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BACKGROUNDA significant gap in pancreatic ductal adenocarcinoma (PDAC) patient’s care is the lack of molecular parameters characterizing tumors and allowing a personalized treatment. The goal of this study was to examine whole PDAC transcriptomic profiles to define a signature that would predict aggressiveness and treatment responsiveness better than done until now.METHODS AND PATIENTSTumors were obtained from 76 consecutive resectable (n=40) or unresectable (n=36) tumors. PDAC were transplanted in mice to produce patient-drived xenografts (PDX). PDX were classified according to their histology into five groups, from highly undifferentiated to well differentiated. This classification resulted strongly associated with tumors aggressiveness. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n=598) of resected tumors; ii/ 60 advanced tumors obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumors.RESULTSA unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumors (e.g. 308 consecutive resected PDAC, HR=0.321 95% CI [0.207;0.5] and 60 locally-advanced or metastatic PDAC, HR=0.308 95% CI [0.113;0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumor response: -0.67, p-value < 0.001).CONCLUSIONWe identified a transcriptomic signature (PAMG) that, unlike all other stratification schemas already proposed, classifies PDAC along a continuous gradient. It can be performed on formalin-fixed paraffin-embedded samples and EUS-guided biopsies showing a strong prognostic value and predicting mFOLFIRINOX responsiveness. We think that PAMG could unify all PDAC preexisting classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.Trial RegistrationThe PaCaOmics study is registered atwww.clinicaltrials.govwith registration numberNCT01692873. The validation BACAP study is registered atwww.clinicaltrials.govwith registration numberNCT02818829.

Objectives To evaluate the histopathological results after radical prostatectomy (RP) in patients that had normal preoperative multiparametric magnetic resonance imaging (mpMRI), in order to determine whether they had significant or insignificant disease. Moreover, we evaluated the influence of the expertise of the radiologist on the results. Patients and Methods We retrospectively included patients who underwent RP in our centre and who had a preoperative negative mpMRI. The MRIs were considered negative when no suspicious lesion was seen or when the Prostate Imaging Reporting and Data System version 1 score was

The influence of radiotherapy dose parameters on longterm local control was studied in 134 clinical stage I-II breast cancer patients treated by tumorectomy and telecesium therapy during the 1960s. Recurrence in the breast was more frequent in patients receiving 75 Gy or less to the tumor bed (31% versus 15% for higher doses, p less than 0.05), and weekly dose rates of less than 8 Gy/week were associated with increased local-regional failure (30% versus 15% for higher weekly doses, p less than 0.01). The majority of local-regional failures were observed in the 53 patients having "inadequate" total or weekly radiotherapy doses (18/53, 34% versus 9/81, 11%, p less than 0.001). The importance of adequate radiotherapy applied to both older patients, as well as those younger than 40, who appear inherently to have a higher risk of local relapse. The mean interval to recurrence was markedly longer for inadequate radiotherapy (111 months, versus 75 months for adequate treatment), so that significant differences in local control became apparent only after 5 years. These results underscore the importance of radiotherapy technique in breast-conserving treatment, and suggest that an excessive reduction in the intensity of radiotherapy may result in an inordinate number of late local failures.

The feasibility of conservative salvage surgery was addressed in a clinicopathologic study of the results of wide excision for 50 selected parenchymal intramammary recurrences after standard breast conserving treatment. After median follow-up of 51 months, 16 (32%) second local failures were observed (5-year local control 62%). Cox multivariate analysis of 18 parameters indicated that only disease-free interval and resection margins significantly influenced local control. 5-year local control was 92% for recurrences occurring after 5 years vs. 49% for shorter intervals, and 73% for negative vs. 36% for positive or indeterminate margins. Local control appeared independent of morphologic features, initial tumour stage, patient age, recurrent tumour size and location. Median survival after second local failure was 33 months; tertiary therapy obtained ultimate local-regional control in 8 of 16 cases. The authors conclude that wide excision is a particularly satisfactory alternative to salvage mastectomy for late recurrences. Negative margins are essential. Further study will be required to establish additional guidelines allowing improved patient selection.

