined modality approach: three courses of primary 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) chemotherapy followed by locoregional treatment and subsequent adjuvant chemotherapy consisting of three courses of FAC alternating with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Clinical response to primary FAC was 65% (complete 10%). Residual tumour mass in the mastectomy specimen was > 1 and < or = 1 cm in 82 and 18% of cases, respectively. Complete pathological response following primary chemotherapy was achieved in only 3.5% of cases. After primary FAC and local treatment, 97% of patients were disease-free. Overall survival (S) and progression-free survival (PFS) at 5 years were 56 and 34%, respectively. Univariate analysis showed that age, receptor status and clinical and pathological response to primary chemotherapy did not appear to influence treatment outcome significantly, whereas stage, presence of inflammatory disease and number of involved nodes had a significant impact on both S and PFS.

Adenocarcinoma↗

Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer.

Forty-two patients with clinical stage IIIA or IIIB breast cancer were treated with neoadjuvant chemotherapy followed by mastectomy and radiotherapy. The median follow-up was 32 months (range 10-72 months) and the median time to progression was 17 months (range 10-30 months). A multivariate analysis showed that a longer disease-free survival (DFS) was related to more chemotherapy cycles given (P = 0.003), a better pathological response to chemotherapy (P = 0.04) and fewer positive axillary lymph nodes (P = 0.05). A better overall survival (OS) was related to more chemotherapy cycles given (P = 0.03) and better pathological response to chemotherapy (P = 0.04). In patients with residual tumour after neoadjuvant chemotherapy, high levels of staining for Ki-67 was correlated with a worse DFS (P = 0.008). Other biological characteristics, including oestrogen receptor status, microvessel density (CD31 staining), P-glycoprotein (P-gp) staining and nuclear accumulation of p53, were not independent prognostic factors for either DFS or OS. If both P-gp and p53 were expressed, DFS and OS were worse in the uni- and multivariate analysis. The preliminary results of this phase II study suggest that coexpression of P-gp/p53 and a high level of staining for Ki-67 after chemotherapy are associated with a worse prognosis, and that prolonged neoadjuvant chemotherapy and the attainment of a pathological complete remission are important factors in determining outcome for patients with this disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Preoperative radiotherapy (RT) for rectal cancer: predictive factors of tumor downstaging and residual tumor cell density (RTCD): prognostic implications.

PURPOSE: To determine predictive factors and prognostic value of tumor downstaging and tumor sterilization after preoperative RT for rectal cancer. METHODS AND MATERIALS: Between 1977 and 1994, 167 patients with a histologically proven adenocarcinoma (70 T2, 65 T3, 29 T4, and 3 local recurrences) underwent preoperative RT. Median dose was 44 Gy (5-73 Gy). Surgery was performed in a mean time of 5 weeks after RT. Pathologic specimens have been reviewed by the same pathologist in order to specify the modified Astler Coller classification (MAC), and to quantify the residual tumor cell density (RTCD). RESULTS: According to the MAC, there was 9 stage 0 (5%), 10 stage A (6%), 103 stage B1-B3 (62%), and 45 stage C1-C3 (27%) tumors. Seventeen percent and 56% of the patients who received a dose > or = 44 Gy had respectively a 0-A and a B tumor, compared to 4 and 69% in those who received a dose < 44 Gy (p = 0.04). Tumor differentiation and a longer interval before surgery were significantly associated with a more frequent downstaging, and preoperative staging correlated well to the postoperative pathological findings. According to the RTCD, 62 tumors (37%) showed no or only rare foci of residual tumor cells (Group 1); 62 (37%) showed an intermediate RTCD (Group 2); and 43 (26%) a high RTCD (Group 3). No predictive factor of RTCD was statistically significant. In univariate analysis, postoperative staging was a significant prognostic factor, with corresponding 5-year overall survival rates in 0-A, B, and C stages of 92, 67, and 26% (p < 0.01). RTCD was not a prognostic factor. However, overall and disease-free survival rates for patients with complete pathologic response of 83% at 2 and 5 years suggested a better outcome in this subgroup of patients. CONCLUSION: The favorable influence of higher doses of preoperative RT on pathologic stage has been observed. Tumor differentiation, preoperative classification and time before surgery were the other predictive factors of tumor downstaging. However, there was no predictive factor of complete pathologic response. Even after preoperative RT, postoperative staging remained a prognostic factor.

Adenocarcinoma↗

High-dose chemotherapy with autologous peripheral stem cell support in advanced ovarian cancer.

