Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small cell lung cancer.

BACKGROUND: PD-L1 tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitors (ICI) efficacy in non-small cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. METHODS: Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. RESULTS: In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ=0.53, P<0.0001) and high for TMB (ρ=0.80, P<0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS≥+50%) and decreases (ΔTPS≤-50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P=0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q<0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and OS to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. CONCLUSION: Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment prior to ICI initiation when feasible.

Tumor mutational burden for the prediction of PD-(L)1 blockade efficacy in cancer: challenges and opportunities.

Tumor mutational burden (TMB) is a biomarker that measures the number of somatic mutations in a tumor's genome. TMB has emerged as a predictor of response to immune checkpoint inhibitors (ICIs) in various cancer types, and several studies have shown that patients with high TMB have better outcomes when treated with programmed death-ligand 1-based therapies. Recently, the Food and Drug Administration has approved TMB as a companion diagnostic for the use of pembrolizumab in solid tumors. However, despite its potential, the use of TMB as a biomarker for immunotherapy efficacy is limited by several factors. Here we review the limitations of TMB in predicting immunotherapy outcomes in patients with cancer and discuss potential strategies to optimize its use in the clinic.

Clonal KEAP1 mutations with loss of heterozygosity share reduced immunotherapy efficacy and low immune cell infiltration in lung adenocarcinoma.

BACKGROUND: KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11/KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs. PATIENTS AND METHODS: Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation [KEAP1 clonal diploid-subclonal (KEAP1 CD-SC)] in the Memorial Sloan Kettering Cancer Center (MSK) MetTropism cohort (N = 2550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N = 237; DFCI N = 461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort). RESULTS: Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P = 0.001; OS log-rank P < 0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P = 0.006; OS log-rank P = 0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features. CONCLUSIONS: KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs.

Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer.

BACKGROUND: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized. PATIENTS AND METHODS: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype. RESULTS: Of 2327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n = 354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRASG12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRASnon-G12D. CONCLUSIONS: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.

Antibiotic-exposed patients with non-small-cell lung cancer preserve efficacy outcomes following first-line chemo-immunotherapy.

BACKGROUND: Prior antibiotic therapy (pATB) is known to impair efficacy of single-agent immune checkpoint inhibitors (ICIs), potentially through the induction of gut dysbiosis. Whether ATB also affects outcomes to chemo-immunotherapy combinations is still unknown. PATIENTS AND METHODS: In this international multicentre study, we evaluated the association between pATB, concurrent ATB (cATB) and overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) treated with first-line chemo-immunotherapy at eight referral institutions. RESULTS: Among 302 patients with stage IV NSCLC, 216 (71.5%) and 61 (20.2%) patients were former and current smokers, respectively. Programmed death-ligand 1 tumour expression in assessable patients (274, 90.7%) was ≥50% in 76 (25.2%), 1%-49% in 84 (27.9%) and <1% in 113 (37.5%). Multivariable analysis showed pATB-exposed patients to have similar OS {hazard ratio (HR) = 1.42 [95% confidence interval (CI): 0.91-2.22]; P = 0.1207} and PFS [HR = 1.12 (95% CI: 0.76-1.63); P = 0.5552], compared to unexposed patients, regardless of performance status. Similarly, no difference with respect to ORR was found across pATB exposure groups (42.6% versus 57.4%, P = 0.1794). No differential effect was found depending on pATB exposure duration (≥7 versus <7 days) and route of administration (intravenous versus oral). Similarly, cATB was not associated with OS [HR = 1.29 (95% CI: 0.91-1.84); P = 0.149] and PFS [HR = 1.20 (95% CI: 0.89-1.63); P = 0.222] when evaluated as time-varying covariate in multivariable analysis. CONCLUSIONS: In contrast to what has been reported in patients receiving single-agent ICIs, pATB does not impair clinical outcomes to first-line chemo-immunotherapy of patients with NSCLC. pATB status should integrate currently available clinico-pathologic factors for guiding first-line treatment decisions, whilst there should be no concern in offering cATB during chemo-immunotherapy when needed.

Second primary neoplasms in patients with lung and gastroenteropancreatic neuroendocrine neoplasms: Data from a retrospective multi-centric study.