Retrospective analysis of results of treatment of 132 subclinical ductal carcinomas in situ, non-palpable.Patients were treated with limited surgery and 70 Gy radiation therapy (70 Gy).With a median follow-up of 7 years, the total recurrence rate was 6%, and the actuarial rate at 5 years 4% and at 10 years 13% at. These have no influence on recurrence on the specific actuarial survival rate which was 100% at 10 years. In spite of five infiltrating recurrences of seven, no metastasis appeared 48 months after the salvage surgery. The global rate of breast preservation was 92% at 7 years.Therapeutic indications were developed taking into account the present analysis and a literature review (2,338 in situ ductal carcinomas, palpable or not, treated with conservative surgery, with or without adjuvant radio-therapy).

102 patients with sub-clinical intra ductal non invasive breast cancer (T0N0) treated by limited surgery and curative radiation therapy. Follow-up ranged from 2 to 10 years with a median follow-up of 59 months. The long term survival rate of this therapeutic approach, consisting of simple excision without any adjuvant treatment and radical mastectomy was close to 100%. The actuarial local recurrence rate was only 8.6% at 10 years (confidence interval: 4.6 to 12.6%), which strongly suggests that radiation therapy is active on multicentric foci. Salvage surgery could be performed in every case of local recurrence. The survival rate of in situ breast cancer (T0N0) treated by conservative radio-surgery is comparable to that of radical mastectomy, while cosmetic results and psychological impact appear to be better for the conservative technique (breast preservation rate = 91 to 96%).

Between 1970 and 1990, 162 patients with carcinoma of the pancreas or the periampullary region were operated upon. A prospective study was conducted in 85 of them who underwent surgery after 1983. The tumour was resected in 63 patients (ductal adenocarcinoma in 43, periampullary carcinoma in 20). Biliary and/or gastrointestinal bypass was performed in 76 patients, and exploratory laparotomy in 23. The operative mortality rate was 3 percent (2/63) among patients with resection and 24 percent (24/99) among those with laparotomy with or without bypass. The longest survival (median: 33 months) was obtained in patients with periampullary tumours; it was 12 months after resection in patients with ductal adenocarcinoma and 4 months in the other cases. The preoperative estimate of unresectability was erroneous in 36.5 percent of the cases. Periampullary tumours were diagnosed only after pathological examination of the lesion removed in 47 percent. These results are in favour of radical surgery, especially since the operative mortality of resection is low and since resection, even palliative, gives a better survival rate than mere bypass.

Factors associated with inoperable local recurrence were investigated by a clinical and pathologic review of 596 patients with Stages I and II carcinoma of the breast treated by breast-conserving operations and megavoltage radiotherapy. After a median follow-up period of 71 months, 13 of 70 local recurrences observed were anatomically unsuitable for salvage surgical treatment, affecting 2.2 per cent of patients initially treated. In most, inoperable recurrences clinically resembled primary inflammatory carcinoma of the breast. All inoperable failures occurred in patients with invasive ductal carcinoma and were associated with the presence of unfavorable prognostic features (positive nodes, histologic grade 3, negative estrogen receptor, vascular invasion and lymphocytic stromal reaction). Despite doxorubicin-based chemotherapy, prognosis after inoperable recurrence was quite poor, although survival time in excess of two years was seen in receptor positive, lower grade recurrent tumors in which treatment included hormone therapy.

Out of 150 carcinomas of the pancreas operated from 1970 through 1989, 50 pancreatectomies were performed, including 4 cases of segmental resection of portal vein with total pancreatectomy (2 cases) or duodenopancreatectomy (2 cases). The technical procedure is described and discussed. Segmental resection of portal vein is rare in our experience and has been always performed out of necessity because of the over estimation of the resectability. However, mortality and post-operative stay are not increased.