Twenty patients with advanced (stage III-IV), previously untreated ovarian carcinoma were treated by: (a) induction chemotherapy (40 mg/m2 cisplatin, days 1-4; 1.5 g/m2 cyclophosphamide, day 4; every 4 weeks for two cycles) followed by (b) intensification chemotherapy (100 mg/m2 cisplatin, day 1; 650 mg/m2 etoposide, day 2; 1.8 g/m2 carboplatin, day 3). Eligibility criteria further included: age less than 55 years, moderately good to poor tumour grade, macroscopic (> 0.5 cm) residual tumour. Autologous peripheral stem cells were recruited after the induction cycles and, to ensure haematological support, autologous bone marrow harvesting was routinely performed in the first 14 cases. Haematological support consisted of autologous peripheral stem cells and autologous bone marrow transplant in 16 and four patients, respectively. All patients are evaluable for toxicity and 19 for pathological response, one being dead of systemic mycosis 35 days after the autologous bone marrow transplant. Severe extra-haematological toxicities were the following: gastrointestinal (100%), neurological (10%), hepatic (10%). Pathological response was detected in 84% of cases (CR 37%, microscopic PR 26%, macroscopic PR 21%). Median follow-up times of 48 and 41 months have been reached respectively from enrolment and second-look. Four-year 62% overall and 57% progression-free survivals have been reached. Ten patients are still alive with NED (six of seven with CR, three of five with microscopic PR, and one of four with macroscopic PR). Autologous peripheral stem cell transplant significantly reduced the duration of aplasia compared with autologous bone marrow transplant, and toxicity was proved to be manageable in those patients undergoing autologous peripheral stem cell transplant. The prolonged disease-free survival in patients showing CR and microscopic PR suggests that further investigation on this new approach is worthwhile.

Adult↗

Chemotherapy as a substitute for surgery in the treatment advanced resectable head and neck cancer. A report from the Northern California Oncology Group.

This trial determines the feasibility for patients with resectable Stages III/IV head and neck cancer who achieved a complete response to induction chemotherapy of eliminating surgery from their treatment program. Thirty patients were treated with three cycles of cisplatin and 5-fluorouracil (5-FU), followed by reendoscopy and biopsy. Twelve patients achieved a complete pathologic response at the primary and received radiation (interstitial and/or external beam) only. The remainder underwent surgical resection and postoperative radiation. At 2 years, the relapse-free survival was 52%, and the survival was 53% for the entire group. For the 12 complete responders who had surgery eliminated, the relapse-free survival was 60%, and the survival was 70%. This pilot study suggests that for patients with resectable disease who achieve a complete pathologic response to induction chemotherapy at their primary, it is feasible to omit surgery and treat with primary radiation without compromise in survival. This approach warrants further study in a randomized trial.

Adult↗

[Tumor downstaging through preoperative chemoradiotherapy in locally advanced rectal cancer].

OBJECTIVE: To evaluate the impact of preoperative chemoradiotherapy on patients with locally advanced rectal cancer by clinical and pathological characteristics. METHODS: From July 1994 to May 1995, 36 patients with locally advanced rectal cancer were treated. Pathology: adenocarcinoma 27, mucinous adenocarcinoma 7 and ductal adenocarcinoma 6. The protocol was carried out in sequence of chemo-->radio-->surgery-->chemotherapy. The treatment began with preoperative chemotherapy with folinic acid 50 mg followed by 5-FU bolus of 300 mg/m2 given for two cycles on d1-5 and d22-26 before irradiation. Radiation therapy was delivered to a dose of 45 Gy, 1.8 Gy per fraction, 5 days a week. Surgery was done 4-6 weeks after this preoperative treatments. Another 2 to 4 cycles of chemotherapy were added 2 to 4 weeks after operation. Twenty-one patients were treated by Dixon's operation, 14 patients by Mile's operation and 1 by local tumorectomy through the rectum. Radical operation was performed in 29 patients and palliative resection was done in 7 patients. RESULTS: Grade III hematological toxicity was observed in only 2(5.6%) patients. No patient had grade III or IV acute toxicity in the gastrointestinal, skin or urological systems. All patients underwent surgery. The perioperative morbidity rate was 13.8% with no mortality or late toxicity. As a result of this preoperative management, the tumor was reduced by an average of 28.0%, with a complete pathological response in 4(11.1%) patients. In 28 CR + PR (77.8%) patients, a downstaging in 19(52.8%) patients was observed. Sixty percent of positive lymph nodes as assessed by transrectal ultrasonography before therapy became pathologically negative postoperatively, with the frequency of lymph node metastasis decreased by 46.0%(83.0% to 37.0%). CONCLUSION: Preoperative radiochemotherapy is proved as a safe method with a tolerable toxicity. Complete pathological response, shrinkage of the primary tumor and decrease in lymph node metastasis are observed after preoperative radiochemotherapeutic regimen. An overall benefit of downstaging the primary tumor and a greatly enhanced effect of surgery is enjoyed by the patients.

Adult↗

Cisplatin-, epirubicin- and paclitaxel-containing chemotherapy in uterine adenocarcinoma.