BACKGROUND: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population. AIM: This study aimed to analyze the occurrence of second primary malignancies. METHODS: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included. RESULTS: Between 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms. CONCLUSION: In NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy.

Risk of preoperative understaging of duodenal neuroendocrine neoplasms: a plea for caution in the treatment strategy.

PURPOSE: Pretreatment staging is the milestone for planning either surgical or endoscopic treatment in duodenal neuroendocrine neoplasms (dNENs). Herein, a series of surgically treated dNEN patients was evaluated to assess the concordance between the pre- and postsurgical staging. METHODS: Retrospective analysis of patients with a histologically confirmed diagnosis of dNENs, who underwent surgical resection observed at eight Italian tertiary referral centers. The presurgical TNM stage, based on the radiological and functional imaging, was compared with the pathological TNM stage, after surgery. RESULTS: From 2000 to 2019, 109 patients were included. Sixty-six patients had G1, 26 a G2, 7 a G3 dNEN (Ki-67 not available in 10 patients). In 46/109 patients (42%) there was disagreement between the pre- and postsurgical staging, being it understaged in 42 patients (38%), overstaged in 4 (3%). As regards understaging, in 25 patients (22.9%), metastatic loco-regional nodes (N) resulted undetected at both radiological and functional imaging. Understaging due to the presence of distal micrometastases (M) was observed in 2 cases (1.8%). Underestimation of tumor extent (T) was observed in 12 patients (11%); in three cases the tumor was understaged both in T and N extent. CONCLUSIONS: Conventional imaging has a poor detection rate for loco-regional nodes and micrometastases in the presurgical setting of the dNENs. These results represent important advice when local conservative approaches, such as endoscopy or local surgical excision are considered and it represents a strong recommendation to include endoscopic ultrasound in the preoperative tools for a more accurate local staging.

Clinicopathological and genomic correlates of programmed cell death ligand 1 (PD-L1) expression in nonsquamous non-small-cell lung cancer.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) is the primary clinically-available biomarker of response to immunotherapy in non-small-cell lung cancer (NSCLC), but factors associated with PD-L1 expression are not well understood. MATERIALS AND METHODS: Consecutive nonsquamous NSCLCs with successful PD-L1 assessment and targeted next-generation sequencing were included in this retrospective study. Clinicopathological characteristics, gene mutations, and copy number changes in gene and chromosomal arms were compared among three PD-L1 expression groups: negative (TPS < 1%), low (TPS 1%-49%), and high (TPS ≥ 50%). A Q-value <0.25 was considered significant after multiple comparisons correction. RESULTS: A total of 909 nonsquamous NSCLCs were included. High PD-L1 expression compared with low and negative PD-L1 expression was associated with increased tobacco exposure (median pack-years: 25 versus 20 versus 20, respectively; P = 0.01), advanced stage at diagnosis (76% versus 67% versus 61% with advanced stage of disease, respectively; P < 0.001), and higher tumor mutational burden (TMB) (median 12.2 versus 10.6 versus 10.6 mutations/megabase, respectively; P < 0.001). Negative PD-L1 expression when compared with high PD-L1 expression was associated with: mutations in STK11 (19% versus 5%; Q < 0.001), EGFR (22% versus 11%; Q < 0.001), CTNNB1 (4.3% versus 0.4%; Q = 0.04), APC (5% versus 1%; Q = 0.17), and SMARCA4 (9% versus 4%; Q = 0.20); copy number loss of CD274 (PD-L1, 28% versus 6%; Q < 0.001), PDCD1LG2 (PD-L2, 28% versus 6%; Q < 0.001), and JAK2 genes (27% versus 7%; Q < 0.001), loss of chromosomal arm 9p (23% versus 10%; Q = 0.04), and gain of 1q (46% versus 21%; Q < 0.001). High PD-L1 expression compared with negative PD-L1 expression was associated with copy number gain of CD274 (11% versus 3%; Q = 0.01) and PDCD1LG2 (11% versus 3%; Q = 0.01). NSCLCs with CD274 loss, compared with those without loss, had a lower response rate (23% versus 9%; P = 0.006) and shorter progression-free survival (3.3 versus 2.0 months; P = 0.002) on immunotherapy. CONCLUSIONS: PD-L1 expression is associated with specific genomic alterations and clinicopathologic characteristics in nonsquamous NSCLC.