This study concerns the correlation between ER and PR status, menopausal status and the effect of adjuvant hormonotherapy in high risk primary breast cancer patients. We have compared the results obtained in a randomized trial (Institut Paoli-Calmettes, Marseille) with those of a historic series (Centre René Huguenin, Saint-Cloud). The patients presented the same clinical and histological criteria and received identical therapeutic protocols (chemotherapy and/or hormonotherapy). Compared with patients receiving no adjuvant treatment, it appeared that: 1) in post-menopausal patients, a significant detrimental effect of tamoxifen was found in ER-negative patients, while in ER-positive patients hormonal treatment was well correlated with both the presence and level of steroid receptors; 2) in pre-menopausal patients, hormonal therapy (oophorectomy + tamoxifen) appeared to be mediated by a complex mechanism involving more than an ER-positive cell population. In the light of the published results, the present findings underline the importance of reevaluating the indications of hormonotherapy in terms of hormone receptors and menopausal status. They also indicate the importance of biological factors in the evaluation of response to therapy. They can identify, subsets of patients in whom a given therapeutic protocol is detrimental, even though it may be beneficial for the overall population. heterogeneity in response to therapy among patient subsets is one of the most important problems which confronts medical statisticians and clinical investigators.

Of 586 unilateral stage I-II breast cancers treated with conservative surgery and radiotherapy, 61 patients were found to have two or more macroscopic tumor nodules, diagnosed either clinically (n = 20), mammographically (n = 2), or on gross pathologic examination (n = 39). After a median follow-up of 71 months, 15 of 61 (25%) of the patients with multiple tumors developed recurrence in the treated breast, compared to 56 of 525 (11%) of patients with single cancers (p less than 0.005). Local failure occurred in 6 of 37 (16%) of bifocal tumors and in 9 of 24 (35%) of patients with 3 or more tumor foci. Recurrence was more frequent for multiplicity diagnosed clinically or mammographically (8 of 22 patients, 36%) than when it was apparent only to the pathologist (7 of 39 patients, 18%). Only 1 of 21 bifocal tumors diagnosed on gross examination recurred. Local failure occurred in only 1 of 22 cases with clearly negative resection margins; the remaining recurrences were associated with positive (n = 3) or indeterminate margins (n = 11). In contrast with recurrences of unifocal breast cancers, local failures in these patients tended to be located at a distance from the original foci, to be multifocal, or to be diffuse, including skin involvement. Only four recurrences presented as a single focus in the vicinity of the original primary tumors. This study indicates that macroscopically multiple breast cancers are at higher local failure risk, especially if multiplicity is clinically apparent, or if three or more gross nodules are seen on pathologic examination. Negative resection margins appear to be essential for satisfactory results.

Risk factors for local failure were evaluated for 496 clinical Stage I-II patients with infiltrating ductal carcinomas (median follow-up, 71 months) treated by conservative surgery and radiotherapy. Monofactorial analysis identified the following factors to be correlated with increased risk: moderate/marked mononuclear cell reaction (MCR), high histologic grade (G), extensive intraductal component (EIC), tumor necrosis, macroscopic multiplicity, estrogen receptor negativity, anatomic tumor size, age younger than 40 years, and vascular invasion. Only MCR, G, and EIC proved significant in Cox multivariate analysis. These risk factors were highly age dependent, with EIC markedly more prevalent in women younger than 50, MCR and G in women younger than 40. Separate Cox analysis for premenopausal patients showed that MCR/EIC determined risk independent of resection margins: tumors with MCR had a 28%, and with EIC a 22% probability of recurring locally by 5 years. Premenopausal patients with neither risk factor had a very low failure rate (2.6% at 5 years), regardless of age. For postmenopausal patients risk of breast recurrence was determined both by adequacy of resection margins and grade, with a high local failure rate for patients having G3 tumors with positive or indeterminate margins (31% at 5 years). The authors conclude that the microscopic examination is the only useful tool for assessing the risk of local failure, which is quite low for the majority of patients treated with breast conservation. High-risk patients can be recognized morphologically. The age dependence of morphologic risk factors appears to explain the high local failure rate seen in patients younger than 40.