PURPOSE: To evaluate the toxic effects and antitumour activity of a multidrug regimen with cisplatin, epirubicin and paclitaxel (CEP) as initial therapy in patients with uterine adenocarcinoma. PATIENTS AND METHODS: Forty-nine patients with histologically-confirmed diagnoses of locally advanced, recurrent or metastatic cervical or endometrial adenocarcinoma entered the study. Treatment consisted of epirubicin (E) given at 70 mg/m2 followed by paclitaxel (P) (175 mg/m2 over three hours) and cisplatin (C) (50 mg/m2), repeated every three weeks. Eligibility criteria also included age < or = 75 years, no previous chemotherapy, no previous radiotherapy to the tumour parameters, bidimensionally-measurable lesions, no previous or ongoing cardiac disease, and renal and liver function within normal limits. Complete blood cell counts were repeated weekly, and tumor response was assessed every three cycles. A maximum of eight courses was administered in responding patients. RESULTS: From January 1996 to January 1997, 30 patients with endometrial adenocarcinoma and 19 with cervical adenocarcinoma entered the study, for a total of 213 cycles of treatment. In patients with endometrial carcinoma the overall clinical and pathological response rates were 73% (95% CI, range 54%-88%) and 35% (95% CI, range 16%-57%) respectively; in patients with locally advanced cervical carcinoma the overall clinical and pathological response rates were 64% and 62%. WHO grade 3-4 neutropenia occurred in 61% of the patients, with one possible toxic death. Retreatment had to be delayed for at least one week because of persisting neutropenia in 34% of the patients. Mild peripheral neuropathy and stomatitis were observed in 46% and 23% of the patients. One patient presented acute congestive heart failure after the third cycle of treatment. CONCLUSION: The high antitumour activity and the good tolerability of CEP suggest that this regimen should be prospectively compared to standard combinations as initial treatment of advanced endometrial carcinoma.

Adenocarcinoma↗

Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states.

It has recently become accepted that the activated immune system communicates to brain via release of pro-inflammatory cytokines. This review examines the possibility that pro-inflammatory cytokines (interleukins and/or tumor necrosis factor) mediate a variety of commonly studied hyperalgesic states. We will first briefly review basic immune responses and inflammation. We will then develop the concept of illness responses and provide evidence for their existence and for the dramatic changes in neural functioning that they cause. Lastly, we will examine the potential roles that both pro-inflammatory cytokines and the neural circuits that they activate may play in the hyperalgesic states produced by irritants, inflammatory agents, and nerve damage. The possibility is raised that apparently diverse hyperalgesic states may converge in the central nervous system and activate similar or identical neural circuitry.

Animals↗

The expanding spectrum of Bartonella infections: II. Cat-scratch disease.

Recent advancements and developments in molecular biotechnology have allowed more precise reclassification of many microorganisms. With the use of these new taxonomy tools, several organisms previously thought to belong to other genera have been recently described as bartonellae. Of the 11 organisms now described as Bartonella spp., only four have been shown to be pathogenic for humans. Table 1 lists the four Bartonella human pathogens along with the their known epidemiology and the scope and range of disease associated with each. All are now considered to be bacteria and can be grown on blood-enriched agar although primary isolation in some may best be achieved in cell tissue culture. B. bacilliformis infection is limited to certain geographic regions in South America where the only human reservoir and the sandfly vector(s) that spreads the disease reside together. Specific antibiotic treatment is dramatically effective in treating the highly fatal, acute intraerythrocytic hemolytic form of the disease, but their effectiveness in treating the vascular proliferative forms (verruga peruana) or the chronic asymptomatic, bacteremic, carrier state of the disease has not been effective. This disease should remain confined to its present endemic geographic areas in South American unless asymptomatic bacteremic persons from these areas migrate to areas where sandflies and humans exist that are capable of establishing this infection in new endemic areas. B. quintana and B. henselae cause a wide range of clinical diseases in humans, the type and extent of which varies significantly with the immune status of the host. In immunocompetent hosts the pathologic response is granulomatous, suppurative, extracellular and intracellular, generally self-limited and usually unresponsive to antibiotic treatment, even to those drugs to which the organism is shown to be sensitive in vitro. In contrast, in immunocompromised hosts the pathologic response is vasculoproliferative, organisms may be seen intracellularly but they are often seen in abundance in extracellular clumps and infection is usually progressive and fatal unless treated. In these patients clinical response to treatment with drugs that are effective in vitro against these organisms has usually been dramatic. Of these agents those that penetrate cells and are found in high concentrations intracellularly, such as erythromycin, clarithromycin, azithromycin, rifampin, doxycycline and gentamicin, appear to be most effective. These agents not only appear to provide the most dramatic treatment response in patients with BA, BP and PRFB and other manifestations of B. henselae (and B. quintana as well) in immunocompromised persons, they appear to be the most promising agents for treatment of persons with both typical and atypical CSD. Further studies will be necessary to more clearly elucidated the mechanisms responsible for the diverse clinical presentations of infection with these organisms in human hosts relative to their immune status. In addition clarification of the epidemiology of B. elizabethae infections in humans may be helpful in understanding the nature of infection with Bartonella organisms.

Bartonella henselae↗