The functioning side of the pancreas: a review on insulinomas.

PURPOSE: Insulinomas are a rare type of neuroendocrine tumors, originating in the pancreas, difficult to diagnose and to treat. Due to its rarity, insulinomas are a not well-known pathological entity; thus, the diagnostic process is frequently a medical challenge with many possible differential diagnoses. The diagnostic process varies between non-invasive procedures, such as the fasting test or imaging techniques, and invasive ones. Insulinomas are rarely malignant, but the glycemic imbalance correlated with this tumor can frequently alter the quality of life of the patients and the consequent hypoglycemia can be extremely dangerous. Moreover, insulinomas can be associated with different genetic syndromes, such as Multiple Endocrine Neoplasia 1, accompanied by other specific symptoms. There are many different treatment strategies, depending on the need to control symptoms or control diseases progression, the only curative one being surgery. METHODS AND RESULTS: We reviewed the evidences present in the literature on insulinomas and reported its main clinical characteristics and management strategies. CONCLUSION: The aim of this review of the literature is to present the current knowledge on insulinomas, exploring the main clinical characteristics, the diagnostic tools, and the therapeutic strategies.

Determination of Mammalian Target of Rapamycin Hyperactivation as Prognostic Factor in Well-Differentiated Neuroendocrine Tumors.

PURPOSE: To evaluate the role of the activation of mTOR (phosphorylated mTOR, p-mTOR) and the expression SSTR2A and IGF-1R as prognostic factor in well-differentiated neuroendocrine tumors. METHODS: A retrospective study was conducted on data from patients with diagnosis of neuroendocrine tumor originated from pancreas (pNET) or gastrointestinal tract (stomach, appendix, and ileus; GI-NET) made between January 2003 and December 2004 and followed up at our institution. Archival material should be available for revision according to WHO 2010 neuroendocrine tumor classification and for p-mTOR, SSTR2A, and IGF-1R immunostaining, calculating a quantitative score (QS). We evaluated clinical, pathological, and immunohistochemistry features for association with the presence of advanced disease at diagnosis and disease relapse in patients who have undergone radical surgery. RESULTS: Archival material from 64 patients was analyzed (37 pNETs and 27 GI-NETs). In these patients, G2 grading, low SSTR2A QS, and high p-mTOR QS were associated with advanced disease at diagnosis at multivariate analysis. Risk of recurrence in 49 patients with R0-resected tumors was higher for G2 grading, stage IIIB-IV, low IGF-1R QS, and high p-mTOR QS at univariate analysis. CONCLUSIONS: With the limits of retrospective data, activation of m-TOR is correlated with advanced disease at diagnosis and with shorter disease-free survival after R0 resection. Validation through prospective studies is needed.

Analysis of Italian regulations on pathways of care for patients in a vegetative or minimally conscious state.

Different rehabilitation models for persons diagnosed with disorders of consciousness have been proposed in Europe during the last decade. In Italy, the Ministry of Health has defined a national healthcare model, although, to date, there is a lack of information on how this has been implemented at regional level. The INCARICO project collected information on different regional regulations, analysing ethical aspects and mapping care facilities (numbers of beds and medical units) in eleven regional territories. The researchers found a total of 106 laws; differences emerged both between regions and versus the national model, showing that patients with the same diagnosis may follow different pathways of care. An ongoing cultural shift from a treatment-oriented medical approach towards a care-oriented integrated biopsychosocial approach was found in all the welfare and healthcare systems analysed. Future studies are needed to explore the relationship between healthcare systems and the quality of services provided.

Ruthenium-106 eye plaque brachytherapy in the conservative treatment of uveal melanoma: a mono-institutional experience.