The influence of patient age on risk of recurrence in the breast was retrospectively studied in 496 stage I-II invasive ductal carcinomas treated by macroscopically complete primary tumor excision followed by radiotherapy. With a median follow-up of 71 months, local recurrence occurred in 13 of 62 (21%) patients younger than 40 years, compared with 48 of 434 (11%) older patients (P less than .025). Cox multivariate analysis of 18 parameters identified four that significantly determined risk: major lymphocytic stromal reaction (MCR), unsatisfactory resection margins, increasing histologic grade, and extensive intraductal cancer (DCIS) within the primary tumor. Compared with older patients, those younger than 40 years had tumors that more often exhibited MCR (36% v 20%, P less than .01), histologic grade 3 (42% v 28%, P less than .025), and very extensive DCIS (21% v 6%, P less than .001). The status of resection margins did not differ significantly between younger and older patients. Restriction of Cox analysis to patients younger than 40 indicated that risk was adequately described by MCR and percentage of DCIS, without consideration of grade or margins. For patients younger than 40, local failure occurred in four of five (80%) tumors with both MCR and more than 50% DCIS, in eight of 25 (32%) with either, and one of 32 (3.1%) with neither of these morphologic features. This study suggests that the higher local failure risk observed in patients younger than 40 years reflects the greater prevalence of certain morphologic characteristics in breast cancers in younger patients. Age itself does not appear to be an independent determinate of risk.

The total amount of cathepsin-D (mature forms and pro-enzyme especially) in the cytosol of 88 breast cancers including 85 primary cancers and 11 axillary lymph node metastasis was measured by way of immuno-radiometric assay. Maximum follow-up is 58 months. Cathepsin-D was found to be independent of clinical and biological parameters including axillary lymph node involvement and oestradiol receptors (RE). Univariate analysis has pointed out a significant linkage between overall survival and cathepsin-D, using a cut-off level of 30 pmol/mg protein which is the most discriminating value. Cathepsin-D appeared to be particularly useful in lymph-node-positive and RE-negative patients but it was not significant in the node-negative population. Multivariate analysis of the overall survival (Cox model) revealed that it was strongly related to oestradiol receptor, lymph node involvement and cathepsin-D.

Of 178 local recurrences occurring in 1593 patients with clinical Stages I-II breast cancer treated by conservative surgery and megavoltage radiotherapy, 71 were diagnosed after the 5th year. Compared with recurrences occurring prior to 60 months, late recurrences were less frequently inoperable (1/71, 1.4%, versus 18/107, 17%, p less than 0.001), were more often located at a distance from the initial primary tumor (23/71, 32%, versus 15/106, 14%, p less than 0.005), and had a more favorable prognosis (5-year survival 84% versus 61% for late and early operable recurrences, respectively, p = 0.05). Five-year metastasis-free survival after late failure depended mainly on the anatomic extent of the recurrence (87% for recurrences apparently confined to the breast versus 34% for relapses involving the axilla, p less than 0.002). Prognosis of late recurrence appeared to be unaffected both by location of the recurrence within the breast and by the type of salvage operation used (mastectomy versus wide excision). Local-regional control after salvage surgery was satisfactory (89% at 5 years). Whereas recurrence in the breast prior to 5 years profoundly affected survival after initial diagnosis, patients with late failure had identical 15-year survival as other 5-year survivors who never failed locally. Late recurrences were more frequent in patients younger than 40 at initial treatment, and in patients who had inadequate radiotherapy. We conclude that late local recurrences after breast conservation do not represent a serious management problem.

A retrospective analysis was performed of 118 surgically treated mammary recurrences, occurring following primary conservative excision and radiation therapy for clinical Stages I and II breast cancer. Actuarial cancer-specific survival following salvage surgery was 72% at 5 years and 58% at 10 years. With a median followup of 7 years, further local-regional recurrences were observed in 20 of the 118 patients, many of whom could be treated by further surgery. Actuarial survival after recurrence was significantly influenced by initial clinical stage, as well as by the disease-free interval following primary therapy, but was similar for both premenopausal and postmenopausal patients and for patients treated by radical or breast-conserving salvage operations. For recurrences after the fifth year, actuarial survival following salvage surgery was 83% and 68% at 5 and 10 years, respectively. Survival for Stage I patients was favorable regardless of disease-free interval. It is concluded that recurrences in the breast following primary treatment with limited surgery and irradiation have a considerably more favorable prognosis than that of local failures after primary radical surgery. Suggestions for the management of these recurrences are presented.