BACKGROUND: Traditional treatment for uveal melanoma is the enucleation of the eye with outcomes cosmetically unacceptable and loss of useful vision. Plaque brachytherapy, compared to enucleation, had the advantage to preserve the eye with outcomes cosmetically acceptable and preservation of vision. PATIENTS AND METHODS: From July 1990 to December 2009 one hundred forty-two (142) patients (51 males and 91 females) with small to medium uveal melanoma were treated with 106Ru plaque brachytherapy. The patients underwent a complete staging before brachytherapy with indirect ophthalmoscopy and ultrasounds. Mean tumour thickness was 3.26 mm (1.6-6 mm). The dose scheduled was 80-100 Gy to the apex with a maximum dose of 800 Gy to the sclera. RESULTS: One hundred forty-two have been treated, nine patients had lost the follow-up and drop out; 133 patients were assessed. Mean follow-up was 7.7 years (6 months-18 years). The overall survival at 5, 10 and 15 years was 92%, 85% and 78% respectively. Cancer fee survival was 95%, 90% and 83%, respectively at 5, 10 and 15 year. Radiation-induced toxicity was represented in 47 patients with a 5 year actuarial survival rate free from complications of 54%. CONCLUSIONS: 106Ru plaque brachytherapy is a valid approach for treatment of uveal melanoma. This technique is efficacy and safe, with a low toxicity profile.

Effect of hinged lamellar keratotomy on postkeratoplasty eyes.

PURPOSE: To evaluate the effect of a hinged lamellar keratotomy on refraction, vision, and corneal topography of postkeratoplasty eyes with high-degree astigmatism. DESIGN: Noncomparative, interventional case series. PARTICIPANTS: A hinged lamellar keratotomy was performed on nine eyes of nine patients at least 9 months after penetrating keratoplasty and with high-degree astigmatism. All patients were spectacle and contact lens intolerant. INTERVENTION: A superiorly hinged lamellar keratotomy (corneal flap), 160 microm in thickness and 9 mm in diameter, was created on all eyes included in this study. Each patient was examined 1 day, 1 month, and 3 months after surgery. MAIN OUTCOME MEASURES: Uncorrected visual acuity, best spectacle-corrected visual acuity, refraction, computerized analysis of corneal topography. RESULTS: At each postoperative examination time, there was a significant reduction in both average spherical equivalent (P < 0.05) and average absolute value of astigmatism (P < 0.01) over mean preoperative values. The major changes were seen as early as 1 day after surgery, but both progression and regression of the effect were documented at later postoperative examinations. In all patients best spectacle-corrected acuity was maintained or improved after the procedure. Postoperatively, four patients could be successfully corrected either with spectacles (n = 2) or with gas-permeable contact lenses (n = 2). There were no surgical flap or corneal graft complications. CONCLUSIONS: Hinged lamellar keratotomy improves vision and refraction of postkeratoplasty eyes with high-degree astigmatism. In some cases it may be so effective as to make planned excimer laser treatment unnecessary.

Intraoperative cauterization of the cornea can reduce postkeratoplasty refractive error in patients with keratoconus.

OBJECTIVE: This study aimed to evaluate the effect of intraoperative corneal cauterization on the postkeratoplasty refraction of patients with keratoconus. DESIGN: A randomized clinical trial. PARTICIPANTS: Thirty eyes of 29 patients with keratoconus undergoing standard penetrating keratoplasty by the same surgeon were evaluated (MB). INTERVENTION: Standard penetrating keratoplasty included the use of an 8.0-mm donor button sutured into a 7.5-mm recipient bed by means of two running 10-0 nylon sutures with 16 bites each. Before trephination of the recipient bed, superficial cauterization causing tissue shrinkage was applied to a 6-mm central area of the cornea of only 15 eyes (group A). The remaining 15 eyes (group B) did not undergo intraoperative cauterization. Before surgery, 6 months, and 13 months after surgery, a complete ophthalmologic examination was performed on each patient, including uncorrected and best-corrected visual acuity, refraction, keratometry, computerized corneal topography, as well as A-scan contact ultrasonography. MAIN OUTCOME MEASURES: Postkeratoplasty refractive error was measured. RESULTS: Both 6 months (sutures still in place) and 13 months (suture removal performed in all patients) after surgery, the average spherical equivalent was significantly less myopic in the patients undergoing cauterization. At 6 months, it was +1.72 diopters (D) +/- 1.13 D in group A and -3.16 D +/- 2.84 D in group B; at 13 months, it was +0.09 D 1.52 D in group A and -3.89 D +/- 3.01 D in group B. The average keratometric astigmatism also was significantly lower in group A than in group B both at 6 (2.5 D +/- 1.6 D vs. 4.1 D +/- 2.3 D) and 13 months (2.7 D +/- 1.5 D vs. 4.4 D +/- 2.4 D) after surgery. CONCLUSION: Cauterization of the central cornea improves the postkeratoplasty refractive results of patients with keratoconus.