Prognosis was analyzed as a function of histologic grade, axillary gland spread and hormonal receptors in a consecutive series of 1000 patients with breast cancer (stages I and II) treated by conservative tumorectomy and axillary curettage, combined with radiotherapy, and followed up for between 3 and 12 years. The three factors analyzed are of major importance in that they constituted a veritable tumoral identity card. Grade I tumors, the absence of glandular spread and the presence of hormonal receptors are correlated with cancer of good prognosis, whereas grade III tumors, major axillary spread and absence of hormonal receptors are related to a poor prognosis. Their interactions are studied by comparing associations of good and poor prognostic factors, allowing determination of populations at low and high risk of therapeutic failure.

This report describes the results of a program of limited surgery, usually tumor excision, followed by curative radiation therapy in a series of 794 evaluable Stage I and II breast cancer patients treated prior to December, 1976. Clinical cure rates at 5, 10 and 15 years were 85%, 74% and 58% respectively. At 10 years, 86% of the apparently cured patients had the affected breast preserved, 79% of them with a good cosmetic result. In 10-year local/regional recurrence rate was 14%, but 84% of local failures were operable. Salvage surgery provided ultimate local control for 94% of the operable local failures, 61.5% of whom lived for at least 5 years after their secondary operations. It is concluded that a combination of primary tumor excision, limited axillary dissection and curative radiation therapy provides end results which are equivalent to those of primary radical mastectomy and affords the considerable advantage of successful breast preservation in a large majority of cases.

Mammary recurrences were studied in 1593 patients with Stage I and II breast cancer treated by macroscopically complete tumor excision followed by megavoltage radiotherapy, including a boost to the tumor bed (mean dose, 78 Gy). The actuarial freedom from mammary recurrence was 93% at 5, 86% at 10, 82% at 15, and 80% at 20 years. Seventy-nine percent of the recurrences were in the vicinity of the tumor bed, but with increasing time interval, an increasing percentage of recurrences was located elsewhere in the breast. A majority of recurrences after 10 years could be considered new tumors. Only ten of 181 patients with recurrence had prior or concomitant distant metastases, and 159 of 171 isolated mammary recurrences (93%) were operable. Uncorrected overall survival after operable recurrence was 69% at 5 and 57% at 10 years. Prognosis after late recurrence (after 5 years) was favorable (84% 5-year survival). Operable early recurrences retained a favorable prognosis if smaller than 2 cm and confined to the breast (74% 5-year survival). Disease-free interval and histologic grade also appeared to be important prognostic factors after early recurrence. Survival after recurrence did not depend upon the type of salvage operation. Locoregional control was 88% at 5 years after salvage mastectomy and 64% after breast-conserving salvage procedures. The role of adjuvant systemic therapy at time of local recurrence requires additional study. This experience illustrates the important differences between mammary failure and chest wall recurrence after mastectomy, in particular the protracted time course and more favorable prognosis associated with the former.