Changes in S-phase fraction and micronucleus frequency as prognostic factors in radiotherapy of cervical carcinoma.

Twenty-five patients with cervical carcinoma were treated with combined external beam and high dose rate afterloading radiotherapy. Biopsies obtained at different time points in the course of therapy were analysed with respect to cell proliferation and cytogenetic damage. The fraction of cells with an S-phase DNA-content as well as the frequency of micronuclei were determined. These two parameters were then related to treatment outcome, in particular patient survival. Neither S-phase fraction nor the micronucleus frequency before radiotherapy were predictive of treatment outcome in this small group of patients. However, when changes in response to therapy were considered, patients whose S-phase fraction decreased and patients whose micronucleus frequency increased tended to have a better prognosis. Although statistical significance was not achieved with either criterion alone, when applied together the combination predicted patient survival quite reliably; the 5-year survival rate of those patients who showed a decrease in S-phase fraction as well as an increase in micronucleus frequency was about 90% in contrast to less than 30% for the non-responders (p < 0.03).

[Relation of steroid hormone receptors to axillary lymph node metastasis in breast carcinoma]. / Die Beziehung der Steroid-Hormon-Rezeptoren zum axillären Lymphknotenbefall beim Mammakarzinom.

In 337 patients with primary cancer of the breast, the oestrogen and progesterone receptor concentration was correlated to the metastasis of axillary lymph nodes taking into account the age of the patients and the size of the primary tumour. The frequency of axillary lymph node involvement increases significantly with size, although not quite steadily but rather stepwise within the T classification. Whereas the tumour diameter influences the receptor status only slightly, the age of the patients plays a major rôle in the oestrogen receptor concentration. In the age group up to 50 years the oestrogen receptor concentration is significantly lower than in the age group over 50 years. There is no comparable influence of age on progesterone receptor concentration. With all 337 breast cancers, no difference in axillary lymph node metastasis is found either between oestrogen receptor positive and oestrogen receptor negative cancers, or between progesterone receptor positive and progesterone receptor negative cancers. In the age group up to 50 years, if looked upon separately, the oestrogen receptor positive cancers do show significantly more often an axillary lymph node involvement, than do oestrogen receptor negative cancers. As this difference exists in the age group up to 50 years only, it is assumed that endogenous oestradiol favours the axillary spread in oestrogen receptor positive cancers. With oestrogen receptor negative cancers the axillary lymph node involvement increases from the younger to the older age group, explaining why in unselected series the oestrogen receptor negative cancers show a more unfavourable course.

[Birth readiness of the uterine cervix. II. Cervix readiness score and its problems because of the variability of individual criteria]. / Zur Geburtsreife der Zervix Uteri. II. Zervixreife-Scores und ihre Problematik aufgrund der Variabilität der Einzelkriterien.

Cervical ripeness was scored in nulliparous and parous women not in labor at term according to Bishop's pelvic score. The frequency distributions of the scores for the single criteria as well as of the total score reveal the problems of all those scoring systems caused by the grouping process as sequelae of the choice of width of the classes as well as of their limits. E.g. for cervical dilatation in none case 2 or 3 points had been reached and similar findings had to be stated concerning station of the presenting part. An other point of discussion erases from the results of the analysis for linear correlation of the single criteria between each other and between the single criteria and the total score. The total score is mostly influenced by the consistency (r = 0,81 in nulliparous and parous women) and the effacement (r = 0,80 and r = 0,81) of the cervix, whereas for dilatation and station lower correlation coefficients were found. In contrast, when labor had started spontaneously, even if the status of cervix was not advanced, a significant change in the correlative influence of the total score by the single criteria could be stated with high correlation coefficients for dilatation and station and lower one's for consistency and effacement.