Pathologic review of 861 Stage I and II breast cancers yielded 152 patients (18%) with histologic types other than invasive ductal carcinoma. All patients had been treated by breast-conserving surgery and radiotherapy, including supplemental radiation to the tumor bed. For 67 patients with predominantly lobular carcinomas, the actuarial overall 5-year survival was 100% and 77% for node-negative and node-positive patients, respectively. The actuarial probability of recurrence in the treated breast (13.5% at 5 years) appeared to be somewhat greater than that observed after treatment of invasive ductal cancers (8.8% at 5 years, P = 0.11). Of 12 mammary recurrences in patients with lobular carcinoma, four occurred at a considerable distance from the original primary and seven were multifocal, involving more than one quadrant in five patients. Of 47 patients with strictly in situ carcinomas, one patient whose axillary nodal status had not been determined subsequently developed distant metastases. Three additional patients developed mammary recurrence, two at the primary tumor site and one in another quadrant. The actuarial 5-year mammary recurrence and overall survival rates were 4% and 98%, respectively. For 27 patients with true medullary cancers, overall survival at 5 years was 90%. One localized mammary recurrence was observed at the site of the original primary. Actuarial mammary recurrence rate was 4% at 5 years. No relapse was observed in ten patients with colloid and one patient with adenoid cystic carcinoma. The authors conclude that, in addition to its well-established efficacy in the treatment of infiltrating ductal carcinomas, the combination of tumor excision and radiotherapy appears to provide adequate local control for other histologic types as well. However, patients with lobular cancer appear to be at somewhat greater risk of mammary failure, and recurrences in such patients tend to be multifocal and multicentric.

The crude mammary recurrence rate was studied in 5-year age intervals for 1,382 Stage I and II breast cancer patients treated by conservative surgery and radiation therapy and followed for a median of 11 years. Patients younger than 40 had a significantly higher local recurrence rate (41/210, 19%) than did older patients (106/1172, 9%). The majority of excess recurrences in the younger patients occurred early, with recurrence rates between 5 and 10 years being equal for the 2 age groups. A comparison of the clinical characteristics of the patient groups yielded no obvious explanation for the higher local recurrence rate in the younger patients, and 15-year cancer-specific survival was identical. Within the younger age group, recurrence rate was independent of clinical tumor size, and was unaffected by adjuvant treatment. Young patients with positive axillary nodes or negative hormone receptors appear to be at particularly high risk for mammary failure. Despite this apparent correlation with biologic aggressiveness, the 41 patients with mammary recurrence experienced long-term survival from time of primary treatment which was not significantly worse than that of patients not having had local recurrence. For 37 patients with operable mammary recurrence, the 10-year survival from time of salvage surgery was 64%.

We report a series of 413 patients with colo-rectal adenocarcinoma. 328 had a curative resection and 277 of them had elective lymphadenectomy; 51 had no lymphadenectomy because of either age or poor general status. Operative morbidity and mortality were not increased by lymphadenectomy. Survival was related to the lymph node involvement: 70.6% 5 year survival in patients without lymph node metastases, 49.3% 5 year survival in patients with lymph node metastases (P less than 0.001). However lymphadenectomy did not affect the survival rate of the patients. We conclude that lymphadenectomy had no deleterious effect. However, its real benefit on long term survival must be evaluated in further prospective randomised studies.

Eighteen patients underwent gastrocolic resection for cancer. Thirteen had primary gastric cancer and 5 had primary colon cancer (two of these 5 patients had local-regional recurrence after right hemicolectomy). Twelve resections were curative and 6 palliative. Twelve patients had more than 2 organs resected. Involvement of adjacent tissues or organs was present in 15 patients (11/13 gastric cancer and 4/5 colon cancer: 83%). All patients had immediate colonic anastomosis. The mean duration of postoperative stay was 22 +/- 8 days (SD). Mortality was 5.6% (1/18). Seven patients had post-operative complications (41%; 7/17); 3 of these 7 patients had anastomotic leakage (one colonic and two pancreatic fistulae; 3/17: 17.6%); the mean duration of postoperative stay for these three patients was 27 +/- 4 jours, (p less than 0.004). One colonic fistula complicated the 18 colonic anastomoses (5.5%). There was no reoperation in this series. The estimated 2-year survival for the entire group was 20%. The median survival was 9.5 mois; the median survival was 13.5 months after curative resections and 5 months after palliative procedure (p less than 0.01). The median survival was 8 months for gastric adenocarcinoma and 36 months for colon adenocarcinoma (p less than 0.05). Despite the poor results in gastric cancer extending to adjacent organs, complete excision is still recommended whenever feasible. Complete excision of advanced colon cancer may lead to prolonged disease-free survival depending on the lymph node status. With an acceptably low mortality, resection remains a better procedure than palliative diversion or exclusion for these advanced tumours.